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Stephenson KAJ, Dhanji SR, Pakzad-Vaezi K. Is there a predisposition to uveitis in Turner syndrome? Ophthalmic Genet 2025; 46:297-300. [PMID: 40038093 DOI: 10.1080/13816810.2025.2473970] [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: 09/05/2024] [Revised: 02/19/2025] [Accepted: 02/25/2025] [Indexed: 03/06/2025]
Abstract
INTRODUCTION Autoimmunity is prevalent in Turner syndrome (TS) though uveitis is rarely reported. A definite link between TS and uveitis is not yet established. METHODS We report two cases of uveitis with a history of TS and review the literature regarding TS, uveitis and autoimmunity. RESULTS TS-associated uveitis is acute (100%), non-hypertensive (100%) anterior uveitis (87.5%) that usually responds to topical therapy without unexpected long-term visual sequelae. Systemic treatment is uncommonly required as relapses are infrequent. CONCLUSION Reported cases of uveitis in TS were acute/symptomatic, normotensive and both unilateral and bilateral cases have been described. Systemic causes including infectious (e.g. syphilis, tuberculosis), noninfectious (e.g. sarcoidosis, HLA-B27) and specific syndromes (e.g. tubulointerstitial nephritis with uveitis, juvenile idiopathic arthritis) should be sought. Systemic immunosuppression was not needed in most cases as a good response to topical therapy was typical. There are baseline risks in TS (e.g. further growth limitation in children, baseline increased risk of solid tumors, diabetes mellitus), which should be considered before commencing systemic corticosteroids or immunosuppressants.
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Affiliation(s)
- Kirk A J Stephenson
- Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Shanil R Dhanji
- Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kaivon Pakzad-Vaezi
- Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada
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Roberts AL, Morea A, Amar A, West M, Karrar S, Lehane R, Tombleson P, Cunningham Grahman D, Reynolds JA, Wong CCY, Morris DL, Small KS, Vyse TJ. Haematopoietic stem cell-derived immune cells have reduced X chromosome inactivation skewing in systemic lupus erythematosus. Ann Rheum Dis 2024; 83:1315-1321. [PMID: 38937070 PMCID: PMC11503196 DOI: 10.1136/ard-2024-225585] [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: 01/25/2024] [Accepted: 05/29/2024] [Indexed: 06/29/2024]
Abstract
OBJECTIVES Systemic lupus erythematosus (SLE) shows a marked female bias in prevalence. X chromosome inactivation (XCI) is the mechanism which randomly silences one X chromosome to equalise gene expression between 46, XX females and 46, XY males. Though XCI is expected to result in a random pattern of mosaicism across tissues, some females display a significantly skewed ratio in immune cells, termed XCI-skew. We tested whether XCI was abnormal in females with SLE and hence contributes to sexual dimorphism. METHODS We assayed XCI in whole blood DNA in 181 female SLE cases, 796 female healthy controls and 10 twin pairs discordant for SLE. Using regression modelling and intra-twin comparisons, we assessed the effect of SLE on XCI and combined clinical, cellular and genetic data via a polygenic score to explore underlying mechanisms. RESULTS Accommodating the powerful confounder of age, XCI-skew was reduced in females with SLE compared with controls (p=1.3×10-5), with the greatest effect seen in those with more severe disease. Applying an XCI threshold of >80%, we observed XCI-skew in 6.6% of SLE cases compared with 22% of controls. This difference was not explained by differential white cell counts, medication or genetic susceptibility to SLE. Instead, XCI-skew correlated with a biomarker for type I interferon-regulated gene expression. CONCLUSIONS These results refute current views on XCI-skew in autoimmunity and suggest, in lupus, XCI patterns of immune cells reflect the impact of disease state, specifically interferon signalling, on the haematopoietic stem cells from which they derive.
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Affiliation(s)
- Amy L Roberts
- Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Alessandro Morea
- Twin Research and Genetic Epidemiology, King's College London, London, UK
- Foundation Institute of Molecular Oncology, IFOM, Milano, Italy
| | - Ariella Amar
- Department of Medical and Molecular Genetics, King's College London, London, UK
| | - Magdalena West
- Department of Medical and Molecular Genetics, King's College London, London, UK
| | - Sarah Karrar
- Department of Medical and Molecular Genetics, King's College London, London, UK
| | - Rhiannon Lehane
- Department of Medical and Molecular Genetics, King's College London, London, UK
| | - Philip Tombleson
- Department of Medical and Molecular Genetics, King's College London, London, UK
| | | | - John A Reynolds
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Chloe C Y Wong
- Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - David L Morris
- Medical and Molecular Genetics, King's College London, London, UK
| | - Kerrin S Small
- Twin Research and Genetic Epidemiology, King's College London, London, UK
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Lee YL, Zaini AA, Idris AN, Abdullah RA, Wong JS, Hong JS, Hussain S, Lim PG, Lim SH, Nor NS, Wu LL, Jalaludin MY. Thyroid autoimmunity and autoimmune thyroid disease in Malaysian girls with Turner syndrome: An understudied population. J Paediatr Child Health 2023; 59:879-884. [PMID: 37066819 DOI: 10.1111/jpc.16405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 02/20/2023] [Accepted: 04/06/2023] [Indexed: 04/18/2023]
Abstract
AIMS Knowledge on the spectrum of thyroid disorders amongst Turner syndrome (TS) patients in Southeast Asia is limited. This study aimed to evaluate the prevalence of thyroid autoimmunity, the spectrum of autoimmune thyroid disease and association with age and karyotype amongst Malaysian TS girls. METHODS A cross-sectional study was conducted at 11 paediatric endocrine units in Malaysia. Blood samples for antithyroglobulin antibodies, antithyroid peroxidase antibodies and thyroid function test were obtained. In patients with pre-existing thyroid disease, information on clinical and biochemical thyroid status was obtained from medical records. RESULTS Ninety-seven TS patients with a mean age of 13.4 ± 4.8 years were recruited. Thyroid autoimmunity was found in 43.8% of TS patients. Nineteen per cent of those with thyroid autoimmunity had autoimmune thyroid disease (Hashimoto thyroiditis in 7.3% and hyperthyroidism in 1% of total population). Patients with isochromosome X and patients with 45,X mosaicism or other X chromosomal abnormalities were more prone to have thyroid autoimmunity compared to those with 45,X karyotype (OR 5.09, 95% CI 1.54-16.88, P = 0.008 and OR 3.41, 95% CI 1.32-8.82, P = 0.01 respectively). The prevalence of thyroid autoimmunity increased with age (33.3% for age 0-9.9 years; 46.8% for age 10-19.9 years and 57.1% age for 20-29.9 years) with autoimmune thyroid disease detected in 14.3% during adulthood. CONCLUSION Thyroid autoimmunity was significantly associated with the non 45,X karyotype group, particularly isochromosome X. Annual screening of thyroid function should be carried out upon diagnosis of TS until adulthood with more frequent monitoring recommended in the presence of thyroid autoimmunity.
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Affiliation(s)
- Yee L Lee
- Paediatric Endocrine Unit, Department of Paediatrics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Azriyanti A Zaini
- Paediatric Endocrine Unit, Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Arini N Idris
- Paediatric Endocrine Unit, Department of Paediatrics, Hospital Tunku Azizah, Kuala Lumpur, Malaysia
| | - Raja A Abdullah
- Paediatric Endocrine Unit, Department of Paediatrics, Hospital Pulau Pinang, Pulau Pinang, Malaysia
| | - Jeanne Sl Wong
- Paediatric Endocrine Unit, Department of Paediatrics, Putrajaya Hospital, Putrajaya, Malaysia
- Sunway Specialist Centre, Kota Damansara, Malaysia
| | - Joyce Ss Hong
- Paediatric Endocrine Unit, Department of Paediatrics, Hospital Pakar Kanak-kanak, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Suhaimi Hussain
- Paediatric Endocrine Unit, Department of Paediatrics, Hospital Universiti Sains Malaysia, Kota Bharu, Malaysia
| | - Poi G Lim
- Paediatric Endocrine Unit, Department of Paediatrics, Hospital Tunku Azizah, Kuala Lumpur, Malaysia
| | - Song H Lim
- Paediatric Endocrine Unit, Department of Paediatrics, Sabah Women and Children's Hospital, Kota Kinabalu, Malaysia
| | - Noor Sm Nor
- Department of Paediatrics, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Shah Alam, Malaysia
- Institute for Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Shah Alam, Malaysia
| | - Loo L Wu
- Subang Jaya Medical Centre, Subang Jaya, Malaysia
| | - Muhammad Y Jalaludin
- Paediatric Endocrine Unit, Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
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Scofield RH, Lewis VM, Cavitt J, Kurien BT, Assassi S, Martin J, Gorlova O, Gregersen P, Lee A, Rider LG, O'Hanlon T, Rothwell S, Lilleker J, Myositis Genetics Consortium, Xiaoxi Liu, Kochi Y, Terao C, Igoe A, Stevens W, Sahhar J, Roddy J, Rischmueller M, Lester S, Proudman S, Chen S, Brown MA, Mayes MD, Lamb JA, Miller FW. 47XXY and 47XXX in Scleroderma and Myositis. ACR Open Rheumatol 2022; 4:528-533. [PMID: 35352506 PMCID: PMC9190224 DOI: 10.1002/acr2.11413] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 01/04/2022] [Accepted: 01/10/2022] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE We undertook this study to examine the X chromosome complement in participants with systemic sclerosis (SSc) as well as idiopathic inflammatory myopathies. METHODS The participants met classification criteria for the diseases. All participants underwent single-nucleotide polymorphism typing. We examined X and Y single-nucleotide polymorphism heterogeneity to determine the number of X chromosomes. For statistical comparisons, we used χ2 analyses with calculation of 95% confidence intervals. RESULTS Three of seventy men with SSc had 47,XXY (P = 0.0001 compared with control men). Among the 435 women with SSc, none had 47,XXX. Among 709 men with polymyositis or dermatomyositis (PM/DM), seven had 47,XXY (P = 0.0016), whereas among the 1783 women with PM/DM, two had 47,XXX. Of 147 men with inclusion body myositis (IBM), six had 47,XXY, and 1 of the 114 women with IBM had 47,XXX. For each of these myositis disease groups, the excess 47,XXY and/or 47,XXX was significantly higher compared with in controls as well as the known birth rate of Klinefelter syndrome or 47,XXX. CONCLUSION Klinefelter syndrome (47,XXY) is associated with SSc and idiopathic inflammatory myopathies, similar to other autoimmune diseases with type 1 interferon pathogenesis, namely, systemic lupus erythematosus and Sjögren syndrome.
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Affiliation(s)
- R. Hal Scofield
- Oklahoma Medical Research Foundation, College of MedicineUniversity of Oklahoma Health Sciences Center, and Oklahoma City US Department of Veterans Affairs Medical CenterOklahoma City
| | - Valerie M. Lewis
- Oklahoma Medical Research Foundation, College of MedicineUniversity of Oklahoma Health Sciences Center, and Oklahoma City US Department of Veterans Affairs Medical CenterOklahoma City
| | - Joshua Cavitt
- Oklahoma Medical Research Foundation, College of MedicineUniversity of Oklahoma Health Sciences Center, and Oklahoma City US Department of Veterans Affairs Medical CenterOklahoma City
| | - Biji T. Kurien
- Oklahoma Medical Research Foundation, College of MedicineUniversity of Oklahoma Health Sciences Center, and Oklahoma City US Department of Veterans Affairs Medical CenterOklahoma City
| | - Shervin Assassi
- University of Texas Health Science Center at Houston McGovern Medical SchoolHoustonTexasUSA
| | - Javier Martin
- Instituto de Parasitología y Biomedicina López‐Neyra, Consejo Superior de Investigaciones CientíficasPTS, GranadaSpain
| | - Olga Gorlova
- Geisel School of MedicineDartmouth College and Dartmouth‐Hitchcock Medical CenterLebanonNew HampshireUSA
| | - Peter Gregersen
- Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institutes for Medical ResearchManhassetNew YorkUSA
| | - Annette Lee
- Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institutes for Medical ResearchManhassetNew YorkUSA
| | - Lisa G. Rider
- National Institute of Environmental Health Science, National Institutes of HealthBethesdaMarylandUSA
| | - Terrance O'Hanlon
- National Institute of Environmental Health Science, National Institutes of HealthBethesdaMarylandUSA
| | | | - James Lilleker
- School of Biological SciencesThe University of Manchester, Manchester, UK, and Salford Royal National Health Service Foundation TrustSalfordUK
| | | | - Yuta Kochi
- Tokyo, Japan, and RIKEN Center for Integrative Medical SciencesTokyo Medical and Dental UniversityYokohamaJapan
| | - Chikacshi Terao
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan, and Shizuoka General Hospital and School of Pharmaceutical SciencesUniversity of ShizuokaShizuokaJapan
| | - Ann Igoe
- Oklahoma Medical Research FoundationOklahoma City
| | | | | | - Janet Roddy
- Fiona Stanley HospitalMurdochWestern AustraliaAustralia
| | - Maureen Rischmueller
- The Queen Elizabeth Hospital and University of AdelaideWoodvilleSouth AustraliaAustralia
| | - Sue Lester
- The Queen Elizabeth Hospital and University of AdelaideWoodvilleSouth AustraliaAustralia
| | | | - Sixia Chen
- College of Public HealthUniversity of Oklahoma Health Sciences CenterOklahoma City
| | - Matthew A. Brown
- Faculty of Life Sciences and MedicineKing's College LondonLondonUK
| | - Maureen D. Mayes
- University of Texas Health Science Center at Houston McGovern Medical SchoolHoustonTexasUSA
| | | | - Frederick W. Miller
- National Institute of Environmental Health Science, National Institutes of HealthBethesdaMarylandUSA
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Preferential X Chromosome Inactivation as a Mechanism to Explain Female Preponderance in Myasthenia Gravis. Genes (Basel) 2022; 13:genes13040696. [PMID: 35456502 PMCID: PMC9031138 DOI: 10.3390/genes13040696] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 04/04/2022] [Accepted: 04/13/2022] [Indexed: 11/17/2022] Open
Abstract
Myasthenia gravis (MG) is a neuromuscular autoimmune disease characterized by prevalence in young women (3:1). Several mechanisms proposed as explanations for gender bias, including skewed X chromosome inactivation (XCI) and dosage or sex hormones, are often involved in the development of autoimmunity. The skewed XCI pattern can lead to an unbalanced expression of some X-linked genes, as observed in several autoimmune disorders characterized by female predominance. No data are yet available regarding XCI and MG. We hypothesize that the preferential XCI pattern may contribute to the female bias observed in the onset of MG, especially among younger women. XCI analysis was performed on blood samples of 284 women between the ages of 20 and 82. XCI was tested using the Human Androgen Receptor Assay (HUMARA). XCI patterns were classified as random (XCI < 75%) and preferential (XCI ≥ 75%). In 121 informative patients, the frequency of skewed XCI patterns was 47%, significantly higher than in healthy controls (17%; p ≤ 0.00001). Interestingly, the phenomenon was observed mainly in younger patients (<45 years; p ≤ 0.00001). Furthermore, considering the XCI pattern and the other clinical characteristics of patients, no significant differences were found. In conclusion, we observed preferential XCI in MG female patients, suggesting its potential role in the aetiology of MG, as observed in other autoimmune diseases in women.
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Mirshahi F, Aqbi HF, Isbell M, Manjili SH, Guo C, Saneshaw M, Dozmorov M, Khosla A, Wack K, Carrasco-Zevallos OM, Idowu MO, Wang XY, Sanyal AJ, Manjili MH, Bandyopadhyay D. Distinct hepatic immunological patterns are associated with the progression or inhibition of hepatocellular carcinoma. Cell Rep 2022; 38:110454. [PMID: 35235789 PMCID: PMC9028248 DOI: 10.1016/j.celrep.2022.110454] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 01/27/2022] [Accepted: 02/04/2022] [Indexed: 12/30/2022] Open
Abstract
To discover distinct immune responses promoting or inhibiting hepatocellular carcinoma (HCC), we perform a three-dimensional analysis of the immune cells, correlating immune cell types, interactions, and changes over time in an animal model displaying gender disparity in nonalcoholic fatty liver disease (NAFLD)-associated HCC. In response to a Western diet (WD), animals mount acute and chronic patterns of inflammatory cytokines, respectively. Tumor progression in males and females is associated with a predominant CD8+ > CD4+, Th1 > Th17 > Th2, NKT > NK, M1 > M2 pattern in the liver. A complete rescue of females from HCC is associated with an equilibrium Th1 = Th17 = Th2, NKT = NK, M1 = M2 pattern, while a partial rescue of males from HCC is associated with an equilibrium CD8+ = CD4+, NKT = NK and a semi-equilibrium Th1 = Th17 > Th2 but a sustained M1 > M2 pattern in the liver. Our data suggest that immunological pattern-recognition can explain immunobiology of HCC and guide immune modulatory interventions for the treatment of HCC in a gender-specific manner. Mirshahi et al. performed a three-dimensional analysis of hepatic and splenic immune cells, correlating the immune cell types, their interactions and proportions, and changes over time. They discover gender-associated immunological patterns determining tumor progression, as well as partial or complete inhibition of hepatocellular carcinoma.
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Affiliation(s)
- Faridoddin Mirshahi
- Department of Internal Medicine, VCU School of Medicine, Richmond, VA 23298, USA
| | - Hussein F Aqbi
- Department of Internal Medicine, VCU School of Medicine, Richmond, VA 23298, USA; VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA; College of Science, Mustansiriyah University, Baghdad, Iraq
| | - Madison Isbell
- Department of Microbiology & Immunology, VCU School of Medicine, Richmond, VA 23298, USA
| | - Saeed H Manjili
- Department of Internal Medicine, VCU School of Medicine, Richmond, VA 23298, USA
| | - Chunqing Guo
- Department of Human & Molecular Genetics, VCU School of Medicine, Richmond, VA 23298, USA
| | - Mulugeta Saneshaw
- VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA
| | - Mikhail Dozmorov
- VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA; Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA
| | | | | | | | - Michael O Idowu
- VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA; Department of Pathology, VCU School of Medicine, Richmond, VA 23298, USA
| | - Xiang-Yang Wang
- VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA; Department of Human & Molecular Genetics, VCU School of Medicine, Richmond, VA 23298, USA; Hunter Holmes McGuire VA Medical Center, Richmond, VA 23298, USA
| | - Arun J Sanyal
- Department of Internal Medicine, VCU School of Medicine, Richmond, VA 23298, USA; VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA.
| | - Masoud H Manjili
- Department of Microbiology & Immunology, VCU School of Medicine, Richmond, VA 23298, USA; VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA; Department of Pathology, VCU School of Medicine, Richmond, VA 23298, USA.
| | - Dipankar Bandyopadhyay
- VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA; Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA
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Bastacky ML, Wang H, Fortman D, Rahman Z, Mascara GP, Brenner T, Najjar YG, Luke JJ, Kirkwood JM, Zarour HM, Davar D. Immune-Related Adverse Events in PD-1 Treated Melanoma and Impact Upon Anti-Tumor Efficacy: A Real World Analysis. Front Oncol 2021; 11:749064. [PMID: 34900695 PMCID: PMC8662734 DOI: 10.3389/fonc.2021.749064] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/03/2021] [Indexed: 12/20/2022] Open
Abstract
Background Anti-PD-1 immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of melanoma by producing durable long-term responses in a subset of patients. ICI-treated patients develop unique toxicities - immune related adverse events (irAEs) – that arise from unrestrained immune activation. The link between irAE development and clinical outcome in melanoma and other cancers is inconsistent; and little data exists on the occurrence of multiple irAEs. We sought to characterize development of single and multiple irAEs, and association of irAE(s) development with clinical variables and impact upon outcomes in advanced melanoma patients treated with anti-PD-1 ICIs. Methods We conducted a retrospective study of 190 patients with metastatic melanoma treated with single-agent anti-PD-1 ICI therapy between June 2014 and August 2020 at a large integrated network cancer center identified through retrospective review of pharmacy records. irAEs were graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results 190 patients were evaluated of whom 114 patients (60.0%) experienced ≥1 irAE, including 30 (15.8%) with grade 3/4 irAEs. The occurrence of any irAE was strongly associated with the development of investigator-assessed response to anti-PD-1 therapy (p < 0.0001); whether evaluated by current (p=0.0082) or best (p=0.0001) response. In patients with ≥2 irAEs, distinct patterns were observed. Median progression-free survival (PFS) and overall survival (OS) were greater in those with any irAE compared to those without (PFS, 28 months vs. 5 months, p < 0.0001; OS, not reached vs. 9 months, p < 0.0001). Development of ≥2 irAEs had a trend towards improved PFS and OS compared to those who developed a single irAE, although this did not reach statistical significance (p=0.2555, PFS; p=0.0583, OS). Obesity but not age or gender was distinctly associated with irAE development. Conclusions In this study, we demonstrated that irAE occurrence was significantly associated with response to anti-PD-1 therapy and improved PFS/OS. Those who developed multiple irAEs had a trend towards improved PFS and OS compared to those who developed only a single irAE. Increased BMI but neither age nor gender were associated with irAE development. Distinct patterns of irAEs observed suggest shared etiopathogenetic mechanisms.
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Affiliation(s)
- Melissa L Bastacky
- Department of Pharmacy, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Hong Wang
- Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
| | - Dylan Fortman
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Zahra Rahman
- University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, United States
| | - Gerard P Mascara
- Department of Pharmacy, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Timothy Brenner
- Department of Pharmacy, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Yana G Najjar
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.,University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, United States
| | - Jason J Luke
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.,University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, United States
| | - John M Kirkwood
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.,University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, United States
| | - Hassane M Zarour
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.,University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, United States
| | - Diwakar Davar
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.,University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, United States
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8
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Gilli F, DiSano KD, Pachner AR. SeXX Matters in Multiple Sclerosis. Front Neurol 2020; 11:616. [PMID: 32719651 PMCID: PMC7347971 DOI: 10.3389/fneur.2020.00616] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 05/27/2020] [Indexed: 12/12/2022] Open
Abstract
Multiple sclerosis (MS) is the most common chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). An interesting feature that this debilitating disease shares with many other inflammatory disorders is that susceptibility is higher in females than in males, with the risk of MS being three times higher in women compared to men. Nonetheless, while men have a decreased risk of developing MS, many studies suggest that males have a worse clinical outcome. MS exhibits an apparent sexual dimorphism in both the immune response and the pathophysiology of the CNS damage, ultimately affecting disease susceptibility and progression differently. Overall, women are predisposed to higher rates of inflammatory relapses than men, but men are more likely to manifest signs of disease progression and worse CNS damage. The observed sexual dimorphism in MS may be due to sex hormones and sex chromosomes, acting in parallel or combination. In this review, we outline current knowledge on the sexual dimorphism in MS and discuss the interplay of sex chromosomes, sex hormones, and the immune system in driving MS disease susceptibility and progression.
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Affiliation(s)
- Francesca Gilli
- Department of Neurology, Dartmouth Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States
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Manjili RH, Zarei M, Habibi M, Manjili MH. COVID-19 as an Acute Inflammatory Disease. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 205:12-19. [PMID: 32423917 PMCID: PMC7333792 DOI: 10.4049/jimmunol.2000413] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 05/06/2020] [Indexed: 02/06/2023]
Abstract
The 2019 coronavirus disease (COVID-19) pandemic caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has created an unprecedented global crisis for the infrastructure sectors, including economic, political, healthcare, education, and research systems. Although over 90% of infected individuals are asymptomatic or manifest noncritical symptoms and will recover from the infection, those individuals presenting with critical symptoms are in urgent need of effective treatment options. Emerging data related to mechanism of severity and potential therapies for patients presenting with severe symptoms are scattered and therefore require a comprehensive analysis to focus research on developing effective therapeutics. A critical literature review suggests that the severity of SARS-CoV-2 infection is associated with dysregulation of inflammatory immune responses, which in turn inhibits the development of protective immunity to the infection. Therefore, the use of therapeutics that modulate inflammation without compromising the adaptive immune response could be the most effective therapeutic strategy.
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Affiliation(s)
| | - Melika Zarei
- Virginia Tech Carilion School of Medicine, Roanoke, VA 24016
| | - Mehran Habibi
- Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD 20215
| | - Masoud H Manjili
- Department of Microbiology and Immunology, VCU Institute of Molecular Medicine, VCU School of Medicine, Richmond, VA 23298; and
- VCU Massey Cancer Center, Richmond, VA 23298
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10
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Möller B, Kollert F, Sculean A, Villiger PM. Infectious Triggers in Periodontitis and the Gut in Rheumatoid Arthritis (RA): A Complex Story About Association and Causality. Front Immunol 2020; 11:1108. [PMID: 32582191 PMCID: PMC7283532 DOI: 10.3389/fimmu.2020.01108] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/07/2020] [Indexed: 12/12/2022] Open
Abstract
Rheumatoid arthritis (RA) is a systemic immune mediated inflammatory disease of unknown origin, which is predominantly affecting the joints. Antibodies against citrullinated peptides are a rather specific immunological hallmark of this heterogeneous entity. Furthermore, certain sequences of the third hypervariable region of human leukocyte antigen (HLA)-DR class II major histocompatibility (MHC) molecules, the so called "shared epitope" sequences, appear to promote autoantibody positive types of RA. However, MHC-II molecule and other genetic associations with RA could not be linked to immune responses against specific citrullinated peptides, nor do genetic factors fully explain the origin of RA. Consequently, non-genetic factors must play an important role in the complex interaction of endogenous and exogenous disease factors. Tobacco smoking was the first environmental factor that was associated with onset and severity of RA. Notably, smoking is also an established risk factor for oral diseases. Furthermore, smoking is associated with extra-articular RA manifestations such as interstitial lung disease in anatomical proximity to the airway mucosa, but also with subcutaneous rheumatoid nodules. In the mouth, Porphyromonas gingivalis is a periodontal pathogen with unique citrullinating capacity of foreign microbial antigens as well as candidate RA autoantigens. Although the original hypothesis that this single pathogen is causative for RA remained unproven, epidemiological as well as experimental evidence linking periodontitis (PD) with RA is rapidly accumulating. Other periopathogens such as Aggregatibacter actinomycetemcomitans and Prevotella intermedia were also proposed to play a specific immunodominant role in context of RA. However, demonstration of T cell reactivity against citrullinated, MHC-II presented autoantigens from RA synovium coinciding with immunity against Prevotella copri (Pc.), a gut microbe attracted attention to another mucosal site, the intestine. Pc. was accumulated in the feces of clinically healthy subjects with citrulline directed immune responses and was correlated with RA onset. In conclusion, we retrieved more than one line of evidence for mucosal sites and different microbial taxa to be potentially involved in the development of RA. This review gives an overview of infectious agents and mucosal pathologies, and discusses the current evidence for causality between different exogenous or mucosal factors and systemic inflammation in RA.
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Affiliation(s)
- Burkhard Möller
- Department for Rheumatology, Immunology and Allergology, Inselspital-University Hospital of Bern, Bern, Switzerland
| | - Florian Kollert
- Department for Rheumatology, Immunology and Allergology, Inselspital-University Hospital of Bern, Bern, Switzerland
| | - Anton Sculean
- Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - Peter M Villiger
- Department for Rheumatology, Immunology and Allergology, Inselspital-University Hospital of Bern, Bern, Switzerland
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11
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Nusbaum JS, Mirza I, Shum J, Freilich RW, Cohen RE, Pillinger MH, Izmirly PM, Buyon JP. Sex Differences in Systemic Lupus Erythematosus: Epidemiology, Clinical Considerations, and Disease Pathogenesis. Mayo Clin Proc 2020; 95:384-394. [PMID: 32029091 DOI: 10.1016/j.mayocp.2019.09.012] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 08/17/2019] [Accepted: 09/20/2019] [Indexed: 12/12/2022]
Abstract
Systemic lupus erythematosus (SLE) is a chronic, multiorgan, systemic autoimmune disease that is more common in women than men and is typically diagnosed during reproductive age, necessitating sex-specific considerations in care. In women there is no substantive evidence to suggest that SLE reduces fertility, but subfertility may occur as a result of active disease, immunosuppressive drugs, and age-related declines in fertility related to delays in childbearing. Although pregnancy outcomes have improved, SLE still poses risks in pregnancy that contribute to poorer maternal and fetal outcomes. Cyclophosphamide, an important agent for the treatment of severe or life-threatening lupus, may adversely affect fertility, particularly with increases in dose and patient age. Fertility preservation techniques are therefore an important consideration for women and men before cytotoxic treatment. There is mixed evidence as to whether exogenous estrogen in the form of oral contraceptive pills or hormone replacement therapy may increase the risk for the development of SLE, but among women with SLE already diagnosed, combined oral contraceptive pills and hormone replacement therapy do not confer risk for severe flare and remain important in reproductive care. The higher incidence of SLE in women may nonetheless be attributable to effects of endogenous estrogen, as well as failures in X chromosome inactivation, increased Toll-like receptor gene products, and changes in microRNA function. A greater appreciation of the biological underpinnings and consequences of sex differences in SLE may lead to more targeted treatments and improved outcomes for patients with SLE.
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Affiliation(s)
- Julie S Nusbaum
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York.
| | - Ibraheem Mirza
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
| | - Justine Shum
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
| | - Robert W Freilich
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
| | - Rebecca E Cohen
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
| | - Michael H Pillinger
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
| | - Peter M Izmirly
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
| | - Jill P Buyon
- Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York
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12
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Kyritsi EM, Kanaka-Gantenbein C. Autoimmune Thyroid Disease in Specific Genetic Syndromes in Childhood and Adolescence. Front Endocrinol (Lausanne) 2020; 11:543. [PMID: 32973676 PMCID: PMC7466763 DOI: 10.3389/fendo.2020.00543] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Accepted: 07/06/2020] [Indexed: 12/14/2022] Open
Abstract
Autoimmune thyroid disease (ATD) is the most frequent cause of acquired thyroid dysfunction, most commonly presenting either as Hashimoto's thyroiditis or Graves' Disease. Hashimoto's thyroiditis is characterized by the presence of thyroid-specific autoantibodies, more commonly anti-thyroperoxidase antibodies in the serum and the typical inhomogeneous echostructure of the thyroid on a thyroid ultrasound examination. Hashimoto's thyroiditis can for a long time be accompanied by normal thyroid function and hypothyroidism can only progressively be established. Graves' disease is much less frequent in childhood and adolescence and presents with overt hyperthyroidism. After the onset of puberty, ATD affects females with a higher incidence than males, while during the prepubertal period there is not such a clear preponderance of affected females. ATD can occur either isolated or in the context of other autoimmune disorders, such as type 1 Diabetes mellitus (T1D), celiac disease, alopecia areata, vitiligo, etc. Especially at the pediatric age, a higher incidence of ATD is also observed in the context of specific genetic syndromes, such as trisomy 21 (Down syndrome), Klinefelter syndrome, Turner syndrome, or 22q11.2 deletion syndrome. Nevertheless, although thyroid dysfunction may also be observed in other genetic syndromes, such as Prader-Willi or Williams syndrome, the thyroid dysfunction in these syndromes is not the result of thyroid autoimmunity. Interestingly, there is emerging evidence supporting a possible link between autoimmunity and RASopathies. In this review article the incidence, as well as the clinical manifestation and accompanied pathologies of ATD in specific genetic syndromes will be presented and regular follow-up for the early identification of the disorder will be proposed.
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Heritability of skewed X-inactivation in female twins is tissue-specific and associated with age. Nat Commun 2019; 10:5339. [PMID: 31767861 PMCID: PMC6877649 DOI: 10.1038/s41467-019-13340-w] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 11/04/2019] [Indexed: 12/16/2022] Open
Abstract
Female somatic X-chromosome inactivation (XCI) balances the X-linked transcriptional dosages between the sexes. Skewed XCI toward one parental X has been observed in several complex human traits, but the extent to which genetics and environment influence skewed XCI is largely unexplored. To address this, we quantify XCI-skew in multiple tissues and immune cell types in a twin cohort. Within an individual, XCI-skew differs between blood, fat and skin tissue, but is shared across immune cell types. XCI skew increases with age in blood, but not other tissues, and is associated with smoking. XCI-skew is increased in twins with Rheumatoid Arthritis compared to unaffected identical co-twins. XCI-skew is heritable in blood of females >55 years old (h2 = 0.34), but not in younger individuals or other tissues. This results in a Gene x Age interaction that shifts the functional dosage of all X-linked heterozygous loci in a tissue-restricted manner. Skewing of X chromosome inactivation (XCI) occurs when the silencing of one parental X chromosome is non-random. Here, Zito et al. report XCI patterns in lymphoblastoid cell lines, blood, subcutaneous adipose tissue samples and skin samples of monozygotic and dizygotic twins and find XCI skew to associate with tissue and age.
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14
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De Sanctis V, Khater D. Autoimmune diseases in Turner syndrome: an overview. ACTA BIO-MEDICA : ATENEI PARMENSIS 2019; 90:341-344. [PMID: 31580326 PMCID: PMC7233727 DOI: 10.23750/abm.v90i3.8737] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 07/31/2019] [Indexed: 12/13/2022]
Abstract
Turner syndrome (TS) results from a sex-chromosomal anomaly characterized by presence of one normal X chromosome and the loss of the second X-chromosome in phenotypic females. Autoimmunity has been recognized as one of the more prominent characteristics of TS. The risk of autoimmune diseases in patients with TS is approximately twice as high as in the general female population. The spectrum includes, Hashimoto’s thyroiditis, coeliac disease (CD), type 1 diabetes (T1DM), alopecia areata, inflammatory bowel disease, juvenile rheumatoid arthritis and some cutaneous disorders as vitiligo and Halo nevus. This review will address the autoimmune disorders associated with TS, their pathophysiologic mechanisms and clinical characteristics. (www.actabiomedica.it)
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Gerussi A, Cristoferi L, Carbone M, Asselta R, Invernizzi P. The immunobiology of female predominance in primary biliary cholangitis. J Autoimmun 2018; 95:124-132. [DOI: 10.1016/j.jaut.2018.10.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 10/17/2018] [Indexed: 12/21/2022]
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16
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Sohrabji F, Selvamani A. Sex differences in miRNA as therapies for ischemic stroke. Neurochem Int 2018; 127:56-63. [PMID: 30391509 DOI: 10.1016/j.neuint.2018.10.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 10/25/2018] [Accepted: 10/26/2018] [Indexed: 01/12/2023]
Abstract
MicroRNAs, a subset of non-coding RNAs, are present in virtually all tissues including body fluids and are global regulators of the transcriptome. In view of the expanding number of microRNAs and the large number of gene targets that each microRNA can potentially regulate, they have been compared to hormones in the scope of their effects. MicroRNA have been implicated as biomarkers for several diseases including stroke, as well as chronic conditions that are associated with stroke. Recent research has focused on manipulating miRNA to improve stroke outcomes. Although several miRNAs have been shown to have neuroprotective properties, the overwhelming majority of these studies have employed only male animals. This review will focus on two miRNAs, Let7f and mir363-3p, whose effectiveness as a stroke neuroprotectant is sex-specific.
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Affiliation(s)
- Farida Sohrabji
- Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan, TX, 77807, USA.
| | - Amutha Selvamani
- Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan, TX, 77807, USA
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17
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Roy SW. Intragenomic Conflict and Immune Tolerance: Do Selfish X-Linked Alleles Drive Skewed X Chromosome Inactivation? Genome Biol Evol 2018; 10:857-862. [PMID: 29092048 PMCID: PMC5861445 DOI: 10.1093/gbe/evx221] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2017] [Indexed: 12/18/2022] Open
Abstract
In mammalian females, diploid somatic cells contain two X chromosomes, one of which is transcriptionally silenced, in a process termed X chromosome inactivation (XCI). Whereas XCI is largely random in placental females, many women exhibit skewed XCI (SXCI), in which the vast majority cells have the same X chromosome inactivated. SXCI has serious health consequences, associated with conditions ranging from Alzheimer’s to various autoimmune disorders. SXCI is also associated with outcomes of pregnancies, with higher rates of recurrent spontaneous abortion in women with SXCI. Here, I suggest that SXCI could be driven by selfish X-linked alleles. Consistent with the association of SXCI with autoimmunity, I first note the possibility that recurrent spontaneous abortion could reflect immune rejection of fetuses inheriting alleles from the largely silenced maternal X chromosome. Preferential abortion of fetuses carrying silenced X-linked alleles implies a transmission advantage for X-linked alleles on the largely expressed chromosome, which could drive the emergence of X-linked alleles that make the chromosome resistant to XCI. I discuss the evolutionary dynamics, fitness tradeoffs and implications of this hypothesis, and suggest future directions.
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Affiliation(s)
- Scott W Roy
- Department of Biology, San Francisco State University
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18
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Tao W, Ayala-Haedo JA, Field MG, Pelaez D, Wester ST. RNA-Sequencing Gene Expression Profiling of Orbital Adipose-Derived Stem Cell Population Implicate HOX Genes and WNT Signaling Dysregulation in the Pathogenesis of Thyroid-Associated Orbitopathy. Invest Ophthalmol Vis Sci 2017; 58:6146-6158. [PMID: 29214313 PMCID: PMC5718600 DOI: 10.1167/iovs.17-22237] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 10/17/2017] [Indexed: 12/16/2022] Open
Abstract
Purpose The purpose of this study was to characterize the intrinsic cellular properties of orbital adipose-derived stem cells (OASC) from patients with thyroid-associated orbitopathy (TAO) and healthy controls. Methods Orbital adipose tissue was collected from a total of nine patients: four controls and five patients with TAO. Isolated OASC were characterized with mesenchymal stem cell-specific markers. Orbital adipose-derived stem cells were differentiated into three lineages: chondrocytes, osteocytes, and adipocytes. Reverse transcription PCR of genes involved in the adipogenesis, chondrogenesis, and osteogenesis pathways were selected to assay the differentiation capacities. RNA sequencing analysis (RNA-seq) was performed and results were compared to assess for differences in gene expression between TAO and controls. Selected top-ranked results were confirmed by RT-PCR. Results Orbital adipose-derived stem cells isolated from orbital fat expressed high levels of mesenchymal stem cell markers, but low levels of the pluripotent stem cell markers. Orbital adipose-derived stem cells isolated from TAO patients exhibited an increase in adipogenesis, and a decrease in chondrogenesis and osteogenesis. RNA-seq disclosed 54 differentially expressed genes. In TAO OASC, expression of early neural crest progenitor marker (WNT signaling, ZIC genes and MSX2) was lost. Meanwhile, ectopic expression of HOXB2 and HOXB3 was found in the OASC from TAO. Conclusion Our results suggest that there are intrinsic genetic and cellular differences in the OASC populations derived from TAO patients. The upregulation in adipogenesis in OASC of TAO may be is consistent with the clinical phenotype. Downregulation of early neural crest markers and ectopic expression of HOXB2 and HOXB3 in TAO OASC demonstrate dysregulation of developmental and tissue patterning pathways.
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Affiliation(s)
- Wensi Tao
- Dr. Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Juan A. Ayala-Haedo
- Dr. Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Matthew G. Field
- The Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Daniel Pelaez
- Dr. Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States
- Department of Biomedical Engineering, University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Sara T. Wester
- Dr. Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States
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Abstract
Female/male ratios of autoimmune diseases range from 10: 1 to 1: 3, with similar severity between the sexes. Men and women respond similarly to the infection and to vaccination, arguing against intrinsic sex differences in immune response. In autoimmune-like illnesses caused by environmental agents sex discrepancy is explained by differences in exposure. Endogenous hormones could cause sex discrepancy if their effect is a threshold off-on switch rather than quantitatively variable. X-inactivation and imprinting could cause sex discrepancy. Other possibilities include chronobiologic differences and pregnancy and menstruation biologies in which men differ from women.
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Affiliation(s)
- M D Lockshin
- Barbara Volcker Center for Women and Rheumatic Disease Joan and Sanford Weill Medical College of Cornell University, Hospital for Special Surgery, New York, NY 10021, USA.
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20
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Abstract
BACKGROUND Sex-specific differences in the prevalence and severity of immune disorders are well-known phenomena; however, it is only recently that we have begun to understand the possible causes of such differences. MATERIAL AND METHODS A literature search on this topic was carried out and the results are summarized. RESULTS In the last few years research has been guided by technological advances in gene sequencing and new insights into the microbiome of the gut, as well as an awareness of sex- and gender-specific risk factors for infections and autoimmunity. CONCLUSION The knowledge acquired in recent years will not only improve diagnostics and early identification of these disorders but also influence future research, prevention and therapy of infections and autoimmune diseases.
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Affiliation(s)
- G Riemekasten
- Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Deutschland,
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21
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Mangano K, Fagone P, Bendtzen K, Meroni PL, Quattrocchi C, Mammana S, Di Rosa M, Malaguarnera L, Coco M, Magro G, Di Marco R, Nicoletti F. Hypomethylating Agent 5-Aza-2′-deoxycytidine (DAC) Ameliorates Multiple Sclerosis in Mouse Models. J Cell Physiol 2014; 229:1918-25. [DOI: 10.1002/jcp.24641] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 03/31/2014] [Indexed: 11/06/2022]
Affiliation(s)
- Katia Mangano
- Department of Bio-medical Sciences; University of Catania; Via Androne Catania (CT) Italy
| | - Paolo Fagone
- Department of Bio-medical Sciences; University of Catania; Via Androne Catania (CT) Italy
| | - Klaus Bendtzen
- Institute for Inflammation Research (IIR); Rigshospitalet University Hospital; Copenhagen Denmark
| | - Pier Luigi Meroni
- Department of Clinical Sciences and Community Health; University of Milan; Istituto G. Pini and IRCCS Istituto Auxologico Italiano; Milan Italy
| | - Cinzia Quattrocchi
- Department of Bio-medical Sciences; University of Catania; Via Androne Catania (CT) Italy
| | - Santa Mammana
- Department of Bio-medical Sciences; University of Catania; Via Androne Catania (CT) Italy
| | - Michelino Di Rosa
- Department of Bio-medical Sciences; University of Catania; Via Androne Catania (CT) Italy
| | - Lucia Malaguarnera
- Department of Bio-medical Sciences; University of Catania; Via Androne Catania (CT) Italy
| | - Marinella Coco
- Department of Bio-medical Sciences; University of Catania; Via Androne Catania (CT) Italy
| | - Gaetano Magro
- Department G.F. Ingrassia; Azienda Ospedaliero-Universitaria “Policlinico-Vittorio Emanuele”, Anatomic Pathology; University of Catania; Catania Italy
| | - Roberto Di Marco
- Department of Medicine and Health Sciences; University of Molise; Campobasso Italy
| | - Ferdinando Nicoletti
- Department of Bio-medical Sciences; University of Catania; Via Androne Catania (CT) Italy
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22
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Kim H, Hwang SS, Uh Y, Kim J, Yoon KJ, Lee JY. A case associated with comorbidities among cerebral infarction, idiopathic thrombocytopenic purpura, and triple x syndrome. Turk J Haematol 2014; 31:184-7. [PMID: 25035678 PMCID: PMC4102048 DOI: 10.4274/tjh.2013.0064] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Accepted: 06/04/2013] [Indexed: 12/03/2022] Open
Abstract
A 46-year-old female presented to the emergency room due to the chief complaint of left-sided weakness. By imaging study, she was diagnosed with cerebral infarction. Thrombolytic and antiplatelet agents were not considered due to the “golden hour” for treatment having passed and a low platelet count. The peripheral blood smear, bone marrow biopsy, and aspirate findings were consistent with immune thrombocytopenic purpura. The chromosome analysis revealed the 47,XXX karyotype. To the best of our knowledge, this is the first case report associated with the comorbidities of cerebral infarction, idiopathic thrombocytopenic purpura, and triple X syndrome.
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Affiliation(s)
- Hanjun Kim
- Yonsei University Wonju College of Medicine, Department of Laboratory Medicine, Wonju, Korea
| | - Sang Sun Hwang
- Yonsei University Wonju College of Medicine, Department of Laboratory Medicine, Wonju, Korea
| | - Young Uh
- Yonsei University Wonju College of Medicine, Department of Laboratory Medicine, Wonju, Korea
| | - Juwon Kim
- Yonsei University Wonju College of Medicine, Department of Laboratory Medicine, Wonju, Korea
| | - Kap Jun Yoon
- Yonsei University Wonju College of Medicine, Department of Laboratory Medicine, Wonju, Korea
| | - Ji-Yong Lee
- Yonsei University Wonju College of Medicine, Department of Neurology, Wonju, Korea
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Wang Y, Smith TJ. Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci 2014; 55:1735-48. [PMID: 24651704 DOI: 10.1167/iovs.14-14002] [Citation(s) in RCA: 167] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Graves' disease (GD) is a common autoimmune condition. At its core, stimulatory autoantibodies are directed at the thyroid-stimulating hormone receptor (TSHR), resulting in dysregulated thyroid gland activity and growth. Closely associated with GD is the ocular condition known as thyroid-associated ophthalmopathy (TAO). The pathogenesis of TAO remains enigmatic as do the connections between the thyroid and orbit. This review highlights the putative molecular mechanisms involved in TAO and suggests how these insights provide future directions for identifying therapeutic targets. Genetic, epigenetic, and environmental factors have been suggested as contributory to the development of GD and TAO. Thyroid-stimulating hormone receptor and insulin-like growth factor receptor (IGF-1R) are expressed at higher levels in the orbital connective tissue from individuals with TAO than in healthy tissues. Together, they form a functional complex and appear to promote signaling relevant to GD and TAO. Orbital fibroblasts display an array of cell surface receptors and generate a host of inflammatory molecules that may participate in T and B cell infiltration. Recently, a population of orbital fibroblasts has been putatively traced to bone marrow-derived progenitor cells, known as fibrocytes, as they express CD45, CD34, CXCR4, collagen I, functional TSHR, and thyroglobulin (Tg). Fibrocytes become more numerous in GD and we believe traffic to the orbit in TAO. Numerous attempts at developing complete animal models of GD have been largely unsuccessful, because they lack fidelity with the ocular manifestations seen in TAO. Better understanding of the pathogenesis of TAO and development of improved animal models should greatly accelerate the identification of medical therapy for this vexing medical problem.
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Affiliation(s)
- Yao Wang
- Department of Ophthalmology and Visual Sciences and Division of Metabolic and Endocrine Disease, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
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25
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Anaya JM, Corena R, Castiblanco J, Rojas-Villarraga A, Shoenfeld Y. The kaleidoscope of autoimmunity: multiple autoimmune syndromes and familial autoimmunity. Expert Rev Clin Immunol 2014; 3:623-35. [DOI: 10.1586/1744666x.3.4.623] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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26
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Chabchoub G. X chromosome inactivation and autoimmune diseases. World J Rheumatol 2013; 3:12-15. [DOI: 10.5499/wjr.v3.i3.12] [Citation(s) in RCA: 4] [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: 05/29/2013] [Revised: 08/21/2013] [Accepted: 09/05/2013] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of autoimmune diseases (AIDs) is characterized by a female preponderance. The causes for this sex imbalance are based on several hypotheses. One of the most intriguing hypotheses is related to an X chromosome inactivation (XCI) process. Females are mosaics for two cell populations, one with the maternal and one with the paternal X as the active chromosome. Skewed XCI is often defined as a pattern where 80% or more of the cells show a preferential inactivation of one X chromosome. The role of skewed XCI has been questioned in the pathogenesis of several AIDs, such as autoimmune thyroid diseases and rheumatoid arthritis.
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27
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Sexual disparities in the incidence and course of SLE and RA. Clin Immunol 2013; 149:211-8. [DOI: 10.1016/j.clim.2013.03.003] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 01/25/2013] [Accepted: 03/07/2013] [Indexed: 02/08/2023]
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28
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Greer JM, McCombe PA. The role of epigenetic mechanisms and processes in autoimmune disorders. Biologics 2012; 6:307-27. [PMID: 23055689 PMCID: PMC3459549 DOI: 10.2147/btt.s24067] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2012] [Indexed: 12/18/2022]
Abstract
The lack of complete concordance of autoimmune disease in identical twins suggests that nongenetic factors play a major role in determining disease susceptibility. In this review, we consider how epigenetic mechanisms could affect the immune system and effector mechanisms in autoimmunity and/or the target organ of autoimmunity and thus affect the development of autoimmune diseases. We also consider the types of stimuli that lead to epigenetic modifications and how these relate to the epidemiology of autoimmune diseases and the biological pathways operative in different autoimmune diseases. Increasing our knowledge of these epigenetic mechanisms and processes will increase the prospects for controlling or preventing autoimmune diseases in the future through the use of drugs that target the epigenetic pathways.
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Affiliation(s)
- Judith M Greer
- The University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, Australia
| | - Pamela A McCombe
- The University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, Australia
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Płoski R, Szymański K, Bednarczuk T. The genetic basis of graves' disease. Curr Genomics 2012; 12:542-63. [PMID: 22654555 PMCID: PMC3271308 DOI: 10.2174/138920211798120772] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2011] [Revised: 08/05/2011] [Accepted: 08/15/2011] [Indexed: 01/09/2023] Open
Abstract
The presented comprehensive review of current knowledge about genetic factors predisposing to Graves’ disease (GD) put emphasis on functional significance of observed associations. In particular, we discuss recent efforts aimed at refining diseases associations found within the HLA complex and implicating HLA class I as well as HLA-DPB1 loci. We summarize data regarding non-HLA genes such as PTPN22, CTLA4, CD40, TSHR and TG which have been extensively studied in respect to their role in GD. We review recent findings implicating variants of FCRL3 (gene for FC receptor-like-3 protein), SCGB3A2 (gene for secretory uteroglobin-related protein 1- UGRP1) as well as other unverified possible candidate genes for GD selected through their documented association with type 1 diabetes mellitus: Tenr–IL2–IL21, CAPSL (encoding calcyphosine-like protein), IFIH1(gene for interferon-induced helicase C domain 1), AFF3, CD226 and PTPN2. We also review reports on association of skewed X chromosome inactivation and fetal microchimerism with GD. Finally we discuss issues of genotype-phenotype correlations in GD.
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Affiliation(s)
- Rafał Płoski
- Department of Medical Genetics, Centre for Biostructure, Medical University of Warsaw, Poland
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Liao J, Liang G, Xie S, Zhao H, Zuo X, Li F, Chen J, Zhao M, Chan TM, Lu Q. CD40L demethylation in CD4(+) T cells from women with rheumatoid arthritis. Clin Immunol 2012; 145:13-8. [PMID: 22889643 DOI: 10.1016/j.clim.2012.07.006] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2012] [Revised: 07/09/2012] [Accepted: 07/11/2012] [Indexed: 01/14/2023]
Abstract
We have previously demonstrated that DNA demethylation of CD40L on the X chromosome is responsible for female susceptibility to systemic lupus erythematosus (SLE). It is unknown whether aberrant methylation of the CD40L gene also contributes to the higher incidence of rheumatoid arthritis (RA) in females. In this study, we used real-time RT-PCR and flow cytometry to compare CD40L expression levels, and bisulfite sequencing to assess the methylation status of the CD40L promoter region. The results show that CD40L is upregrulated in CD4(+) T cells of female patients with RA. In addition, the CD40L promoter region in CD4(+) T cells from female RA patients was found to be demethylated, which corresponded with increased CD40L mRNA expression. These findings suggest that DNA demethylation contributes to CD40L expression in RA CD4(+) T cells and may in part explain the female preponderance of this disease.
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Affiliation(s)
- J Liao
- Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
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31
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Bakalov VK, Gutin L, Cheng CM, Zhou J, Sheth P, Shah K, Arepalli S, Vanderhoof V, Nelson LM, Bondy CA. Autoimmune disorders in women with turner syndrome and women with karyotypically normal primary ovarian insufficiency. J Autoimmun 2012; 38:315-21. [PMID: 22342295 PMCID: PMC3358475 DOI: 10.1016/j.jaut.2012.01.015] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Revised: 01/24/2012] [Accepted: 01/28/2012] [Indexed: 01/15/2023]
Abstract
The higher prevalence of autoimmune diseases in women compared to men could be due to effects of ovarian hormones, pregnancy and/or the presence of a second X chromosome. To elucidate the role of these factors, we investigated the prevalence and spectrum of autoimmune diagnoses in women with primary ovarian insufficiency associated with X chromosome monosomy (Turner syndrome, TS, n = 244) and women with karyotypically normal (46,XX) primary ovarian insufficiency (POI, n = 457) in a prospective study, conducted at the National Institutes of Health. We compared the study group prevalence to normative data for the U.S. population of women. Chronic lymphocytic (Hashimoto's) thyroiditis (HT) occurred in 37% of women with TS vs. 15% with POI (P < 0.0001); HT prevalence in both ovarian insufficiency groups significantly exceeded that in U.S. population of women (5.8%). Inflammatory bowel (IBD, 4%) and celiac disease (CD, 2.7%) were significantly increased in TS, but not in POI. No other autoimmune diagnosis, including Graves' disease or Type 1 diabetes appears to be significantly increased in either group. Women with TS had higher pro-inflammatory IL6 and TGF β1 levels (p < 0.0001 for both), and lower anti-inflammatory IL10 and TGF β2 levels (p < 0.005 for both) compared to POI and to normal volunteers. Lifetime estrogen exposure and parity were significantly lower in TS compared to POI, which were in turn lower than the general population of women. The finding that lymphocytic thyroiditis is greatly increased in both women with TS and POI suggests that factors associated with ovarian insufficiency per se promote this form of autoimmunity. The absence of a normal second X-chromosome further contributes to increased autoimmunity in TS.
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Affiliation(s)
- Vladimir K Bakalov
- Section on Epigenetics & Development, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, 10 Center Dr. CRC 1-3330; Bethesda, MD 20892-1103, USA.
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33
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Abstract
Turner Syndrome (TS) is a common genetic disorder, affecting female individuals, resulting from the partial or complete absence of one sex chromosome, and occurring in approximately 50 per 100,000 liveborn girls. TS is associated with reduced adult height and with gonadal dysgenesis, leading to insufficient circulating levels of female sex steroids and to infertility. Morbidity and mortality are increased in TS but average intellectual performance is within the normal range. TS is closely associated to the presence of autoantibodies and autoimmune diseases (AID), especially autoimmune thyroiditis and inflammatory bowel disease. Despite the fact that the strong association between TS and AID is well known and has been widely studied, the underlying immunopathogenic mechanism remains partially unexplained. Recent studies have displayed how TS patients do not show an excess of immunogenic risk markers. This is evocative for a higher responsibility of X-chromosome abnormalities in the development of AID, and particularly of X-genes involved in immune response. For instance, the long arm of the X chromosome hosts a MHC-locus, so the loss of that region may lead to a deficiency in immune regulation. Currently no firm guidelines for diagnosis exist. In conclusion, TS is a condition associated with a number of autoimmune manifestations. Individuals with TS need life-long medical attention. As a consequence of these findings, early diagnosis and regular screening for potential associated autoimmune conditions are essential in the medical follow-up of TS patients.
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Affiliation(s)
- Ana Lleo
- Center for Autoimmune Liver Diseases, Department of Internal Medicine, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
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34
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Bianchi I, Lleo A, Gershwin ME, Invernizzi P. The X chromosome and immune associated genes. J Autoimmun 2012; 38:J187-J192. [PMID: 22178198 DOI: 10.1016/j.jaut.2011.11.012] [Citation(s) in RCA: 259] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2011] [Accepted: 11/22/2011] [Indexed: 12/13/2022]
Abstract
The X chromosome is known to contain the largest number of immune-related genes of the whole human genome. For this reason, X chromosome has recently become subject of great interest and attention and numerous studies have been aimed at understanding the role of genes on the X chromosome in triggering and maintaining the autoimmune aggression. Autoimmune diseases are indeed a growing heath burden affecting cumulatively up to 10% of the general population. It is intriguing that most X-linked primary immune deficiencies carry significant autoimmune manifestations, thus illustrating the critical role played by products of single gene located on the X chromosome in the onset, function and homeostasis of the immune system. Again, the plethora of autoimmune stigmata observed in patients with Turner syndrome, a disease due to the lack of one X chromosome or the presence of major X chromosome deletions, indicate that X-linked genes play a unique and major role in autoimmunity. There have been several reports on a role of X chromosome gene dosage through inactivation or duplication in women with autoimmune diseases, for example through a higher rate of circulating cells with a single X chromosome (i.e. with X monosomy). Finally, a challenge for researchers in the coming years will be to dissect the role for the large number of X-linked microRNAs from the perspective of autoimmune disease development. Taken together, X chromosome might well constitute the common trait of the susceptibility to autoimmune diseases, other than to explain the female preponderance of these conditions. This review will focus on the available evidence on X chromosome changes and discuss their potential implications and limitations.
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Affiliation(s)
- Ilaria Bianchi
- Center for Autoimmune Liver Diseases, Department of Medicine, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
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35
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Bianco B, Verreschi ITN, Oliveira KC, Guedes AD, Barbosa CP, Lipay MVN. Analysis of vitamin D receptor gene (VDR) polymorphisms in Turner syndrome patients. Gynecol Endocrinol 2012; 28:326-9. [PMID: 22117179 DOI: 10.3109/09513590.2011.631630] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Individuals with Turner syndrome (TS) have increased risk for autoimmune diseases, especially thyroid abnormalities. The function of the vitamin D receptor (VDR) gene is influenced by several genetic polymorphisms which are associated with a susceptibility to a range of autoimmune diseases. Thus, we have hypothesized a possible relationship between thyroid abnormalities and VDR polymorphisms (ApaI/G1025-49T, TaqI/T1056C, FokI/T2C and BsmI G1024 + 283A) in TS patients. A case-control study was performed comprising 101 Brazilian women with TS and a control group consisting of 133 healthy fertile women without a history of autoimmune diseases. In TS group, 21.8% had Hashimoto's thyroiditis. Detection of VDR polymorphisms was performed using TaqMan system by real-time PCR. The χ(2) was used to compare allele and genotype frequencies between groups. Combined genotypes of VDR gene polymorphisms were assessed by the haplotype analysis. A p value <0.05 was considered statistically significant. Relatively similar VDR polymorphisms genotype and allelic frequencies in cases and controls were found, even when only considering the patients with thyroid abnormalities. Haplotype analysis showed that none of the VDR haplotypes were associated to thyroid diseases in TS patients. In conclusion, the results showed no association between VDR gene polymorphisms and thyroid abnormalities in Brazilian TS patients tested.
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Affiliation(s)
- Bianca Bianco
- Division of Endocrinology, Department of Medicine, Universidade Federal de São Paulo, São Paulo, Brazil.
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36
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Selmi C, Brunetta E, Raimondo MG, Meroni PL. The X chromosome and the sex ratio of autoimmunity. Autoimmun Rev 2011; 11:A531-7. [PMID: 22155196 DOI: 10.1016/j.autrev.2011.11.024] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The number of human conditions that are currently considered to be autoimmune diseases (AID) has been steadily growing over the past decades and it is now estimated that over 10 million people are affected in the United States. One of the major shared features among AID is the predominance in the female sex which in some cases changes with the age at disease diagnosis. Numerous hypotheses have been formulated based on intuitive scientific backgrounds to justify this sex imbalance, i.e. sex hormones and reproductive factors, fetal microchimerism, other sex-related environmental factors, a skewing of the X-chromosome inactivation patterns, and major defects in sex chromosomes. Nevertheless, none of these hypotheses has thus far gathered enough convincing evidence and in most cases data are conflicting, as well illustrated by the reports on fetal microchimerism in systemic sclerosis or primary biliary cirrhosis. The present article will critically discuss the main hypotheses (loss of mosaicism, reactivation, and haploinsufficiency) that have been proposed based on findings in female patients with specific AID along with two additional mechanisms (X-chromosome vulnerability and X-linked polyamine genes) that have been observed in AID models. Further, recent data have significantly shifted the paradigm of X chromosome inactivation by demonstrating that a large number of genes can variably escape silencing on one or both chromosomes. As a result we may hypothesize that more than one mechanism may contribute to the female susceptibility to tolerance breakdown while the possibility that unknown factors may indeed protect men from AID should not be overlooked.
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Affiliation(s)
- Carlo Selmi
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA.
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37
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Autoimmune disease and gender: plausible mechanisms for the female predominance of autoimmunity. J Autoimmun 2011; 38:J109-19. [PMID: 22079680 DOI: 10.1016/j.jaut.2011.10.003] [Citation(s) in RCA: 230] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2011] [Accepted: 10/24/2011] [Indexed: 11/21/2022]
Abstract
A large number of autoimmune diseases (ADs) are more prevalent in women. The more frequent the AD and the later it appears, the more women are affected. Many ideas mainly based on hormonal and genetic factors that influence the autoimmune systems of females and males differently, have been proposed to explain this predominance. These hypotheses have gained credence mostly because many of these diseases appear or fluctuate when there are hormonal changes such as in late adolescence and pregnancy. Differences in X chromosome characteristics between men and women with an AD have led researchers to think that the genetic background of this group of diseases also relates to the genetic determinants of gender. These hormonal changes as well as the genetic factors that could explain why women are more prone to develop ADs are herein reviewed.
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38
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Kivity S, Ehrenfeld M. Can we explain the higher prevalence of autoimmune disease in women? Expert Rev Clin Immunol 2011; 6:691-4. [PMID: 20828274 DOI: 10.1586/eci.10.60] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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39
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The unexplained female predominance of systemic lupus erythematosus: clues from genetic and cytokine studies. Clin Rev Allergy Immunol 2011; 40:42-9. [PMID: 20063186 DOI: 10.1007/s12016-009-8192-4] [Citation(s) in RCA: 186] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Despite recent progress in the understanding of systemic lupus erythematosus (SLE), the striking 9:1 female to male ratio of disease incidence remains largely unexplained. In addition, peak SLE incidence rates occur during the early reproductive years in women. Studies which illuminate potential causes underlying this sex difference and characteristic onset during the reproductive years have the potential to fundamentally advance our understanding of disease pathogenesis in SLE. Similarly, progress in this area will likely inform human reproductive immunology. Studies of sex hormone function in the immune system are of obvious importance; however, it seems likely that many other types of sex-related genetic and immunological differences will contribute to SLE. In this review, we will focus on recent work in sex-related differences in cytokine pathways and genetics of these pathways as they relate to SLE pathogenesis. It seems quite possible that many of these sex-related differences could be important to reproductive fitness, which may explain the conservation of these immune system features and the observed female predominance of SLE.
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40
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Abstract
Autoimmune diseases appear to have multiple contributing factors including genetics, epigenetics, environmental factors, and aging. The predominance of females among patients with autoimmune diseases suggests possible involvement of the X chromosome and X chromosome inactivation. X chromosome inactivation is an epigenetic event resulting in multiple levels of control for modulation of the expression of X-linked genes in normal female cells such that there remains only one active X chromosome in the cell. The extent of this control is unique among the chromosomes and has the potential for problems when regulation is disrupted. Here we discuss the X chromosome inactivation process and how the X chromosome and X chromosome inactivation may be involved in development of autoimmune disorders.
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Affiliation(s)
- Wesley H Brooks
- Experimental HTS, Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612-9416, USA.
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41
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The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol 2010; 10:594-604. [DOI: 10.1038/nri2815] [Citation(s) in RCA: 523] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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42
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Bianco B, Verreschi ITN, Oliveira KC, Guedes AD, Galera BB, Galera MF, Barbosa CP, Lipay MVN. PTPN22 Polymorphism is Related to Autoimmune Disease Risk in Patients with Turner Syndrome. Scand J Immunol 2010; 72:256-9. [DOI: 10.1111/j.1365-3083.2010.02438.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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43
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44
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Lu LJ, Wallace DJ, Ishimori ML, Scofield RH, Weisman MH. Review: Male systemic lupus erythematosus: a review of sex disparities in this disease. Lupus 2009; 19:119-29. [PMID: 19946032 DOI: 10.1177/0961203309350755] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Although males with systemic lupus erythematosus (SLE) represent 4-22% of all SLE patients, it may not be appropriate that these cases should be subordinated to females with SLE in terms of most health-related issues. Over the past few decades, some distinctive features of male lupus have been observed with regard to genetic and environmental aspects of sex differences, clinical features, and outcome. In addition, recent insights into sex disparities in this disease have brought forth a few plausible and novel pathogenetic hypotheses. This review discusses these findings and sex disparities in SLE that appear to be especially noteworthy and pertinent to our understanding of male SLE.
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Affiliation(s)
- L-J Lu
- Cedars Sinai Medical Center, Los Angeles, California 90048, USA
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45
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Invernizzi P, Gershwin ME. The genetics of human autoimmune disease. J Autoimmun 2009; 33:290-9. [DOI: 10.1016/j.jaut.2009.07.008] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2009] [Accepted: 07/15/2009] [Indexed: 10/20/2022]
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46
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Knudsen GP. Gender bias in autoimmune diseases. J Neurol Sci 2009; 286:43-6. [DOI: 10.1016/j.jns.2009.04.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2009] [Revised: 03/24/2009] [Accepted: 04/14/2009] [Indexed: 11/27/2022]
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47
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Larizza D, Calcaterra V, Martinetti M. Autoimmune stigmata in Turner syndrome: When lacks an X chromosome. J Autoimmun 2009; 33:25-30. [DOI: 10.1016/j.jaut.2009.03.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2009] [Accepted: 03/03/2009] [Indexed: 01/07/2023]
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48
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Chabchoub G, Uz E, Maalej A, Mustafa CA, Rebai A, Mnif M, Bahloul Z, Farid NR, Ozcelik T, Ayadi H. Analysis of skewed X-chromosome inactivation in females with rheumatoid arthritis and autoimmune thyroid diseases. Arthritis Res Ther 2009; 11:R106. [PMID: 19589151 PMCID: PMC2745787 DOI: 10.1186/ar2759] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2008] [Revised: 06/22/2009] [Accepted: 07/09/2009] [Indexed: 12/12/2022] Open
Abstract
Introduction The majority of autoimmune diseases such as rheumatoid arthritis (RA) and autoimmune thyroid diseases (AITDs) are characterized by a striking female predominance superimposed on a predisposing genetic background. The role of extremely skewed X-chromosome inactivation (XCI) has been questioned in the pathogenesis of several autoimmune diseases. Methods We examined XCI profiles of females affected with RA (n = 106), AITDs (n = 145) and age-matched healthy women (n = 257). XCI analysis was performed by enzymatic digestion of DNA with a methylation sensitive enzyme (HpaII) followed by PCR of a polymorphic CAG repeat in the androgen receptor (AR) gene. The XCI pattern was classified as skewed when 80% or more of the cells preferentially inactivated the same X-chromosome. Results Skewed XCI was observed in 26 of the 76 informative RA patients (34.2%), 26 of the 100 informative AITDs patients (26%), and 19 of the 170 informative controls (11.2%) (P < 0.0001; P = 0.0015, respectively). More importantly, extremely skewed XCI, defined as > 90% inactivation of one allele, was present in 17 RA patients (22.4%), 14 AITDs patients (14.0%), and in only seven controls (4.1%, P < 0.0001; P = 0.0034, respectively). Stratifying RA patients according to laboratory profiles (rheumatoid factor and anti-citrullinated protein antibodies), clinical manifestations (erosive disease and nodules) and the presence of others autoimmune diseases did not reveal any statistical significance (P > 0.05). Conclusions These results suggest a possible role for XCI mosaicism in the pathogenesis of RA and AITDs and may in part explain the female preponderance of these diseases.
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Affiliation(s)
- Ghazi Chabchoub
- Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Avenue Majida Boulila, Sfax, Tunisia.
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Invernizzi P, Pasini S, Selmi C, Miozzo M, Podda M. Skewing of X chromosome inactivation in autoimmunity. Autoimmunity 2009; 41:272-7. [DOI: 10.1080/08916930802024574] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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50
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Cooney CM, Bruner GR, Aberle T, Namjou-Khales B, Myers LK, Feo L, Li S, D'Souza A, Ramirez A, Harley JB, Scofield RH. 46,X,del(X)(q13) Turner's syndrome women with systemic lupus erythematosus in a pedigree multiplex for SLE. Genes Immun 2009; 10:478-81. [PMID: 19458623 PMCID: PMC2722751 DOI: 10.1038/gene.2009.37] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2008] [Accepted: 03/24/2009] [Indexed: 11/09/2022]
Abstract
Systemic lupus erythematosus (SLE) disproportionately affects women. Recent work demonstrates that men with Klinefelter's syndrome (47,XXY men) have a similar risk of developing SLE as do women. We present an unusual African-American family with two SLE-affected individuals in which one of the patients with SLE also has Turner's syndrome (46,X,del(X)(q13)). Although not definitive, this family raises interesting questions regarding the function of genes located on the X chromosome in the development of SLE. The paucity of case reports documenting the overlap of SLE with Turner's syndrome while there is an association of male SLE with Klinefelter's syndrome suggests a lower risk of SLE in women with Turner's syndrome. These observations are consistent with a gene dose effect at X with two X chromosomes (46,XX or 47,XXY) conferring higher risk and one X chromosome (46,XY or 45,XO) conferring lower risk of SLE.
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Affiliation(s)
- C M Cooney
- Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
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