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Li L, Peng R, Wang C, Chen X, Gheyret D, Guan S, Chen B, Liu Y, Liu X, Cao Y, Han C, Xiong J, Li F, Lu T, Jia H, Li K, Wang J, Zhang X, Xu J, Wang Y, Xu X, Li T, Zhang J, Zhang S. β2 integrin regulates neutrophil trans endothelial migration following traumatic brain injury. Cell Commun Signal 2025; 23:70. [PMID: 39923080 PMCID: PMC11806581 DOI: 10.1186/s12964-025-02071-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 01/29/2025] [Indexed: 02/10/2025] Open
Abstract
Neutrophils are the first responders among peripheral immune cells to infiltrate the central nervous system following a traumatic brain injury (TBI), triggering neuroinflammation that can exacerbate secondary tissue damage. The precise molecular controls that dictate the inflammatory behavior of neutrophils post-TBI, however, remain largely elusive. Our comprehensive analysis of the molecular landscape surrounding the trauma in TBI mice has revealed a significant alteration in the abundance of β2 integrin (ITGB2), predominantly expressed by neutrophils and closely associated with immune responses. Using the fluid percussion injury (FPI) mouse model, we investigated the therapeutic efficacy of Rovelizumab, an agent that blocks ITGB2. The treatment has demonstrated significant improvements in neurologic function in TBI mice, attenuating blood-brain barrier permeability, mitigating oxidative stress and inflammatory mediator release, and enhancing cerebral perfusion. Moreover, ITGB2 blockade has effectively limited the adherence, migration, and infiltration of neutrophils, and has impeded the formation of neutrophil extracellular traps (NETs) upon their activation. Finally, it was demonstrated that ITGB2 mediates these effects mainly through its interaction with intercellular adhesion molecule-1 (ICAM 1) of endotheliocyte. These findings collectively illuminate ITGB2 as a crucial molecular switch that governs the adverse effects of neutrophils post-TBI and could be targeted to improve clinical outcome in patients.
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Affiliation(s)
- Lei Li
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
| | - Ruilong Peng
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, 300200, China
| | - Cong Wang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
| | - Xin Chen
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
| | - Dilmurat Gheyret
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
| | - Siyu Guan
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
| | - Bo Chen
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
| | - Yafan Liu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
| | - Xilei Liu
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Yiyao Cao
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Cha Han
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Jianhua Xiong
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
| | - Fanjian Li
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
| | - Taoyuan Lu
- Xuanwu Jinan Hospital, 5106 Jingshi Road, Jinan, 250000, Shandong, China
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China
| | - Haoran Jia
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
| | - Kaiji Li
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
| | - Jinchao Wang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
| | - Xu Zhang
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Jianye Xu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
| | - Yajuan Wang
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xin Xu
- Xuanwu Jinan Hospital, 5106 Jingshi Road, Jinan, 250000, Shandong, China.
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China.
| | - Tuo Li
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, 300200, China.
| | - Jianning Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China.
| | - Shu Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.
- Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China.
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Wagner AS, Smith FM, Bennin DA, Votava JA, Datta R, Giese MA, Zhao W, Skala MC, Fan J, Keller NP, Huttenlocher A. GATA1-deficient human pluripotent stem cells generate neutrophils with improved antifungal immunity that is mediated by the integrin CD18. PLoS Pathog 2025; 21:e1012654. [PMID: 39899622 PMCID: PMC11825098 DOI: 10.1371/journal.ppat.1012654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 02/13/2025] [Accepted: 01/15/2025] [Indexed: 02/05/2025] Open
Abstract
Neutrophils are critical for host defense against fungi. However, the short life span and lack of genetic tractability of primary human neutrophils has limited in vitro analysis of neutrophil-fungal interactions. Human induced pluripotent stem cell (iPSC)-derived neutrophils (iNeutrophils) provide a genetically tractable system to study host defense responses of human neutrophils. Here, we show that deletion of the transcription factor GATA1 from human iPSCs results in iNeutrophils with improved antifungal activity against Aspergillus fumigatus. GATA1-knockout (KO) iNeutrophils have increased maturation, antifungal pattern recognition receptor expression and have improved neutrophil effector functions compared to wild-type iNeutrophils. iNeutrophils also show a shift in their metabolism following stimulation with fungal β-glucan to the pentose phosphate pathway (PPP), similar to primary human neutrophils. Furthermore, we show that deletion of the integrin CD18 attenuates the ability of GATA1-KO iNeutrophils to kill A. fumigatus but is not necessary for the metabolic shift. Collectively, these findings support iNeutrophils as a robust system to study human neutrophil antifungal immunity and has identified specific roles for CD18 in the defense response.
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Affiliation(s)
- Andrew S. Wagner
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Frances M. Smith
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - David A. Bennin
- Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - James A. Votava
- Morgridge Institute for Research, Madison, Wisconsin, United States of America
| | - Rupsa Datta
- Morgridge Institute for Research, Madison, Wisconsin, United States of America
| | - Morgan A. Giese
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Wenxuan Zhao
- Morgridge Institute for Research, Madison, Wisconsin, United States of America
| | - Melissa C. Skala
- Morgridge Institute for Research, Madison, Wisconsin, United States of America
| | - Jing Fan
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
- Morgridge Institute for Research, Madison, Wisconsin, United States of America
| | - Nancy P. Keller
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
- Department of Plant Pathology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Anna Huttenlocher
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
- Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
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Wagner AS, Smith FM, Bennin DA, Votava JA, Datta R, Giese MA, Zhao W, Skala MC, Fan J, Keller NP, Huttenlocher A. GATA1-deficient human pluripotent stem cells generate neutrophils with improved antifungal immunity that is mediated by the integrin CD18. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.11.617742. [PMID: 39416161 PMCID: PMC11482877 DOI: 10.1101/2024.10.11.617742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Neutrophils are critical for host defense against fungi. However, the short life span and lack of genetic tractability of primary human neutrophils has limited in vitro analysis of neutrophil-fungal interactions. Human induced pluripotent stem cell (iPSC)-derived neutrophils (iNeutrophils) are a genetically tractable alternative to primary human neutrophils. Here, we show that deletion of the transcription factor GATA1 from human iPSCs results in iNeutrophils with improved antifungal activity against Aspergillus fumigatus. GATA1 knockout (KO) iNeutrophils have increased maturation, antifungal pattern recognition receptor expression and more readily execute neutrophil effector functions compared to wild-type iNeutrophils. iNeutrophils also show a shift in their metabolism following stimulation with fungal β-glucan, including an upregulation of the pentose phosphate pathway (PPP), similar to primary human neutrophils in vitro. Furthermore, we show that deletion of the integrin CD18 attenuates the ability of GATA1-KO iNeutrophils to kill A. fumigatus but is not necessary for the upregulation of PPP. Collectively, these findings support iNeutrophils as a robust system to study human neutrophil antifungal immunity and has identified specific roles for CD18 in the defense response.
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Affiliation(s)
- Andrew S. Wagner
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Frances M. Smith
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - David A. Bennin
- Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | | | - Rupsa Datta
- Morgridge Institute for Research, Madison, WI, USA
| | - Morgan A. Giese
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Wenxuan Zhao
- Morgridge Institute for Research, Madison, WI, USA
| | | | - Jing Fan
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Morgridge Institute for Research, Madison, WI, USA
| | - Nancy P. Keller
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Department of Plant Pathology, University of Wisconsin-Madison, WI, USA
| | - Anna Huttenlocher
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
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Cinicola BL, Uva A, Duse M, Zicari AM, Buonsenso D. Mucocutaneous Candidiasis: Insights Into the Diagnosis and Treatment. Pediatr Infect Dis J 2024; 43:694-703. [PMID: 38502882 PMCID: PMC11191067 DOI: 10.1097/inf.0000000000004321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/08/2024] [Indexed: 03/21/2024]
Abstract
Recent progress in the methods of genetic diagnosis of inborn errors of immunity has contributed to a better understanding of the pathogenesis of chronic mucocutaneous candidiasis (CMC) and potential therapeutic options. This review describes the latest advances in the understanding of the pathophysiology, diagnostic strategies, and management of chronic mucocutaneous candidiasis.
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Affiliation(s)
- Bianca Laura Cinicola
- From the Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Andrea Uva
- Pediatrics and Neonatology Unit, Maternal-Child Department, Santa Maria Goretti Hospital, Sapienza University of Rome, Latina, Italy
| | - Marzia Duse
- From the Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
| | - Anna Maria Zicari
- From the Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
| | - Danilo Buonsenso
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Center for Global Health Research and Studies, Università Cattolica del Sacro Cuore, Roma, Italia
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Saad MM, Alkady R, Eldash A, El Hawary RE, Meshaal SS, Galal NM, Elmarsafy AM. Analysis of Clinical, Immunological and Molecular Features of Leukocyte Adhesion Deficiency Type I in Egyptian Children. J Clin Immunol 2024; 44:92. [PMID: 38578558 PMCID: PMC10997710 DOI: 10.1007/s10875-024-01693-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 03/16/2024] [Indexed: 04/06/2024]
Abstract
PURPOSE Leukocyte adhesion deficiency (LAD) represents a rare group of inherited inborn errors of immunity (IEI) characterized by bacterial infections, delayed umbilical stump separation, and autoimmunity. This single-center study aimed at describing the clinical, immunological, and molecular characterizations of 34 LAD-I Egyptian pediatric patients. METHODS Details of 34 patients' personal medical history, clinical and laboratory findings were recorded; Genetic material from 28 patients was studied. Mutational analysis was done by Sanger sequencing. RESULTS Omphalitis, skin and soft tissue infections with poorly healing ulcers, delayed falling of the umbilical stump, and recurrent or un-resolving pneumonia were the most common presentations, followed by chronic otitis media, enteropathy, periodontitis; and recurrent oral thrush. Persistent leukocytosis and neutrophilia were reported in all patients, as well as CD18 and CD11b deficiency. CD18 expression was < 2% in around 90% of patients. Sixteen different pathological gene variants were detected in 28 patients who underwent ITGß2 gene sequencing, of those, ten were novel and six were previously reported. Three families received a prenatal diagnosis. Patients were on antimicrobials according to culture's results whenever available, and on prophylactic Trimethoprim-Sulfamethoxazole 5 mg/kg once daily, with regular clinical follow up. Hematopoietic stem cell transplantation (HSCT) was offered for 4 patients. However due to severity of the disease and delay in diagnosis, 58% of the patients passed away in the first 2 years of life. CONCLUSION This study highlights the importance of early diagnosis and distribution of ITGß2 gene mutation in Egyptian children. Further molecular studies, however, remain a challenging necessity for better disease characterization in the region.
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Affiliation(s)
- Mai Magdy Saad
- Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, 11562, Egypt.
| | - Radwa Alkady
- Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, 11562, Egypt
| | - Alia Eldash
- Clinical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Rabab E El Hawary
- Clinical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Safa S Meshaal
- Clinical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Nermeen M Galal
- Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, 11562, Egypt
| | - Aisha M Elmarsafy
- Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, 11562, Egypt
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Choi Y. Association of neutrophil defects with oral ulcers but undetermined role of neutrophils in recurrent aphthous stomatitis. Heliyon 2024; 10:e26740. [PMID: 38439826 PMCID: PMC10911260 DOI: 10.1016/j.heliyon.2024.e26740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 02/17/2024] [Accepted: 02/19/2024] [Indexed: 03/06/2024] Open
Abstract
Objective Recurrent oral ulcers and severe periodontal diseases in patients with quantitative or qualitative neutrophil defects highlight the important role of neutrophils in maintaining oral mucosal barrier homeostasis. Recurrent aphthous stomatitis (RAS) is a common oral mucosal disease affecting up to 25% of the population, yet its etiopathogenesis remains unclear, and management is unsatisfactory. This review aims to gain insight into the pathogenesis of RAS. Design This narrative review examines the characteristics of oral and blood neutrophils, the associations between neutrophil defects and the occurrence of oral ulcers, and the evidence for the involvement of neutrophils in RAS. To conduct the review, relevant literature was searched in PubMed and Google Scholar, which was then thoroughly reviewed and critically appraised. Results Neutropenia, specifically a decrease in the number of oral neutrophils, impaired extravasation, and defective ROS production appear to be associated with oral ulcers, while defects in granule enzymes or NETosis are unlikely to have a link to oral ulcers. The review of the histopathology of RAS shows that neutrophils are concentrated in the denuded area but are latecomers to the scene and early leavers. However, the evidence for the involvement of neutrophils in the pathogenesis of RAS is inconsistent, leading to the proposal of two different scenarios involving either impaired or hyperactive neutrophils in the pathogenesis of RAS.
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Affiliation(s)
- Youngnim Choi
- Department of Immunology and Molecular Microbiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea
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Alasmari BG, Alomari M, Alotaibi WN, Hommadi A, Elmugadam AA, Abdalla K, Al-Tala SM. LAD-III, a Mild Phenotype Resulting From a Novel Variant of FERMT3 Gene: A Case Report. Cureus 2023; 15:e51062. [PMID: 38269242 PMCID: PMC10806943 DOI: 10.7759/cureus.51062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/25/2023] [Indexed: 01/26/2024] Open
Abstract
Leukocyte adhesion deficiency-III (LAD-III) is a rare recessive autosomal disorder characterized by bleeding syndrome of Glanzmann-type and life-threatening infections. The main etiology of this condition is variations in the FERMT3 gene, which encodes kindlin-3, an integrin-binding protein. This protein is responsible for the activation of fibrinogen receptors and integrin-mediated hematopoietic cell adhesion. So far, only limited cases of LAD-III have been reported. This case report discusses a two-year-old male infant from the Asir region, Saudi Arabia, who was referred to the pediatric hematology service due to recurrent ecchymosis and epistaxis. He was born at full term with a history of transient tachypnea of the newborn and recurrent bronchiolitis. The patient exhibited normal platelet count and coagulation profiles alongside a familial history of bleeding disorders, including a cousin with a similar condition. The patient also presented with hypospadias and café-au-lait spots. Laboratory findings revealed anemia, microcytosis, and hypochromia indicative of iron deficiency anemia. Whole exome sequencing (WES) identified a homozygous variant of uncertain significance in the FERMT3 gene, associated with autosomal recessive LAD-III. The patient was subsequently referred to an immunology subspecialty for further investigation and bone marrow transplant preparation. This case underscores the importance of comprehensive clinical and genetic evaluations in pediatric patients with unexplained bleeding tendencies.
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Affiliation(s)
| | - Mohammed Alomari
- Pediatrics, Armed Forces Hospital Southern Region, Khamis Mushait, SAU
| | - Wejdan N Alotaibi
- Pediatrics, Armed Forces Hospital Southern Region, Khamis Mushait, SAU
| | - Ashwaq Hommadi
- Pediatrics, Armed Forces Hospital Southern Region, Khamis Mushait, SAU
| | | | - Khalid Abdalla
- Pediatric Hematology Oncology, King Abdulaziz Medical City, Jeddah, SAU
| | - Saeed M Al-Tala
- Pediatrics, Armed Forces Hospital Southern Region, Khamis Mushait, SAU
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Jacoby E, Adam E, Hutt D, Somech R, Malkiel S, Toren A, Bielorai B. Improved Outcome Following Busulfan-Based Conditioning in Children with Functional Neutrophil Disorders Undergoing Hematopoietic Stem Cell Transplant from HLA-Matched Donors. J Clin Immunol 2023; 43:1603-1610. [PMID: 37310531 DOI: 10.1007/s10875-023-01535-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 06/08/2023] [Indexed: 06/14/2023]
Abstract
Hematopoietic stem-cell transplantation (HSCT) is the only curative treatment for chronic granulomatous disease (CGD) and leukocyte-adhesion deficiency (LAD), but both diseases have high rates of graft failure in transplant and patients with these diseases are often referred to HSCT with significant comorbidity. The intensity of the conditioning regimen should be balanced between the need to ensure durable engraftment and to minimize toxicity when transplanting young children with infections and organ damage. We report on 26 children transplanted at our institution with CGD and LAD over 24 years. We found a higher incidence of graft failure in patients receiving treosulfan based conditioning for their first transplant. There was no effect of conditioning regimen on overall survival, as all 8 patients that proceeded to a second busulfan-based HSCT were salvaged. We recommend giving patients with CGD and LAD fully myeloablative conditioning with either a busulfan-based regimen or the combination of treosulfan, fludarabine, and thiotepa.
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Affiliation(s)
- Elad Jacoby
- Division of Pediatric Hematology, Oncology and BMT, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Etai Adam
- Division of Pediatric Hematology, Oncology and BMT, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Daphna Hutt
- Division of Pediatric Hematology, Oncology and BMT, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
| | - Raz Somech
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pediatric Department A and the Immunology Service, Jeffrey Modell Foundation Center, The Edmond And Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
| | - Sarah Malkiel
- Division of Pediatric Hematology, Oncology and BMT, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Amos Toren
- Division of Pediatric Hematology, Oncology and BMT, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Bella Bielorai
- Division of Pediatric Hematology, Oncology and BMT, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Bondarenko AV, Boyarchuk OR, Sakovich IS, Polyakova EA, Migas AA, Kupchinskaya AN, Opalinska A, Reich A, Volianska L, Hilfanova AM, Lapiy FI, Chernyshova LI, Volokha AP, Zabara DV, Belevtsev MV, Shman TV, Kukharenko LV, Goltsev MV, Dubouskaya TG, Hancharou AY, Ji W, Lakhani S, Lucas CL, Aleinikova OV, Sharapova SO. Variable CD18 expression in a 22-year-old female with leukocyte adhesion deficiency I: Clinical case and literature review. Clin Case Rep 2023; 11:e7791. [PMID: 37601427 PMCID: PMC10432584 DOI: 10.1002/ccr3.7791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 08/22/2023] Open
Abstract
Key Clinical Message Partial leukocyte adhesion deficiency type 1 (LAD-1) deficiency is extremely rare condition with milder infectious manifestation and immune system imbalance leads to increased risks of autoinflammatory complications, such as pyoderma gangrenosum, that can be triggered by trauma or pregnancy. In patients with spice-site ITGB2 variants, partial expression can occur due to different β2 integrin isophorms expression. Abstract LAD-1, OMIM ID #116920 is a rare, autosomal recessive disorder that results from mutations in the ITGB2 gene that encodes the CD18 β2 integrin subunit. According to the CD18 expression, LAD-1 is categorized as severe (<2%), moderate (2%-30%), or mild (>30%). Here, we describe a 22-year-old female, who presented with inflammatory skin disease and oral cavity, as well as respiratory tract infections during the first year of life. LAD-1 was diagnosed at the age of 2 years by low expression of CD18 (1%). Whole-exome sequencing identified homozygous c. 59-10C>A variant in the ITGB2 gene. Despite severe phenotype, the patient survived to adulthood without hematopoietic stem cell transplantation and became pregnant at the age of 20 years, with pregnancy complicated by a pyoderma gangrenosum-like lesion. During her life, CD18 expression increased from 1% to 9%; at 22 years of age, 5% of neutrophils and 9% of lymphocytes were CD18+. All CD18+-lymphocytes were predominantly memory/effector cytotoxic T cells. However, revertant mosaicism was not being established suggesting that CD18 expression variability may be mediated by other mechanisms such as different β2 integrin isophorms expression.
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Affiliation(s)
- Anastasiia V. Bondarenko
- Department of Pediatrics, Immunology, Infectious and Rare Diseases, European Medical SchoolInternational European UniversityKyivUkraine
| | - Oksana R. Boyarchuk
- Department of Children's Diseases and Pediatric SurgeryI. Horbachevsky Ternopil National Medical UniversityTernopilUkraine
| | - Inga S. Sakovich
- Research DepartmentBelarusian Research Center for Pediatric Oncology, Hematology and ImmunologyMinskBelarus
| | - Ekaterina A. Polyakova
- Research DepartmentBelarusian Research Center for Pediatric Oncology, Hematology and ImmunologyMinskBelarus
| | - Alexander A. Migas
- Research DepartmentBelarusian Research Center for Pediatric Oncology, Hematology and ImmunologyMinskBelarus
| | - Aleksandra N. Kupchinskaya
- Research DepartmentBelarusian Research Center for Pediatric Oncology, Hematology and ImmunologyMinskBelarus
| | - Aleksandra Opalinska
- Department of Dermatology, Institute of Medical SciencesMedical College of Rzeszow UniversityRzeszowPoland
| | - Adam Reich
- Department of Dermatology, Institute of Medical SciencesMedical College of Rzeszow UniversityRzeszowPoland
| | - Liubov Volianska
- Department of Children's Diseases and Pediatric SurgeryI. Horbachevsky Ternopil National Medical UniversityTernopilUkraine
| | - Anna M. Hilfanova
- Department of Pediatrics, Immunology, Infectious and Rare Diseases, European Medical SchoolInternational European UniversityKyivUkraine
| | - Fedir I. Lapiy
- Department of Pediatrics, Immunology, Infectious and Rare Diseases, European Medical SchoolInternational European UniversityKyivUkraine
| | | | | | - Dariia V. Zabara
- Institute of Pediatrics, Obstetrics and Gynecology named after Academician O.M. Lukyanova of the NAMS of UkraineKyivUkraine
| | - Mikhail V. Belevtsev
- Research DepartmentBelarusian Research Center for Pediatric Oncology, Hematology and ImmunologyMinskBelarus
| | - Tatsiana V. Shman
- Research DepartmentBelarusian Research Center for Pediatric Oncology, Hematology and ImmunologyMinskBelarus
| | - Lyudmila V. Kukharenko
- Department of Medical and Biological PhysicsBelarusian State Medical UniversityMinskBelarus
| | - Mikhail V. Goltsev
- Department of Medical and Biological PhysicsBelarusian State Medical UniversityMinskBelarus
| | | | | | - Weizhen Ji
- Department of PediatricsYale UniversityNew HavenConnecticutUSA
- Yale University Pediatric Genomics Discovery ProgramNew HavenConnecticutUSA
| | - Saquib Lakhani
- Department of PediatricsYale UniversityNew HavenConnecticutUSA
- Yale University Pediatric Genomics Discovery ProgramNew HavenConnecticutUSA
| | - Carrie L. Lucas
- Yale University Pediatric Genomics Discovery ProgramNew HavenConnecticutUSA
- Department of ImmunobiologyYale UniversityNew HavenConnecticutUSA
| | - Olga V. Aleinikova
- Research DepartmentBelarusian Research Center for Pediatric Oncology, Hematology and ImmunologyMinskBelarus
| | - Svetlana O. Sharapova
- Research DepartmentBelarusian Research Center for Pediatric Oncology, Hematology and ImmunologyMinskBelarus
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10
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Erdem S, Haskologlu S, Haliloglu Y, Çelikzencir H, Arik E, Keskin O, Eltan SB, Yucel E, Canatan H, Avcilar H, Yilmaz E, Ozcan A, Unal E, Karakukcu M, Celiksoy MH, Kilic SS, Demir A, Genel F, Gulez N, Koker MY, Ozen AO, Baris S, Metin A, Guner SN, Reisli I, Keles S, Dogu EF, Ikinciogullari KA, Eken A. Defective Treg generation and increased type 3 immune response in leukocyte adhesion deficiency 1. Clin Immunol 2023:109691. [PMID: 37433423 DOI: 10.1016/j.clim.2023.109691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/26/2023] [Accepted: 07/05/2023] [Indexed: 07/13/2023]
Abstract
In 15 Turkish LAD-1 patients and controls, we assessed the impact of pathogenic ITGB2 mutations on Th17/Treg differentiation and functions, and innate lymphoid cell (ILC) subsets. The percentage of peripheral blood Treg cells, in vitro-generated induced Tregs differentiated from naive CD4+ T cells were decreased despite the elevated absolute counts of CD4+ cells in LAD1 patients. Serum IL-23 levels were elevated in LAD1 patients. Post-curdlan stimulation, LAD1 patient-derived PBMCs produced more IL-17A. Additionally, the percentages of CD18-deficient Th17 cells expanded from total or naïve CD4+ T cells were higher. The blood ILC3 subset was significantly elevated in LAD1. Finally, LAD1 PBMCs showed defects in trans-well migration and proliferation and were more resistant to apoptosis. Defects in de novo generation of Tregs from CD18-deficient naïve T cells and elevated Th17s, and ILC3s in LAD1 patients' peripheral blood suggest a type 3-skewed immunity and may contribute to LAD1-associated autoimmune symptoms.
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Affiliation(s)
- Serife Erdem
- Erciyes University School of Medicine, Department of Medical Biology, Kayseri, Turkey; Erciyes University, Betul-Ziya Eren Genome and Stem Cell Center, Kayseri, Turkey
| | - Sule Haskologlu
- Ankara University School of Medicine, Department of Pediatric Allergy and Immunology, Ankara, Turkey
| | - Yesim Haliloglu
- Erciyes University School of Medicine, Department of Medical Biology, Kayseri, Turkey; Erciyes University, Betul-Ziya Eren Genome and Stem Cell Center, Kayseri, Turkey
| | - Huriye Çelikzencir
- Erciyes University School of Medicine, Department of Immunology, Kayseri, Turkey.
| | - Elif Arik
- Gaziantep University School of Medicine, Department of Pediatric Allergy and Immunology, Gaziantep, Turkey
| | - Ozlem Keskin
- Gaziantep University School of Medicine, Department of Pediatric Allergy and Immunology, Gaziantep, Turkey
| | - Sevgi Bilgic Eltan
- Marmara University School of Medicine, Department of Pediatric Allergy and Immunology, Istanbul, Turkey
| | - Esra Yucel
- Istanbul University School of Medicine, Department of Pediatric Allergy and Immunology, Istanbul, Turkey
| | - Halit Canatan
- Erciyes University School of Medicine, Department of Medical Biology, Kayseri, Turkey; Erciyes University, Betul-Ziya Eren Genome and Stem Cell Center, Kayseri, Turkey
| | - Huseyin Avcilar
- Erciyes University, Betul-Ziya Eren Genome and Stem Cell Center, Kayseri, Turkey
| | - Ebru Yilmaz
- Erciyes University School of Medicine, Department of Pediatric Hematology and Oncology, Kayseri, Turkey
| | - Alper Ozcan
- Erciyes University School of Medicine, Department of Pediatric Hematology and Oncology, Kayseri, Turkey
| | - Ekrem Unal
- Erciyes University, Betul-Ziya Eren Genome and Stem Cell Center, Kayseri, Turkey; Erciyes University School of Medicine, Department of Pediatric Hematology and Oncology, Kayseri, Turkey
| | - Musa Karakukcu
- Erciyes University School of Medicine, Department of Pediatric Hematology and Oncology, Kayseri, Turkey
| | - Mehmet Halil Celiksoy
- İstanbul Başakşehir Çam ve Sakura City Hospital, Pediatric Allergy and Immunology Clinic Istanbul, Turkey
| | - Sara Sebnem Kilic
- Bursa Uludag University, Department of Pediatric Immunology and Rheumatology, Bursa, Turkey.
| | - Ayca Demir
- Dr Behcet Uz Children's Education and Research Hospital, University of Health Sciences, Department of Pediatric Allergy and Immunology, Izmir, Turkey
| | - Ferah Genel
- Dr Behcet Uz Children's Education and Research Hospital, University of Health Sciences, Department of Pediatric Allergy and Immunology, Izmir, Turkey
| | - Nesrin Gulez
- Dr Behcet Uz Children's Education and Research Hospital, University of Health Sciences, Department of Pediatric Allergy and Immunology, Izmir, Turkey
| | - Mustafa Yavuz Koker
- Erciyes University School of Medicine, Department of Immunology, Kayseri, Turkey.
| | - Ahmet Oguzhan Ozen
- Marmara University School of Medicine, Department of Pediatric Allergy and Immunology, Istanbul, Turkey
| | - Safa Baris
- Marmara University School of Medicine, Department of Pediatric Allergy and Immunology, Istanbul, Turkey
| | - Ayse Metin
- Ankara City Hospital, Department of Pediatric Allergy and Immunology, Ankara, Turkey
| | - Sukru Nail Guner
- Necmettin Erbakan University School of Medicine, Department of Pediatric Allergy and Immunology, Konya, Turkey
| | - Ismail Reisli
- Necmettin Erbakan University School of Medicine, Department of Pediatric Allergy and Immunology, Konya, Turkey
| | - Sevgi Keles
- Necmettin Erbakan University School of Medicine, Department of Pediatric Allergy and Immunology, Konya, Turkey
| | - Esin Figen Dogu
- Ankara University School of Medicine, Department of Pediatric Allergy and Immunology, Ankara, Turkey
| | | | - Ahmet Eken
- Erciyes University School of Medicine, Department of Medical Biology, Kayseri, Turkey; Erciyes University, Betul-Ziya Eren Genome and Stem Cell Center, Kayseri, Turkey.
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11
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Janus-Bell E, Mangin PH. The relative importance of platelet integrins in hemostasis, thrombosis and beyond. Haematologica 2023; 108:1734-1747. [PMID: 36700400 PMCID: PMC10316258 DOI: 10.3324/haematol.2022.282136] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 01/09/2023] [Indexed: 01/27/2023] Open
Abstract
Integrins are heterodimeric transmembrane receptors composed of α and β chains, with an N-terminal extracellular domain forming a globular head corresponding to the ligand binding site. Integrins regulate various cellular functions including adhesion, migration, proliferation, spreading and apoptosis. On platelets, integrins play a central role in adhesion and aggregation on subendothelial matrix proteins of the vascular wall, thereby ensuring hemostasis. Platelet integrins belong either to the β1 family (α2β1, α5β1 and α6β1) or to the β3 family (αIIbβ3 and αvβ3). On resting platelets, integrins can engage their ligands when the latter are immobilized but not in their soluble form. The effects of various agonists promote an inside-out signal in platelets, increasing the affinity of integrins for their ligands and conveying a modest signal reinforcing platelet activation, called outside-in signaling. This outside-in signal ensures platelet adhesion, shape change, granule secretion and aggregation. In this review, we examine the role of each platelet integrin in hemostatic plug formation, hemostasis and arterial thrombosis and also beyond these classical functions, notably in tumor metastasis and sepsis.
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Affiliation(s)
- Emily Janus-Bell
- Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg.
| | - Pierre H Mangin
- Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg
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12
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Fazlollahi MR, Hamidieh AA, Moradi L, Shokouhi Shoormati R, Sabetkish N, Esmaeili B, Badalzadeh M, Alizadeh Z, Shamlou S, Movahedi M, Mahloujirad M, Razaghian A, Arshi S, Gharagozlou M, Kalantari A, Bemanian MH, Safari M, Heidarzadeh Arani M, Nabavi M, Parvaneh N, Sadeghi-Shabestari M, Behfar M, Behniafard N, Sherkat R, Ahmadian Heris J, Shariat M, Radmehr R, Houshmand M, Kazemnejad A, Molitor A, Carapito R, Bahram S, Pourpak Z, Moin M. Clinical and immunological characteristics of 69 leukocyte adhesion deficiency-I patients. Pediatr Allergy Immunol 2023; 34:e13990. [PMID: 37492921 DOI: 10.1111/pai.13990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 06/14/2023] [Accepted: 06/20/2023] [Indexed: 07/27/2023]
Abstract
BACKGROUND In order to support the comprehensive classification of Leukocyte Adhesion Deficiency-I (LAD-I) severity by simultaneous screening of CD11a/CD18, this study assessed clinical, laboratory, and genetic findings along with outcomes of 69 LAD-I patients during the last 15 years. METHODS Sixty-nine patients (40 females and 29 males) with a clinical phenotype suspected of LAD-I were referred to Immunology, Asthma, and Allergy research institute, Tehran, Iran between 2007 and 2022 for further advanced immunological screening and genetic evaluations as well as treatment, were enrolled in this study. RESULTS The diagnosis median age of the patients was 6 months. Delayed umbilical cord separation was found in 25 patients (36.2%). The median diagnostic delay time was 4 months (min-max: 0-82 months). Forty-six patients (66.7%) were categorized as severe (CD18 and/or CD11a: below 2%); while 23 children (33.3%) were in moderate category (CD18 and/or CD11a: 2%-30%). During the follow-ups, 55.1% of children were alive with a mortality rate of 44.9%. Skin ulcers (75.4%), omphalitis (65.2%), and gingivitis (37.7%) were the most frequent complaints. Genetic analysis of the patients revealed 14 previously reported and three novel pathogenic mutations in the ITGB2 gene. The overall survival of patients with and without hematopoietic stem cell transplantation was 79.3% and 55.6%, respectively. CONCLUSION Physicians' awareness of LAD-I considering delayed separation of umbilical cord marked neutrophilic leukocytosis, and variability in CD11 and CD18 expression levels, and genetic analysis leads to early diagnosis and defining disease severity. Moreover, the prenatal diagnosis would benefit families with a history of LAD-I.
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Affiliation(s)
- Mohammad Reza Fazlollahi
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Hamidieh
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Moradi
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Raheleh Shokouhi Shoormati
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Nastaran Sabetkish
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnaz Esmaeili
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
- Department of Basic Sciences, Khoy University of Medical Sciences, Khoy, Iran
| | - Mohsen Badalzadeh
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Alizadeh
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Shamlou
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Movahedi
- Department of Allergy and Clinical Immunology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Mahloujirad
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Anahita Razaghian
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Saba Arshi
- Department of Allergy and Immunology, Rasool-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Gharagozlou
- Department of Allergy and Clinical Immunology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Arash Kalantari
- Department of Pediatrics, Valiasr Hospital, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassan Bemanian
- Department of Allergy and Immunology, Rasool-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mojgan Safari
- Department of Pediatrics, School of Medicines, Hamadan University of Medical Science, Hamedan, Iran
| | | | - Mohammad Nabavi
- Department of Allergy and Immunology, Rasool-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Nima Parvaneh
- Department of Allergy and Clinical Immunology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahnaz Sadeghi-Shabestari
- Immunology Research Center of Tabriz, TB and Lung Disease Research Center, Children Hospital, Tabriz University of Medical Science, Tabriz, Iran
| | - Maryam Behfar
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasrin Behniafard
- Children Growth Disorder Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Roya Sherkat
- Immunodeficiency Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mansoureh Shariat
- Department of Allergy and Clinical Immunology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Roshanak Radmehr
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Massoud Houshmand
- National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
| | - Anoshirvan Kazemnejad
- Department of Biostatistics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Anne Molitor
- Laboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, Strasbourg, France
- Service d'Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France
| | - Raphael Carapito
- Laboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, Strasbourg, France
- Service d'Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France
| | - Seiamak Bahram
- Laboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, Strasbourg, France
- Service d'Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France
| | - Zahra Pourpak
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Mostafa Moin
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
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Al-Mousa H, Barbouche MR. Genetics of Inborn Errors of Immunity in highly consanguineous Middle Eastern and North African populations. Semin Immunol 2023; 67:101763. [PMID: 37075586 DOI: 10.1016/j.smim.2023.101763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
Consanguineous marriages in Middle Eastern and North African (MENA) countries are deeply-rooted tradition and highly prevalent resulting into increased prevalence of autosomal recessive diseases including Inborn Errors of Immunity (IEIs). Molecular genetic testing is an important diagnostic tool for IEIs since it provides a definite diagnosis, genotype-phenotype correlation, and guide therapy. In this review, we will discuss the current state and challenges of genomic and variome studies in MENA region populations, as well as the importance of funding advanced genome projects. In addition, we will review the MENA underlying molecular genetic defects of over 2457 patients published with the common IEIs, where autosomal recessive mode of inheritance accounts for 76% of cases with increased prevalence of combined immunodeficiency diseases (50%). The efforts made in the last three decades in terms of international collaboration and of in situ capacity building in MENA region countries led to the discovery of more than 150 novel genes involved in IEIs. Expanding sequencing studies within the MENA will undoubtedly be a unique asset for the IEI genetics which can advance research, and support precise genomic diagnostics and therapeutics.
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Affiliation(s)
- Hamoud Al-Mousa
- Section of Allergy and Immunology, Department of Pediatrics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
| | - Mohamed-Ridha Barbouche
- Department of Microbiology, Immunology and Infectious Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.
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14
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Kahraman AB, Yaz I, Gocmen R, Aytac S, Metin A, Kilic SS, Tezcan I, Cagdas D. Clinical and Osteopetrosis-Like Radiological Findings in Patients with Leukocyte Adhesion Deficiency Type III. J Clin Immunol 2023:10.1007/s10875-023-01479-7. [PMID: 37014583 DOI: 10.1007/s10875-023-01479-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 03/25/2023] [Indexed: 04/05/2023]
Abstract
BACKGROUND Leukocyte and platelet integrin function defects are present in leukocyte adhesion deficiency type III (LAD-III) due to mutations in FERMT3. Additionally, osteoclast/osteoblast dysfunction develops in LAD-III. AIM To discuss the distinguishing clinical, radiological, and laboratory features of LAD-III. METHODS This study included the clinical, radiological, and laboratory characteristics of twelve LAD-III patients. RESULTS The male/female ratio was 8/4. The parental consanguinity ratio was 100%. Half of the patients had a family history of patients with similar findings. The median age at presentation and diagnosis was 18 (1-60) days and 6 (1-20) months, respectively. The median leukocyte count on admission was 43,150 (30,900-75,700)/μL. The absolute eosinophil count was tested in 8/12 patients, and eosinophilia was found in 6/8 (75%). All patients had a history of sepsis. Other severe infections were pneumonia (66.6%), omphalitis (25%), osteomyelitis (16.6%), gingivitis/periodontitis (16%), chorioretinitis (8.3%), otitis media (8.3%), diarrhea (8.3%), and palpebral conjunctiva infection (8.3%). Four patients (33.3%) received hematopoietic stem cell transplantation (HSCT) from HLA-matched-related donors, and one deceased after HSCT. At initial presentation, 4 (33.3%) patients were diagnosed with other hematologic disorders, three patients (P5, P7, and P8) with juvenile myelomonocytic leukemia (JMML), and one (P2) with myelodysplastic syndrome (MDS). CONCLUSION In LAD-III, leukocytosis, eosinophilia, and bone marrow findings may mimic pathologies such as JMML and MDS. In addition to non-purulent infection susceptibility, patients with LAD-III exhibit Glanzmann-type bleeding disorder. In LAD-III, absent integrin activation due to kindlin-3 deficiency disrupts osteoclast actin cytoskeleton organization. This results in defective bone resorption and osteopetrosis-like radiological changes. These are distinctive features compared to other LAD types.
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Affiliation(s)
- Ayca Burcu Kahraman
- Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey
- Ihsan Dogramaci Childrens Hospital, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Ismail Yaz
- Department of Pediatric Immunology, Institute of Child Health, Hacettepe University, Ankara, Turkey
| | - Rahsan Gocmen
- Department of Radiology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Selin Aytac
- Ihsan Dogramaci Childrens Hospital, Hacettepe University Faculty of Medicine, Ankara, Turkey
- Department of Pediatrics, Division of Pediatric Hematology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Ayse Metin
- Department of Pediatrics, Division of Immunology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey
| | - Sara Sebnem Kilic
- Department of Pediatrics, Division of Immunology and Rheumatology, Uludag University Faculty of Medicine, Bursa, Turkey
| | - Ilhan Tezcan
- Ihsan Dogramaci Childrens Hospital, Hacettepe University Faculty of Medicine, Ankara, Turkey
- Department of Pediatric Immunology, Institute of Child Health, Hacettepe University, Ankara, Turkey
- Department of Pediatrics, Division of Immunology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Deniz Cagdas
- Ihsan Dogramaci Childrens Hospital, Hacettepe University Faculty of Medicine, Ankara, Turkey.
- Department of Pediatric Immunology, Institute of Child Health, Hacettepe University, Ankara, Turkey.
- Department of Pediatrics, Division of Immunology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
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15
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Roos D, van Leeuwen K, Madkaikar M, Kambli PM, Gupta M, Mathews V, Rawat A, Kuhns DB, Holland SM, de Boer M, Kanegane H, Parvaneh N, Lorenz M, Schwarz K, Klein C, Sherkat R, Jafari M, Wolach B, den Dunnen JT, Kuijpers TW, Köker MY. Hematologically important mutations: Leukocyte adhesion deficiency (second update). Blood Cells Mol Dis 2023; 99:102726. [PMID: 36696755 DOI: 10.1016/j.bcmd.2023.102726] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 01/16/2023] [Accepted: 01/16/2023] [Indexed: 01/22/2023]
Abstract
Leukocyte adhesion deficiency (LAD) is an immunodeficiency caused by defects in the adhesion of leukocytes (especially neutrophils) to the blood vessel wall. As a result, patients with LAD suffer from severe bacterial infections and impaired wound healing, accompanied by neutrophilia. In LAD-I, characterized directly after birth by delayed separation of the umbilical cord, mutations are found in ITGB2, the gene that encodes the β subunit (CD18) of the β2 integrins. In the rare LAD-II disease, the fucosylation of selectin ligands is disturbed, caused by mutations in SLC35C1, the gene that encodes a GDP-fucose transporter of the Golgi system. LAD-II patients lack the H and Lewis Lea and Leb blood group antigens. Finally, in LAD-III, the conformational activation of the hematopoietically expressed β integrins is disturbed, leading to leukocyte and platelet dysfunction. This last syndrome is caused by mutations in FERMT3, encoding the kindlin-3 protein in all blood cells, involved in the regulation of β integrin conformation. This article contains an update of the mutations that we consider to be relevant for the various forms of LAD.
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Affiliation(s)
- Dirk Roos
- Sanquin Research, and Landsteiner Laboratory, Amsterdam University Medical Center, location AMC, University of Amsterdam, Amsterdam, the Netherlands.
| | - Karin van Leeuwen
- Sanquin Research, and Landsteiner Laboratory, Amsterdam University Medical Center, location AMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Manisha Madkaikar
- Pediatric Immunology and Leukocyte Biology Lab CMR, National Institute of Immunohaematology, K E M Hospital, Parel, Mumbai, India
| | - Priyanka M Kambli
- Pediatric Immunology and Leukocyte Biology Lab CMR, National Institute of Immunohaematology, K E M Hospital, Parel, Mumbai, India
| | - Maya Gupta
- Pediatric Immunology and Leukocyte Biology Lab CMR, National Institute of Immunohaematology, K E M Hospital, Parel, Mumbai, India
| | - Vikram Mathews
- Dept of Hematology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Amit Rawat
- Paediatric Allergy Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Chandigarh, India
| | - Douglas B Kuhns
- Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Steven M Holland
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - Martin de Boer
- Sanquin Research, and Landsteiner Laboratory, Amsterdam University Medical Center, location AMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Hirokazu Kanegane
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Nima Parvaneh
- Infectious Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Myriam Lorenz
- Institute for Transfusion Medicine, University Ulm, Ulm, Germany
| | - Klaus Schwarz
- Institute for Transfusion Medicine, University Ulm, Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Württemberg - Hessen, Ulm, Germany
| | - Christoph Klein
- Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Roya Sherkat
- Immunodeficiency Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahbube Jafari
- Immunodeficiency Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Baruch Wolach
- Pediatric Immunology Service, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Johan T den Dunnen
- Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - Taco W Kuijpers
- Sanquin Research, and Landsteiner Laboratory, Amsterdam University Medical Center, location AMC, University of Amsterdam, Amsterdam, the Netherlands; Emma Children's Hospital, Amsterdam University Medical Centre, location AMC, Amsterdam, the Netherlands
| | - M Yavuz Köker
- Department of Immunology, Erciyes Medical School, University of Erciyes, Kayseri, Türkiye
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16
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Sanabria D, Giménez V, Martínez-de Cuellar C, Benegas S, Godoy AM, Carpinelli MM, Olmedo G, De Los Santos S. [Leucocyte adhesion deficiency: detection of the first cases in Paraguay]. REVISTA ALERGIA MÉXICO 2023; 69:109-118. [PMID: 36869010 DOI: 10.29262/ram.v69i3.1131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 10/22/2022] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE To implement the diagnostic technique for LAD by evaluating the expression of CD18 and CD15 in healthy patients and in a group with clinical suspicion. METHODS Observational, descriptive, and cross-secctional study, carried out in pediatric patients attended in the Instituto de Investigaciones en Ciencias de la Salud, and patients from public hospitals with clinical suspicion of LAD were studied. The molecules CD18 and CD15 in peripheral blood leukocytes was evaluated by flow cytometry, establishing a normal range in healthy patients. The presence of LAD was established by decreased expression of CD18 or CD15. RESULTS Sixty pediatric patients were evaluated: 20 apparently healthy and 40 with clinical suspicion of leukocyte adhesion deficiency; 12 of 20 healthy patients were male (median age: 14 years) and 27 of 40 with suspected disease were female (median age: 2 years). Persistent leukocytosis and respiratory tract (32%) infections predominated. The expression range of CD18 and CD15 in healthy patients was 95%-100%, and in patients with clinical suspicion it was 0%-100%. One patient with 0% of CD18 (LAD-1) and one patient with 0% of CD15 (LAD-2) were detecte. CONCLUSIONS The implementation of a new diagnostic technique allowed to establish a normal range of CD18 and CD15 by flow cytometry, and it was possible to detect the first two cases of LAD in Paraguay.
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Affiliation(s)
- Diana Sanabria
- Universidad Nacional de Asunción, Instituto de Investigaciones en Ciencias de la Salud, Departamento de Inmunología, San Lorenzo, Paraguay.
| | - Vivian Giménez
- Universidad Nacional de Asunción, Instituto de Investigaciones en Ciencias de la Salud, Departamento de Inmunología, San Lorenzo, Paraguay
| | - Celia Martínez-de Cuellar
- Ministerio de Salud Pública y Bienestar Social, Instituto de Medicina Tropical, Centro Nacional de Referencia de Inmunodeficiencias Primarias, Asunción, Paraguay
| | - Sara Benegas
- Universidad Nacional de Asunción, Instituto de Investigaciones en Ciencias de la Salud, Departamento de Inmunología, San Lorenzo, Paraguay
| | - Ana María Godoy
- Universidad Nacional de Asunción, Instituto de Investigaciones en Ciencias de la Salud, Departamento de Inmunología, San Lorenzo, Paraguay
| | - María Mercedes Carpinelli
- Universidad Nacional de Asunción, Instituto de Investigaciones en Ciencias de la Salud, Departamento de Inmunología, San Lorenzo, Paraguay
| | - Guadalupe Olmedo
- Ministerio de Salud Pública y Bienestar Social, Banco de Sangre del Centro Médico Hospital Nacional, Itauguá, Paraguay
| | - Sandra De Los Santos
- Ministerio de Salud Pública y Bienestar Social, Banco de Sangre del Centro Médico Hospital Nacional, Itauguá, Paraguay
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17
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Gupta S, Agrawal A. Dendritic cells in inborn errors of immunity. Front Immunol 2023; 14:1080129. [PMID: 36756122 PMCID: PMC9899832 DOI: 10.3389/fimmu.2023.1080129] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 01/06/2023] [Indexed: 01/24/2023] Open
Abstract
Dendritic cells (DCs) are crucial cells for initiating and maintaining immune response. They play critical role in homeostasis, inflammation, and autoimmunity. A number of molecules regulate their functions including synapse formation, migration, immunity, and induction of tolerance. A number of IEI are characterized by mutations in genes encoding several of these molecules resulting in immunodeficiency, inflammation, and autoimmunity in IEI. Currently, there are 465 Inborn errors of immunity (IEI) that have been grouped in 10 different categories. However, comprehensive studies of DCs have been reported in only few IEI. Here we have reviewed biology of DCs in IEI classified according to recently published IUIS classification. We have reviewed DCs in selected IEI in each group category and discussed in depth changes in DCs where significant data are available regarding role of DCs in clinical and immunological manifestations. These include severe immunodeficiency diseases, antibody deficiencies, combined immunodeficiency with associated and syndromic features, especially disorders of synapse formation, and disorders of immune regulation.
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Affiliation(s)
- Sudhir Gupta
- Division of Basic and Clinical Immunology, University of California, Irvine, CA, United States
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18
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Suksawat Y, Pacharn P, Siripipattanamongkol N, Boonyawat B. Three novel homozygous ITGB2 mutations among two patients with leukocyte adhesion defect type-1: Two case reports. World J Clin Pediatr 2022; 11:429-436. [PMID: 36185095 PMCID: PMC9516493 DOI: 10.5409/wjcp.v11.i5.429] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/10/2022] [Accepted: 08/22/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND A leukocyte adhesion defect (LAD) is a rare primary immunodeficiency disorder. LAD type 1 (LAD-1) is the most common, which is caused by ITGB2 mutation resulting in dysfunction of β2 integrin, which impairs leukocyte adherence to the endothelium.
CASE SUMMARY The first two cases of LAD-1 in Thailand presented with recurrent omphalitis, soft tissue infection, marked leukocytosis, and neutrophilia. One patient experienced delayed umbilical cord separation. Mutation analysis was performed by direct DNA sequencing of the ITGB2 gene. The results revealed two novel homozygous missense mutations, c.920C>T (p.Leu307Pro) in exon 8 and c.758G>A (p.Arg253His) in exon 7, and one novel homozygous nonsense mutation, c.262C>T (p.Gln88Ter) in exon 4, in the genomic DNA of the first and second patients, respectively. Heterozygous mutations were identified in the parents of both patients, suggesting a carrier status. The patients were administered intravenous antibiotics for infections with good clinical responses. Hematopoietic stem cell transplantation could not be performed due to the unavailability of matched donors. However, a significant decline in infections was observed after antibiotic prophylaxis. Several follow-up visits were conducted for both patients. They are currently 6 years old.
CONCLUSION Molecular analysis is essential for definitive diagnosis, early treatment implementation, and prevention of LAD-1 in future pregnancy.
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Affiliation(s)
- Yiwa Suksawat
- Division of Allergy and Immunology, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, Bangkok 10400, Thailand
| | - Punchama Pacharn
- Division of Allergy and Immunology, Department of Pediatrics, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Nunthana Siripipattanamongkol
- Division of Allergy and Immunology, Department of Pediatrics, Chiangrai Prachanukroh Regional Hospital, Chiangrai 57000, Thailand
| | - Boonchai Boonyawat
- Division of Medical Genetics, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, Bangkok 10400, Thailand
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19
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Akar-Ghibril N. Defects of the Innate Immune System and Related Immune Deficiencies. Clin Rev Allergy Immunol 2022; 63:36-54. [PMID: 34417936 DOI: 10.1007/s12016-021-08885-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/30/2021] [Indexed: 01/12/2023]
Abstract
The innate immune system is the host's first line of defense against pathogens. Toll-like receptors (TLRs) are pattern recognition receptors that mediate recognition of pathogen-associated molecular patterns. TLRs also activate signaling transduction pathways involved in host defense, inflammation, development, and the production of inflammatory cytokines. Innate immunodeficiencies associated with defective TLR signaling include mutations in NEMO, IKBA, MyD88, and IRAK4. Other innate immune defects have been associated with susceptibility to herpes simplex encephalitis, viral infections, and mycobacterial disease, as well as chronic mucocutaneous candidiasis and epidermodysplasia verruciformis. Phagocytes and natural killer cells are essential members of the innate immune system and defects in number and/or function of these cells can lead to recurrent infections. Complement is another important part of the innate immune system. Complement deficiencies can lead to increased susceptibility to infections, autoimmunity, or impaired immune complex clearance. The innate immune system must work to quickly recognize and eliminate pathogens as well as coordinate an immune response and engage the adaptive immune system. Defects of the innate immune system can lead to failure to quickly identify pathogens and activate the immune response, resulting in susceptibility to severe or recurrent infections.
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Affiliation(s)
- Nicole Akar-Ghibril
- Division of Pediatric Immunology, Allergy, and Rheumatology, Joe DiMaggio Children's Hospital, 1311 N 35th Ave, Suite 220, 33021, Hollywood, FL, USA. .,Department of Pediatrics, Florida Atlantic University Charles E. Schmidt College of Medicine, Boca Raton, FL, USA.
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20
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Tahata S, Raymond K, Quade M, Barnes S, Boyer S, League S, Kumanovics A, Abraham R, Jacob E, Menon P, Morava E. Defining the mild variant of leukocyte adhesion deficiency type II (SLC35C1-congenital disorder of glycosylation) and response to l-fucose therapy: Insights from two new families and review of the literature. Am J Med Genet A 2022; 188:2005-2018. [PMID: 35338746 DOI: 10.1002/ajmg.a.62737] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 10/17/2021] [Accepted: 10/29/2021] [Indexed: 11/06/2022]
Abstract
Leukocyte adhesion deficiency type II (LAD II, also known as SLC35C1-congenital disorder of glycosylation) is an autosomal recessive disorder characterized by growth and cognitive impairment, peripheral neutrophilia, recurrent infections, and the Bombay blood phenotype. A subset of patients with a milder presentation has been described with short stature and developmental delay but minimal immune and hematologic features. Some patients with LAD II benefit from oral fucose therapy, though this has not been previously studied in patients with milder disease. In this study, we describe two new patients from separate families with the milder variant of LAD II and review the published literature on this rare disorder. We demonstrate improvement in speech and cognition, CD15 expression, and core fucosylation of serum glycoproteins after 27 months of oral fucose supplementation in one patient. These patients further support the stratification of this disorder into distinct subtypes, a classical severe and an attenuated variant, and provide preliminary evidence of benefit of fucose therapy in the latter group.
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Affiliation(s)
- Shawn Tahata
- Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA
| | - Kimiyo Raymond
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Marie Quade
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Sara Barnes
- Division of Transfusion Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Suzanne Boyer
- Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA
| | - Stacy League
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Attila Kumanovics
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Roshini Abraham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.,Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Eapen Jacob
- Division of Transfusion Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Prem Menon
- Asthma, Allergy, and Immunology Center, Baton Rouge, Louisiana, USA
| | - Eva Morava
- Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA
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21
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Adhikari E, Liu Q, Burton C, Mockabee-Macias A, Lester DK, Lau E. l-fucose, a sugary regulator of antitumor immunity and immunotherapies. Mol Carcinog 2022; 61:439-453. [PMID: 35107186 DOI: 10.1002/mc.23394] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/20/2022]
Abstract
l-fucose is a dietary sugar that is used by cells in a process called fucosylation to posttranslationally modify and regulate protein behavior and function. As fucosylation plays essential cellular functions in normal organ and immune developmental and homeostasis, it is perhaps not surprising that it has been found to be perturbed in a number of pathophysiological contexts, including cancer. Increasing studies over the years have highlighted key roles that altered fucosylation can play in cancer cell-intrinsic as well as paracrine signaling and interactions. In particular, studies have demonstrated that fucosylation impact tumor:immunological interactions and significantly enhance or attenuate antitumor immunity. Importantly, fucosylation appears to be a posttranslational modification that can be therapeutically targeted, as manipulating the molecular underpinnings of fucosylation has been shown to be sufficient to impair or block tumor progression and to modulate antitumor immunity. Moreover, the fucosylation of anticancer agents, such as therapeutic antibodies, has been shown to critically impact their efficacy. In this review, we summarize the underappreciated roles that fucosylation plays in cancer and immune cells, as well as the fucosylation of therapeutic antibodies or the manipulation of fucosylation and their implications as new therapeutic modalities for cancer.
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Affiliation(s)
- Emma Adhikari
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Qian Liu
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Chase Burton
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Immunology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Andrea Mockabee-Macias
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Daniel K Lester
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Eric Lau
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
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22
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Gonzalez C. Pediatric immune deficiencies: current treatment approaches. Curr Opin Pediatr 2022; 34:61-70. [PMID: 34907131 DOI: 10.1097/mop.0000000000001092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE OF REVIEW To summarize the currently available definitive therapies for patients with inborn errors of immunity (IEIs) with a strong focus on recent advances in allogeneic hematopoietic cell transplantation (HCT) and gene therapy, including the use of alternative donors, graft manipulation techniques, less toxic approaches for pretransplant conditioning and gene transfer using autologous hematopoietic stem cells. RECENT FINDINGS In the absence of a matched sibling or a matched related donor, therapeutic alternatives for patients with IEIs include alternative donor transplantation or autologous gene therapy, which is only available for selected IEIs. In recent years, several groups have published their experience with haploidentical hematopoietic cell transplantation (HHCT) using different T-cell depletion strategies. Overall survival and event free survival results, although variable among centers, are encouraging. Preliminary results from autologous gene therapy trials with safer vectors and low-dose busulfan conditioning have shown reproducible and successful results. Both strategies have become valid therapeutic options for patients with IEIs. A new promising and less toxic conditioning regimen strategy is also discussed. SUMMARY Definitive therapies for IEIs with HCT and gene therapy are in stage of evolution, not only to refine their efficacy and safety but also their reach to a larger number of patients.
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Affiliation(s)
- Corina Gonzalez
- Immune Deficiency Cellular Therapy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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23
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Reynolds S, Devlia D, Stearns R, Cole T. Should all infants with delayed umbilical cord separation be investigated for leucocyte adhesion deficiency? Arch Dis Child 2021; 106:1233-1236. [PMID: 34598939 DOI: 10.1136/archdischild-2020-321313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 09/08/2021] [Indexed: 11/03/2022]
Affiliation(s)
- Sarah Reynolds
- Neonatal Unit, John Radcliffe Hospital, Oxford, Oxfordshire, UK .,Home, Windsor, UK
| | - Devika Devlia
- Department of Paediatrics, Wexham Park Hospital, Slough, UK
| | | | - Theresa Cole
- Allergy and Immunology Department, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia
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24
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Park JH, Marquardt T. Treatment Options in Congenital Disorders of Glycosylation. Front Genet 2021; 12:735348. [PMID: 34567084 PMCID: PMC8461064 DOI: 10.3389/fgene.2021.735348] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/23/2021] [Indexed: 12/15/2022] Open
Abstract
Despite advances in the identification and diagnosis of congenital disorders of glycosylation (CDG), treatment options remain limited and are often constrained to symptomatic management of disease manifestations. However, recent years have seen significant advances in treatment and novel therapies aimed both at the causative defect and secondary disease manifestations have been transferred from bench to bedside. In this review, we aim to give a detailed overview of the available therapies and rising concepts to treat these ultra-rare diseases.
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Affiliation(s)
- Julien H Park
- Department of General Pediatrics, Metabolic Diseases, University Children's Hospital Münster, Münster, Germany
| | - Thorsten Marquardt
- Department of General Pediatrics, Metabolic Diseases, University Children's Hospital Münster, Münster, Germany
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25
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Donadieu J, Frenz S, Merz L, Sicre De Fontbrune F, Rotulo GA, Beaupain B, Biosse-Duplan M, Audrain M, Croisille L, Ancliff P, Klein C, Bellanné-Chantelot C. Chronic neutropenia: how best to assess severity and approach management? Expert Rev Hematol 2021; 14:945-960. [PMID: 34486458 DOI: 10.1080/17474086.2021.1976634] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Neutropenia is a relatively common finding in medical practice and the medical approach requires a gradual and pertinent diagnostic procedure as well as adapted management. AREAS COVERED The area of chronic neutropenia remains fragmented between diverse diseases or situations. Here physicians involved in different aspects of chronic neutropenia gather both the data from medical literature till the end of May 2021 and their experience to offer a global approach for the diagnosis of chronic neutropenia as well as their medical care. EXPERT OPINION In most cases, the neutropenia is transient, frequently related to a viral infection, and not harmful. However, neutropenia can be chronic (i.e. >3 months) and related to a number of etiologies, some clinically benign, such as so-called 'ethnic' neutropenia. Autoimmune neutropenia is the common form in young children, whereas idiopathic/immune neutropenia is a frequent etiology in young females. Inherited neutropenia (or congenital neutropenia) is exceptional, with approximately 30 new cases per 106 births and 30 known subtypes. Such patients have a high risk of invasive bacterial infections, and oral infections. Supportive therapy, which is primarily based on daily administration of an antibiotic prophylaxis and/or treatment with granulocyte-colony stimulating factor (G-CSF), contributes to avoiding recurrent infections.
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Affiliation(s)
- Jean Donadieu
- Centre De Référence Des Neutropénies Chroniques, Registre National Des Neutropénies Congénitales, Service d'Hémato-oncologie Pédiatrique, Hôpital Armand Trousseau Aphp, Paris, France
| | - Stephanie Frenz
- Dr. Von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Lauren Merz
- Brigham and Women's Hospital, Department of Internal Medicine, Boston, MA, USA
| | | | - Gioacchino Andrea Rotulo
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (Dinogmi), University of Genoa, Italy
| | - Blandine Beaupain
- Centre De Référence Des Neutropénies Chroniques, Registre National Des Neutropénies Congénitales, Service d'Hémato-oncologie Pédiatrique, Hôpital Armand Trousseau Aphp, Paris, France
| | | | - Marie Audrain
- Service d'Immunologie Laboratoire De Biologie Chu De Nantes 9 Quai Moncousu
| | | | - Phil Ancliff
- Pediatric Hematology, Great Ormond Street Hospital London, UK
| | - Christoph Klein
- Dr. Von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
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26
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Rotulo GA, Plat G, Beaupain B, Blanche S, Moushous D, Sicre de Fontbrune F, Leblanc T, Renard C, Barlogis V, Vigue MG, Freycon C, Piguet C, Pasquet M, Fieschi C, Abou-Chahla W, Gandemer V, Rialland F, Millot F, Marie-Cardine A, Paillard C, Levy P, Aladjidi N, Biosse-Duplan M, Bellanné-Chantelot C, Donadieu J. Recurrent bacterial infections, but not fungal infections, characterise patients with ELANE-related neutropenia: a French Severe Chronic Neutropenia Registry study. Br J Haematol 2021; 194:908-920. [PMID: 34340247 DOI: 10.1111/bjh.17695] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/21/2021] [Indexed: 11/29/2022]
Abstract
Among 143 patients with elastase, neutrophil-expressed (ELANE)-related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte-colony stimulating factor (G-CSF), on G-CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem-cell transplantation. During the disease's natural history period (without G-CSF; 1913 person-years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37·4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (<200/mm3 ), high lymphocyte count (>3000/mm3 ) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G-CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism.
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Affiliation(s)
- Gioacchino A Rotulo
- Registre des Neutropénies Chroniques, Centre de Référence des Neutropénies Chroniques, Hôpital Trousseau, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.,Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy
| | - Geneviève Plat
- Hématologie Oncologie et Immunologie Pédiatrique, Hôpital des Enfants, Toulouse, France
| | - Blandine Beaupain
- Registre des Neutropénies Chroniques, Centre de Référence des Neutropénies Chroniques, Hôpital Trousseau, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Stéphane Blanche
- APHP, UIHR CEREDIH, Hôpital Necker-Enfants Malade, Paris, France
| | - Despina Moushous
- APHP, UIHR CEREDIH, Hôpital Necker-Enfants Malade, Paris, France
| | | | - Thierry Leblanc
- Department of Pediatric Hematology and Immunology, Hôpital Robert-Debré, APHP, Paris, France
| | - Cécile Renard
- Service de Pédiatrie, Institut d'Hématologie et Oncologie Pédiatrique, Centre Hospitalier Universitaire (CHU) de Lyon, Lyon, France
| | - Vincent Barlogis
- Department of Pediatric Hematology, Timone Hospital, Assistance Publique-Hôpitaux de Marseille, Marseille, France
| | - Marie-Gabrielle Vigue
- Pediatrics, Infectiology, Rhumatology, Hôpital Arnaud-de-Villeneuve, CHRU de Montpellier, Montpellier, France
| | - Claire Freycon
- Service d'Onco-Hématologie Pédiatrique, CHU de Grenoble, Grenoble, France
| | - Christophe Piguet
- Service d'Hémato-Oncologie Pédiatrie, CHU de Limoges, Limoges, France
| | - Marlène Pasquet
- Hématologie Oncologie et Immunologie Pédiatrique, Hôpital des Enfants, Toulouse, France
| | - Claire Fieschi
- Department of Clinical Immunology, Saint-Louis Hospital, APHP, Paris, France
| | - Wadih Abou-Chahla
- Department of Pediatric Hematology, Jeanne-de-Flandre Hospital, CHU de Lille, Lille, France
| | - Virginie Gandemer
- Service d'Hémato-Oncologie Pédiatrique, CHU de Rennes, Rennes, France
| | - Fanny Rialland
- Service d'Oncologie Pédiatrique, CHU de Nantes, Nantes, France
| | - Frédéric Millot
- Service d'Hémato-Oncologie Pédiatrique, CHU de Poitiers, Poitiers, France
| | | | - Catherine Paillard
- Service d'Hématologie Oncologie Pédiatrique, CHU de Strasbourg, Strasbourg, France
| | - Pacifique Levy
- Département de Génétique, DMU BioGeM, CHU Pitié-Salpêtrière, APHP, Sorbonne Université, Paris, France
| | - Nathalie Aladjidi
- Service d'Hémato-Oncologie Pédiatrique, CHU de Bordeaux, Bordeaux, France
| | | | | | - Jean Donadieu
- Registre des Neutropénies Chroniques, Centre de Référence des Neutropénies Chroniques, Hôpital Trousseau, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
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Yaz I, Ozbek B, Bildik HN, Tan C, Oskay Halacli S, Soyak Aytekin E, Esenboga S, Cekic S, Kilic SS, Keskin O, van Leeuwen K, Roos D, Cagdas D, Tezcan I. Clinical and laboratory findings in patients with leukocyte adhesion deficiency type I: A multicenter study in Turkey. Clin Exp Immunol 2021; 206:47-55. [PMID: 34310689 DOI: 10.1111/cei.13645] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 07/16/2021] [Accepted: 07/18/2021] [Indexed: 12/27/2022] Open
Abstract
Leukocyte adhesion deficiency type I is a rare primary immunodeficiency disorder characterized by mutations in the ITGB2 gene encoding CD18. We present clinical and immunological features of 15 patients with leukocyte adhesion deficiency type 1 (LAD-1). Targeted next-generation sequencing was performed with either a primary immunodeficiency gene panel comprising 266 genes or a small LAD-panel consisting of five genes for genetic analysis. To measure the expression level of integrins on the leukocyte surface, flow cytometry analysis was performed. The median age of the patients at diagnosis was 3 (1-48) months. Eleven (73%) of the 15 patients had a LAD-1 diagnosis in their first 6 months and 14 (93%) patients had consanguineous parents. Delayed separation of the umbilical cord was present in 80% (n = 12) of the patients in our cohort, whereas omphalitis was observed in 53% (n = 8) of the patients. Leukocytosis with neutrophil predominance was observed in 73% (n = 11) patients. Nine distinct variants in the ITGB2 gene in 13 of the 15 patients with LAD-1 were characterized, two of which (c.305_306delAA and c.779_786dup) are novel homozygous mutations of ITGB2. Four unrelated patients from Syria had a novel c.305_306delAA mutation that might be a founder effect for patients of Syrian origin. Four (27%) patients underwent hematopoietic stem cell transplantation. Two patients died because of HSCT complications and the other two are alive and well. Early differential diagnosis of the patients is critical in the management of the disease and genetic evaluation provides a basis for family studies and genetic counseling.
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Affiliation(s)
- Ismail Yaz
- Division of Pediatric Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Turkey
| | - Begum Ozbek
- Division of Pediatric Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Turkey
| | - Hacer Neslihan Bildik
- Division of Pediatric Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Turkey
| | - Cagman Tan
- Division of Pediatric Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Turkey
| | - Sevil Oskay Halacli
- Division of Pediatric Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Turkey
| | - Elif Soyak Aytekin
- Division of Pediatric Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Turkey
| | - Saliha Esenboga
- Division of Pediatric Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Turkey
| | - Sukru Cekic
- Department of Pediatrics, Uludag University Medical School, Bursa, Turkey
| | - Sara Sebnem Kilic
- Department of Pediatrics, Uludag University Medical School, Bursa, Turkey
| | - Ozlem Keskin
- Department of Pediatric Immunology and Allergy, Gaziantep University Medical School, Gaziantep, Turkey
| | - Karin van Leeuwen
- Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Dirk Roos
- Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Deniz Cagdas
- Division of Pediatric Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Turkey
| | - Ilhan Tezcan
- Division of Pediatric Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Turkey
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Pyoderma Gangrenosum with an Underlying Leukocyte Adhesion Deficiency Type 1 (LAD-1) and Pregnancy in the Shade of COVID-19 Epidemic: A Patient and Physician Experience. Dermatol Ther (Heidelb) 2021; 11:643-653. [PMID: 33686591 PMCID: PMC7939102 DOI: 10.1007/s13555-021-00507-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Indexed: 11/06/2022] Open
Abstract
In the first part of this article, the anonymous patient diagnosed with leukocyte adhesion deficiency type 1 (LAD-1) and pyoderma gangrenosum (PG) discusses her experience of her medical history and treatment in a foreign country during her pregnancy and the coronavirus disease-19 (COVID-19) pandemic. The patient’s dermatologists, immunologist, and diagnostician refer to the epidemiology, genetics, diagnosis, morphologic manifestations, including skin lesions, treatment, and prognosis in LAD-1. The patient’s diagnostic and therapeutic process was discussed in the last part of this paper.
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29
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Papa R, Penco F, Volpi S, Gattorno M. Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation. Front Immunol 2021. [PMID: 33488606 DOI: 10.3389/fimmu.2020.604206)] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
A growing number of monogenic immune-mediated diseases have been related to genes involved in pathways of actin cytoskeleton remodeling. Increasing evidences associate cytoskeleton defects to autoinflammatory diseases and primary immunodeficiencies. We reviewed the pathways of actin cytoskeleton remodeling in order to identify inflammatory and immunological manifestations associated to pathological variants. We list more than twenty monogenic diseases, ranging from pure autoinflammatory conditions as familial Mediterranean fever, mevalonate kinase deficiency and PAPA syndrome, to classic and novel primary immunodeficiencies as Wiskott-Aldrich syndrome and DOCK8 deficiency, characterized by the presence of concomitant inflammatory and autoimmune manifestations, such as vasculitis and cytopenia, to severe and recurrent infections. We classify these disorders according to the role of the mutant gene in actin cytoskeleton remodeling, and in particular as disorders of transcription, elongation, branching and activation of actin. This expanding field of rare immune disorders offers a new perspective to all immunologists to better understand the physiological and pathological role of actin cytoskeleton in cells of innate and adaptive immunity.
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Affiliation(s)
- Riccardo Papa
- Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Federica Penco
- Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Stefano Volpi
- Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Marco Gattorno
- Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genoa, Italy
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30
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Papa R, Penco F, Volpi S, Gattorno M. Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation. Front Immunol 2021; 11:604206. [PMID: 33488606 PMCID: PMC7817698 DOI: 10.3389/fimmu.2020.604206] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/19/2020] [Indexed: 12/12/2022] Open
Abstract
A growing number of monogenic immune-mediated diseases have been related to genes involved in pathways of actin cytoskeleton remodeling. Increasing evidences associate cytoskeleton defects to autoinflammatory diseases and primary immunodeficiencies. We reviewed the pathways of actin cytoskeleton remodeling in order to identify inflammatory and immunological manifestations associated to pathological variants. We list more than twenty monogenic diseases, ranging from pure autoinflammatory conditions as familial Mediterranean fever, mevalonate kinase deficiency and PAPA syndrome, to classic and novel primary immunodeficiencies as Wiskott-Aldrich syndrome and DOCK8 deficiency, characterized by the presence of concomitant inflammatory and autoimmune manifestations, such as vasculitis and cytopenia, to severe and recurrent infections. We classify these disorders according to the role of the mutant gene in actin cytoskeleton remodeling, and in particular as disorders of transcription, elongation, branching and activation of actin. This expanding field of rare immune disorders offers a new perspective to all immunologists to better understand the physiological and pathological role of actin cytoskeleton in cells of innate and adaptive immunity.
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Affiliation(s)
- Riccardo Papa
- Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Federica Penco
- Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Stefano Volpi
- Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Marco Gattorno
- Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genoa, Italy
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31
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Yahya AM, AlMulla AA, AlRufaye HJ, Al Dhaheri A, Elomami AS, Al-Hammadi S, Kailas L, Vijayan R, Souid AK. Case Report: A Case of Leukocyte Adhesion Deficiency, Type III Presenting With Impaired Platelet Function, Lymphocytosis and Granulocytosis. Front Pediatr 2021; 9:713921. [PMID: 34485203 PMCID: PMC8415448 DOI: 10.3389/fped.2021.713921] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/19/2021] [Indexed: 11/13/2022] Open
Abstract
Fermitin family homolog 3 (FERMT3), alternatively kindlin-3 (KIND3), is an integrin binding protein (of 667 residues) encoded by the FERMT3 gene. The molecule is essential for activating integrin αIIbβ3 (the fibrinogen receptor) on platelets and for the integrin-mediated hematopoietic cell (including platelets, T lymphocytes, B lymphocytes, and granulocytes) adhesion. Its defects are associated with impaired primary hemostasis, described as "Glanzmann's thrombasthenia (MIM#273800)-like bleeding problem." The defects are also associated with infections, designated as "LAD1 (leukocyte adhesion deficiency, type I; MIM#116920)-like immune deficiency." The entity that joins the impaired primary hemostasis with the leukocyte malfunction has been termed "leukocyte adhesion deficiency, type III" (LAD3, autosomal recessive, MIM#612840), representing a defective activation of the integrins β1, β2, and β3 on leukocytes and platelets. Here, we report a male toddler with novel compound heterozygous variants, NM_178443.2(FERMT3):c.1800G>A, p.Trp600* (a non-sense variant) and NM_178443.2(FERMT3):c.2001del p.*668Glufs*106 (a non-stop variant). His umbilical cord separated at about 3 weeks of age. A skin rash (mainly petechiae and purpura) and recurrent episodes of severe epistaxis required blood transfusions in early infancy. His hemostatic work-up was remarkable for a normal platelet count, but abnormal platelet function screen with markedly prolonged collagen-epinephrine and collagen-ADP closure times. The impaired platelet function was associated with reduced platelet aggregation with all agonists. The expression of platelet receptors was normal. Other remarkable findings were persistent lymphocytosis and granulocytosis, representing defects in diapedesis due to the integrin dysfunction. The natural history of his condition, structure and sequence analysis of the variations, and comparison with other LAD3 cases reported in the literature are presented.
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Affiliation(s)
- Amal M Yahya
- Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates
| | - Asia A AlMulla
- Department of Hematology-Oncology, Tawam Hospital, Al Ain, United Arab Emirates
| | - Haydar J AlRufaye
- Department of Hematology-Oncology, Tawam Hospital, Al Ain, United Arab Emirates
| | - Ahmed Al Dhaheri
- Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates
| | | | - Suleiman Al-Hammadi
- College of Medicine, Mohamed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates.,Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Lalitha Kailas
- Department of Pediatrics, Sree Gokulam Medical College, Thiruvananthapuram, India
| | - Ranjit Vijayan
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Abdul-Kader Souid
- Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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32
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Kambli PM, Bargir UA, Yadav RM, Gupta MR, Dalvi AD, Hule G, Kelkar M, Sawant-Desai S, Setia P, Jodhawat N, Nambiar N, Dhawale A, Gaikwad P, Shinde S, Taur P, Gowri V, Pandrowala A, Gupta A, Joshi V, Sharma M, Arora K, Pilania RK, Chaudhary H, Agarwal A, Katiyar S, Bhattad S, Ramprakash S, Cp R, Jayaram A, Gornale V, Raj R, Uppuluri R, Sivasankaran M, Munirathnam D, Lashkari HP, Kalra M, Sachdeva A, Sharma A, Balaji S, Govindraj GM, Karande S, Nanavati R, Manglani M, Subramanyam G, Sampagar A, Ck I, Gutha P, Kanakia S, Mundada SP, Krishna V, Nampoothiri S, Nemani S, Rawat A, Desai M, Madkaikar M. Clinical and Genetic Spectrum of a Large Cohort of Patients With Leukocyte Adhesion Deficiency Type 1 and 3: A Multicentric Study From India. Front Immunol 2020; 11:612703. [PMID: 33391282 PMCID: PMC7772426 DOI: 10.3389/fimmu.2020.612703] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 11/09/2020] [Indexed: 12/11/2022] Open
Abstract
Leukocyte adhesion deficiency (LAD) syndrome is a group of inborn errors of immunity characterized by a defect in the cascade of the activation and adhesion leading to the failure of leukocyte to migrate to the site of tissue injury. Three different types of LAD have been described. The most common subtype is LAD type 1 (LAD1) caused due to defects in the ITGβ2 gene. LAD type 2 (LAD2) is caused by mutations in the SLC35C1 gene leading to a generalized loss of expression of fucosylated glycans on the cell surface and LAD type 3 (LAD3) is caused by mutations in the FERMT3 gene resulting in platelet function defects along with immunodeficiency. There is a paucity of data available from India on LAD syndromes. The present study is a retrospective analysis of patients with LAD collated from 28 different centers across India. For LAD1, the diagnosis was based on clinical features and flow cytometric expression of CD18 on peripheral blood leukocytes and molecular confirmation by Sanger sequencing. For patients with LAD3 diagnosis was largely based on clinical manifestations and identification of the pathogenic mutation in the FERMT3 gene by next-generation Sequencing. Of the total 132 cases diagnosed with LAD, 127 were LAD1 and 5 were LAD3. The majority of our patients (83%) had CD18 expression less than 2% on neutrophils (LAD1°) and presented within the first three months of life with omphalitis, skin and soft tissue infections, delayed umbilical cord detachment, otitis media, and sepsis. The patients with CD18 expression of more than 30% (LAD1+) presented later in life with skin ulcers being the commonest manifestation. Bleeding manifestations were common in patients with LAD3. Persistent neutrophilic leukocytosis was the characteristic finding in all patients. 35 novel mutations were detected in the ITGβ2 gene, and 4 novel mutations were detected in the FERMT3 gene. The study thus presents one of the largest cohorts of patients from India with LAD, focusing on clinical features, immunological characteristics, and molecular spectrum.
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Affiliation(s)
- Priyanka Madhav Kambli
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Umair Ahmed Bargir
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Reetika Malik Yadav
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Maya Ravishankar Gupta
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Aparna Dhondi Dalvi
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Gouri Hule
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Madhura Kelkar
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Sneha Sawant-Desai
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Priyanka Setia
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Neha Jodhawat
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Nayana Nambiar
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Amruta Dhawale
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Pallavi Gaikwad
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Shweta Shinde
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
| | - Prasad Taur
- Department of Immunology, Bai Jerbai Wadia Hospital for Children, Mumbai, India
| | - Vijaya Gowri
- Department of Immunology, Bai Jerbai Wadia Hospital for Children, Mumbai, India
| | - Ambreen Pandrowala
- Department of Bone Marrow Transplant, Bai Jerbai Wadia Hospital for Children, Mumbai, India
| | - Anju Gupta
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Vibhu Joshi
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Madhubala Sharma
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Kanika Arora
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Rakesh Kumar Pilania
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Himanshi Chaudhary
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Amita Agarwal
- Department of Clinical Immunology & Rheumatology, Sanjay Gandhi Postgraduate Institute, Lucknow, India
| | - Shobita Katiyar
- Department of Clinical Immunology & Rheumatology, Sanjay Gandhi Postgraduate Institute, Lucknow, India
| | - Sagar Bhattad
- Department of Pediatric Immunology and Rheumatology, Aster CMI Hospital, Bengaluru, India
| | - Stalin Ramprakash
- Pediatric Hemat-Oncology and Bone Marrow Transplant Unit, Aster CMI Hospital, Bengaluru, India
| | - Raghuram Cp
- Pediatric Hemat-Oncology and Bone Marrow Transplant Unit, Aster CMI Hospital, Bengaluru, India
| | - Ananthvikas Jayaram
- Department of Hematology and Pathology, Neuberg Anand Diagnostic and Research Centre, Bangalore, India
| | - Vinod Gornale
- Department of pediatric, Indira Gandhi Institute of Child Health, Bangalore, India
| | - Revathi Raj
- Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Teynampet, India
| | - Ramya Uppuluri
- Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Teynampet, India
| | - Meena Sivasankaran
- Department of Pediatric, Hemato-oncology, Kanchi Kamakoti Childs Trust Hospital, Chennai, India
| | | | - Harsha Prasad Lashkari
- Department of Paediatrics, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India
| | - Manas Kalra
- Department of Pediatric Hematology Oncology BMT, Sir Ganga Ram Hospital, New Delhi, India
| | - Anupam Sachdeva
- Department of Pediatric Hematology Oncology BMT, Sir Ganga Ram Hospital, New Delhi, India
| | - Avinash Sharma
- Dr. Rajendra Prasad Government Medical College, Tanda, India
| | - Sarath Balaji
- Department of Paediatrics, Institute of Child Health and Hospital for Children, Chennai, India
| | | | - Sunil Karande
- Department of Pediatrics, King Edward Memorial Hospital, Mumbai, India
| | - Ruchi Nanavati
- Department of Neonatology, King Edward Memorial Hospital, Mumbai, India
| | - Mamta Manglani
- Department of Pediatric, Oncology, Hematology & BMT, Comprehensive Thalassemia Care Center and Bone Marrow, Mumbai, India
| | | | - Abhilasha Sampagar
- Department of Pediatrics, KIES Dr. Prabhakar Kore Hospital & Medical Research, Belgaum, India
| | - Indumathi Ck
- Department of Pediatrics, St. John's Medical College, Bengaluru, India
| | - Parinitha Gutha
- Department of Paediatric Haematology and Oncology, Little Stars Children's Hospital, Hyderabad, India
| | - Swati Kanakia
- Department of Hematology-Oncology, Lilavati Hospital and Research Centre, Mumbai, India
| | | | - Vidya Krishna
- Department of Pediatrics, Sri Ramachandra Medical College, Chennai, India
| | - Sheela Nampoothiri
- Department of Pediatric Genetics, Amrita Institute of Medical Science & Research Center, Cochin, India
| | - Sandeep Nemani
- Nihira Diagnostic Lab, Arihant Galaxy, Ganesh Naga, Sangli, India
| | - Amit Rawat
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Mukesh Desai
- Department of Immunology, Bai Jerbai Wadia Hospital for Children, Mumbai, India
| | - Manisha Madkaikar
- Center of Excellence for PIDs, Department of Pediatric Immunology and Leukocyte Biology, Indian Council of Medical Research- National Institute of Immunohaematology, Mumbai, India
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Kolev M, West EE, Kunz N, Chauss D, Moseman EA, Rahman J, Freiwald T, Balmer ML, Lötscher J, Dimeloe S, Rosser EC, Wedderburn LR, Mayer-Barber KD, Bohrer A, Lavender P, Cope A, Wang L, Kaplan MJ, Moutsopoulos NM, McGavern D, Holland SM, Hess C, Kazemian M, Afzali B, Kemper C. Diapedesis-Induced Integrin Signaling via LFA-1 Facilitates Tissue Immunity by Inducing Intrinsic Complement C3 Expression in Immune Cells. Immunity 2020; 52:513-527.e8. [PMID: 32187519 PMCID: PMC7111494 DOI: 10.1016/j.immuni.2020.02.006] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 12/30/2019] [Accepted: 02/19/2020] [Indexed: 12/12/2022]
Abstract
Intrinsic complement C3 activity is integral to human T helper type 1 (Th1) and cytotoxic T cell responses. Increased or decreased intracellular C3 results in autoimmunity and infections, respectively. The mechanisms regulating intracellular C3 expression remain undefined. We identified complement, including C3, as among the most significantly enriched biological pathway in tissue-occupying cells. We generated C3-reporter mice and confirmed that C3 expression was a defining feature of tissue-immune cells, including T cells and monocytes, occurred during transendothelial diapedesis, and depended on integrin lymphocyte-function-associated antigen 1 (LFA-1) signals. Immune cells from patients with leukocyte adhesion deficiency type 1 (LAD-1) had reduced C3 transcripts and diminished effector activities, which could be rescued proportionally by intracellular C3 provision. Conversely, increased C3 expression by T cells from arthritis patients correlated with disease severity. Our study defines integrins as key controllers of intracellular complement, demonstrates that perturbations in the LFA-1-C3-axis contribute to primary immunodeficiency, and identifies intracellular C3 as biomarker of severity in autoimmunity.
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Affiliation(s)
- Martin Kolev
- Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Erin E West
- Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Natalia Kunz
- Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Daniel Chauss
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD 20892, USA
| | - E Ashley Moseman
- Viral Immunology & Intravital Imaging Section, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD 20892, USA
| | - Jubayer Rahman
- Viral Immunology & Intravital Imaging Section, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD 20892, USA
| | - Tilo Freiwald
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD 20892, USA
| | - Maria L Balmer
- Department of Biomedicine, Immunobiology, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Jonas Lötscher
- Department of Biomedicine, Immunobiology, University Hospital and University of Basel, Basel 4031, Switzerland
| | - Sarah Dimeloe
- Department of Biomedicine, Immunobiology, University Hospital and University of Basel, Basel 4031, Switzerland; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Elizabeth C Rosser
- Infection, Immunity, Inflammation Programme, University College London (UCL) Great Ormond Street Institute of Child Health, London WC1N 1EH, UK; Arthritis Research UK Centre for Adolescent Rheumatology at UCL, UCHL and GOSH, London WC1N 1EH, UK
| | - Lucy R Wedderburn
- Infection, Immunity, Inflammation Programme, University College London (UCL) Great Ormond Street Institute of Child Health, London WC1N 1EH, UK; Arthritis Research UK Centre for Adolescent Rheumatology at UCL, UCHL and GOSH, London WC1N 1EH, UK; National Institute for Health Research (NIHR) Biomedical Research Centre at Great Ormond Street NHS Foundation Trust, London WC1N 1EH, UK
| | - Katrin D Mayer-Barber
- Inflammation and Innate Immunity Unit, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
| | - Andrea Bohrer
- Inflammation and Innate Immunity Unit, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
| | - Paul Lavender
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 9RT, UK
| | - Andrew Cope
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 9RT, UK
| | - Luopin Wang
- Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN 47907, USA
| | - Mariana J Kaplan
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS), NIH, Bethesda, MD 20892, USA
| | - Niki M Moutsopoulos
- Oral Immunity and Inflammation Unit, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, MD 20892, USA
| | - Dorian McGavern
- Viral Immunology & Intravital Imaging Section, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD 20892, USA
| | - Steven M Holland
- Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA
| | - Christoph Hess
- Department of Biomedicine, Immunobiology, University Hospital and University of Basel, Basel 4031, Switzerland; Department of Medicine, University of Cambridge, Cambridge CB2 0AW, UK
| | - Majid Kazemian
- Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN 47907, USA.
| | - Behdad Afzali
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD 20892, USA.
| | - Claudia Kemper
- Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 9RT, UK; Institute for Systemic Inflammation Research, University of Lübeck, Lübeck 23562, Germany.
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Essa MF, Elbashir E, Alroqi F, Mohammed R, Alsultan A. Successful hematopoietic stem cell transplant in leukocyte adhesion deficiency type III presenting primarily as malignant infantile osteopetrosis. Clin Immunol 2020; 213:108365. [PMID: 32092470 DOI: 10.1016/j.clim.2020.108365] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 01/24/2020] [Accepted: 02/19/2020] [Indexed: 12/16/2022]
Abstract
Leukocyte adhesion deficiency type III (LAD-III) is caused by mutations in FERMT3 that encodes Kindlin-3 which regulates integrins activation. LAD-III predisposes to infections and bleeding. Osteopetrosis was reported in some cases. We report three patients who presented as malignant infantile osteopetrosis. One had recurrent infections and none had bleeding. Exome sequencing revealed a novel homozygous mutation in FERMT3 c.1555C > T (p.Gln519Ter). Two patients underwent successful hematopoietic stem cell transplant (HSCT) from matched siblings with resolution of osteopetrosis. The third patient died secondary to sepsis prior to HSCT. Our results support early HSCT in LAD-III prior to the occurrence of life-threatening complications.
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Affiliation(s)
- Mohammed F Essa
- Department of Pediatric Hematology/Oncology, King Abdullah Specialist Children's Hospital, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia; College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, National Guard Health Affairs, Riyadh, Saudi Arabia.
| | - Enas Elbashir
- Department of Pediatric Hematology/Oncology, King Abdullah Specialist Children's Hospital, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Fayhan Alroqi
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, National Guard Health Affairs, Riyadh, Saudi Arabia; Department of Pediatrics, King Abdullah Specialist Children's Hospital, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Reem Mohammed
- Section of Pediatric Immunology, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Abdulrahman Alsultan
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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35
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Bednarczyk M, Stege H, Grabbe S, Bros M. β2 Integrins-Multi-Functional Leukocyte Receptors in Health and Disease. Int J Mol Sci 2020; 21:E1402. [PMID: 32092981 PMCID: PMC7073085 DOI: 10.3390/ijms21041402] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/11/2020] [Accepted: 02/14/2020] [Indexed: 12/25/2022] Open
Abstract
β2 integrins are heterodimeric surface receptors composed of a variable α (CD11a-CD11d) and a constant β (CD18) subunit and are specifically expressed by leukocytes. The α subunit defines the individual functional properties of the corresponding β2 integrin, but all β2 integrins show functional overlap. They mediate adhesion to other cells and to components of the extracellular matrix (ECM), orchestrate uptake of extracellular material like complement-opsonized pathogens, control cytoskeletal organization, and modulate cell signaling. This review aims to delineate the tremendous role of β2 integrins for immune functions as exemplified by the phenotype of LAD-I (leukocyte adhesion deficiency 1) patients that suffer from strong recurrent infections. These immune defects have been largely attributed to impaired migratory and phagocytic properties of polymorphonuclear granulocytes. The molecular base for this inherited disease is a functional impairment of β2 integrins due to mutations within the CD18 gene. LAD-I patients are also predisposed for autoimmune diseases. In agreement, polymorphisms within the CD11b gene have been associated with autoimmunity. Consequently, β2 integrins have received growing interest as targets in the treatment of autoimmune diseases. Moreover, β2 integrin activity on leukocytes has been implicated in tumor development.
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Affiliation(s)
| | | | | | - Matthias Bros
- Department of Dermatology, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (H.S.); (S.G.)
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Jin F, Wang F. The physiological and pathological roles and applications of sialyl Lewis x, a common carbohydrate ligand of the three selectins. Glycoconj J 2020; 37:277-291. [DOI: 10.1007/s10719-020-09912-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 12/20/2019] [Accepted: 01/29/2020] [Indexed: 12/31/2022]
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Manukjan G, Wiegering VA, Reindl T, Strauß G, Klopocki E, Schulze H, Andres O. Novel variants in FERMT3 and RASGRP2-Genetic linkage in Glanzmann-like bleeding disorders. Pediatr Blood Cancer 2020; 67:e28078. [PMID: 31724816 DOI: 10.1002/pbc.28078] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 10/22/2019] [Accepted: 10/25/2019] [Indexed: 11/07/2022]
Abstract
Defects of platelet intracellular signaling can result in severe platelet dysfunction. Several mutations in each of the linked genes FERMT3 and RASGRP2 on chromosome 11 causing a Glanzmann-like bleeding phenotype have been identified so far. We report on novel variants in two unrelated pediatric patients with severe bleeding diathesis-one with leukocyte adhesion deficiency type III due to a homozygous frameshift in FERMT3 and the other with homozygous variants in both, FERMT3 and RASGRP2. We focus on the challenging genetic and functional variant assessment and aim to accentuate the risk of obtaining misleading results due to the phenomenon of genetic linkage.
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Affiliation(s)
- Georgi Manukjan
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | | | - Tobias Reindl
- Department for Pediatric Hematology and Oncology, Charité-University Medicine Berlin, Berlin, Germany
| | - Gabriele Strauß
- Department for Pediatric Hematology and Oncology, Charité-University Medicine Berlin, Berlin, Germany.,Department for Pediatric Oncology and Hematology, HELIOS Klinikum Berlin-Buch, Berlin, Germany
| | - Eva Klopocki
- Institute of Human Genetics, University of Würzburg, Würzburg, Germany
| | - Harald Schulze
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.,Centre of Inherited Blood Cell Disorders, University Hospital Würzburg, Würzburg, Germany
| | - Oliver Andres
- Department of Pediatrics, University of Würzburg, Würzburg, Germany.,Centre of Inherited Blood Cell Disorders, University Hospital Würzburg, Würzburg, Germany
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38
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Leukocyte adhesion defect: Where do we stand circa 2019? Genes Dis 2019; 7:107-114. [PMID: 32181281 PMCID: PMC7063431 DOI: 10.1016/j.gendis.2019.07.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 07/21/2019] [Accepted: 07/30/2019] [Indexed: 01/13/2023] Open
Abstract
Migration of polymorphonuclear leukocytes from bloodstream to the site of inflammation is an important event required for surveillance of foreign antigens. This trafficking of leukocytes from bloodstream to the tissue occurs in several distinct steps and involves several adhesion molecules. Defect in adhesion of leukocytes to vascular endothelium affecting their subsequent migration to extravascular space gives rise to a group of rare primary immunodeficiency diseases (PIDs) known as Leukocyte Adhesion Defects (LAD). Till date, four classes of LAD are discovered with LAD I being the most common form. LAD I is caused by loss of function of common chain, cluster of differentiation (CD)18 of β2 integrin family. These patients suffer from life-threatening bacterial infections and in its severe form death usually occurs in childhood without bone marrow transplantation. LAD II results from a general defect in fucose metabolism. These patients suffer from less severe bacterial infections and have growth and mental retardation. Bombay blood group phenotype is also observed in these patients. LAD III is caused by abnormal integrin activation. LAD III patients suffer from severe bacterial and fungal infections. Patients frequently show delayed detachment of umbilical cord, impaired wound healing and increased tendency to bleed. LAD IV is the most recently described class. It is caused by defects in β2 and α4β1 integrins which impairs lymphocyte adhesion. LAD IV patients have monogenic defect in cystic-fibrosis-transmembrane-conductance-regulator (CFTR) gene, resulting in cystic fibrosis. Pathophysiology and genetic etiology of all LAD syndromes are discussed in detail in this paper.
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Edel Y, Mamet R, Snast I, Kaftory R, Mazor S, Hodak E, Lapidoth M, Elis A, Molad Y, Levi A. Epidemiology of cutaneous porphyria in Israel: a nationwide cohort study. J Eur Acad Dermatol Venereol 2019; 34:184-187. [PMID: 31264284 DOI: 10.1111/jdv.15769] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 06/13/2019] [Indexed: 11/28/2022]
Abstract
BACKGROUND From a dermatologist's perspective, there are four major types of cutaneous porphyrias (CPs): porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP), variegate porphyria (VP) and hereditary coproporphyria (HCP). Scarce data are available regarding the epidemiology of CPs. OBJECTIVES To describe the epidemiology of CPs in Israel, including distribution, incidence and prevalence rates of major types. METHODS This retrospective study includes all patients who were diagnosed with CPs between the years 1988-2018. It is based on data from Israel's National Service for the Biochemical Diagnoses of Porphyrias, and Israeli patients' nationwide electronic medical charts. Incidence and prevalence rates were calculated. RESULTS Of 173 patients with CPs diagnosed during a 30-year period, 65 (38%) had VP, 62 (36%) had PCT, 31 (18%) had HCP and 15 (9%) had EPP; with incidence rates of 0.29, 0.30, 0.17, 0.07, and prevalence rates of 6.3, 4.8, 2.9, 1.6, respectively, per million population. Characteristics of patients with PCT differed from those with other CPs with regard to lack of family history, older mean age at diagnosis [51 vs. 36 (VP), 35 (HCP) and 25 (EPP) years] and male predominance (81% vs. similar distribution). All patients with PCT were diagnosed at adulthood, while 20%, 19% and 15% of patients with VP, HCP and EPP, respectively, were diagnosed during childhood or adolescence. CONCLUSIONS Variegate porphyria and PCT were found to be the most prevalent in Israel; however, CPs might be underdiagnosed, thus dermatologists' awareness of these rare disorders is highly important.
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Affiliation(s)
- Y Edel
- National Service for the Biochemical Diagnoses of Porphyrias, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.,Rheumatology Unit, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - R Mamet
- National Service for the Biochemical Diagnoses of Porphyrias, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel
| | - I Snast
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Photodermatosis Clinic, Department of Dermatology, Beilinson Hospital, Petach Tikva, Israel
| | - R Kaftory
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - S Mazor
- Department of Community Dentistry, School of Dental Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - E Hodak
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Photodermatosis Clinic, Department of Dermatology, Beilinson Hospital, Petach Tikva, Israel
| | - M Lapidoth
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Photodermatosis Clinic, Department of Dermatology, Beilinson Hospital, Petach Tikva, Israel
| | - A Elis
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department "C" of internal, Belinson Hospital, Petah Tikva, Israel
| | - Y Molad
- Rheumatology Unit, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel
| | - A Levi
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Photodermatosis Clinic, Department of Dermatology, Beilinson Hospital, Petach Tikva, Israel
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Shahid S, Zaidi S, Ahmed S, Siddiqui S, Abid A, Malik S, Shamsi T. A Novel Nonsense Mutation in FERMT3 Causes LAD-III in a Pakistani Family. Front Genet 2019; 10:360. [PMID: 31068971 PMCID: PMC6491447 DOI: 10.3389/fgene.2019.00360] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 04/04/2019] [Indexed: 01/13/2023] Open
Abstract
Leukocyte adhesion deficiency-III (LAD3) is an extremely rare primary immunodeficiency disorder, transmitted with autosomal-recessive inheritance. It is caused by genetic alteration in the FERMT3 gene, which leads to abnormal expression of kindlin-3. This cytoplasmic protein is highly expressed in leukocytes and platelets, and acts as an important regulator of integrin activation. LAD3 has features like bleeding syndrome of Glanzmann-type and leukocyte adhesion deficiency. FERMT3 mutation(s) have not been well characterized in Pakistani patients with LAD3. In this study, an infant and his family of Pakistani origin, presenting with clinical features of LAD, were investigated to determine the underlying genetic defect. Targeted next generation sequencing (TGS) and Sanger sequencing were performed to identify and confirm the causative mutations, respectively, and their segregation within the family. A novel, homozygous FERMT3 nonsense mutation (c.286C > T, p.Q96∗) was found in the proband, and its co-segregation with LAD3 phenotype within the family was consistent with an autosomal recessive inheritance. Both parents were carriers of the same mutation. This family was offered prenatal diagnosis during first trimester of the subsequent pregnancy; the fetus carried the variant. In conclusion, our study is the first report to identify the novel homozygous variant c.286C > T, p.Q96∗in the FERMT3 gene, which might be the causative mutation for LAD3 patients of Pakistani origin.
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Affiliation(s)
- Saba Shahid
- Department of Genomics and Clinical Genetics, National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan
| | - Samreen Zaidi
- Department of Pediatrics, National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan
| | - Shariq Ahmed
- Department of Genomics and Clinical Genetics, National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan
| | - Saima Siddiqui
- Department of Genomics and Clinical Genetics, National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan
| | - Aiysha Abid
- Center of Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Shabbir Malik
- Department of Pediatrics, National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan
| | - Tahir Shamsi
- Department of Clinical Hematology, National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan
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41
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Sun B, Chen Q, Dong X, Liu D, Hou J, Wang W, Ying W, Hui X, Zhou Q, Yao H, Sun J, Wang X. Report of a Chinese Cohort with Leukocyte Adhesion Deficiency-I and Four Novel Mutations. J Clin Immunol 2019; 39:309-315. [PMID: 30919141 DOI: 10.1007/s10875-019-00617-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 03/18/2019] [Indexed: 12/19/2022]
Abstract
PURPOSE We aimed to report the characteristics of leukocyte adhesion deficiency-I (LAD-I) and four novel mutations in the ITGB2 gene in a Chinese cohort. METHODS Seven patients with LAD-I were reported in our study. Clinical manifestations and immunological phenotypes were reviewed. The expression of CD18 was detected by flow cytometry. Next-generation sequencing (NGS) and Sanger sequencing were performed to identify gene mutations. RESULTS The mean onset age of all the patients was 1.3 months. Recurrent bacterial infections of the skin and lungs were the most common symptoms. Most patients (6/7) had delayed cord separation. The number of white blood cells (WBC) was increased significantly, except that two patients had a mild increase in the number of WBC during infection-free periods. The expression of CD18 was very low in all patients. Homozygous or compound heterozygous mutations in the ITGB2 gene were identified in each patient. Four mutations were novel, including c.1794dupC (p.N599Qfs*93), c.1788C>A (p.C596X), c.841-849del9, and c.741+1delG. Two patients had large deletions of the ITGB2 gene. Five patients were cured by hematopoietic stem cell transplantation (HSCT). CONCLUSIONS This study reported the clinical and molecular characteristics of a Chinese patient cohort. It is helpful in understanding the current status of the disease in China.
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Affiliation(s)
- Bijun Sun
- Department of Clinical Immunology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Qiuyu Chen
- Department of Clinical Immunology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Xiaolong Dong
- Department of Clinical Immunology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Danru Liu
- Department of Clinical Immunology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Jia Hou
- Department of Clinical Immunology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Wenjie Wang
- Department of Clinical Immunology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Wenjing Ying
- Department of Clinical Immunology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Xiaoying Hui
- Department of Clinical Immunology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Qinhua Zhou
- Department of Clinical Immunology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Haili Yao
- Department of Clinical Immunology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Jinqiao Sun
- Department of Clinical Immunology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
| | - Xiaochuan Wang
- Department of Clinical Immunology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
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Fagerholm SC, Guenther C, Llort Asens M, Savinko T, Uotila LM. Beta2-Integrins and Interacting Proteins in Leukocyte Trafficking, Immune Suppression, and Immunodeficiency Disease. Front Immunol 2019; 10:254. [PMID: 30837997 PMCID: PMC6389632 DOI: 10.3389/fimmu.2019.00254] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 01/29/2019] [Indexed: 12/21/2022] Open
Abstract
Beta2-integrins are complex leukocyte-specific adhesion molecules that are essential for leukocyte (e.g., neutrophil, lymphocyte) trafficking, as well as for other immunological processes such as neutrophil phagocytosis and ROS production, and T cell activation. Intriguingly, however, they have also been found to negatively regulate cytokine responses, maturation, and migratory responses in myeloid cells such as macrophages and dendritic cells, revealing new, and unexpected roles of these molecules in immunity. Because of their essential role in leukocyte function, a lack of expression or function of beta2-integrins causes rare immunodeficiency syndromes, Leukocyte adhesion deficiency type I, and type III (LAD-I and LAD-III). LAD-I is caused by reduced or lost expression of beta2-integrins, whilst in LAD-III, beta2-integrins are expressed but dysfunctional because a major integrin cytoplasmic regulator, kindlin-3, is mutated. Interestingly, some LAD-related phenotypes such as periodontitis have recently been shown to be due to an uncontrolled inflammatory response rather than to an uncontrolled infection, as was previously thought. This review will focus on the recent advances concerning the regulation and functions of beta2-integrins in leukocyte trafficking, immune suppression, and immune deficiency disease.
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Affiliation(s)
- Susanna C Fagerholm
- Molecular and Integrative Biosciences Research Program, Faculty of Bio- and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Carla Guenther
- Molecular and Integrative Biosciences Research Program, Faculty of Bio- and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Marc Llort Asens
- Molecular and Integrative Biosciences Research Program, Faculty of Bio- and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | | | - Liisa M Uotila
- Research Services, University of Helsinki, Helsinki, Finland
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