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Zhu H, Pan J. Effects of immune cells in mediating the relationship between inflammatory bowel disease and pyoderma gangrenosum: a two-sample, two-step mendelian randomization study. Arch Dermatol Res 2025; 317:176. [PMID: 39760889 DOI: 10.1007/s00403-024-03736-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 07/31/2024] [Accepted: 12/20/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND Although the precise cause of the co-occurrence of pyoderma gangrenosum (PG) and inflammatory bowel disease (IBD) is still unknown, prior research has shown that the two conditions coexist. Moreover, it is currently unknown how immune cells function in influencing the relationship between IBD and PG. METHODS In order to choose independent single nucleotide polymorphism (SNP) as instrumental variables, we were provided with genome-wide association study (GWAS) summary data of European populations from the IEU OpenGWAS project (for IBD) and a the FinnGen database (for PG) publically available. For the MR analysis, a range of analytical techniques were employed to peer into the possible causative relationship between PG and IBD. The two-step MR analysis was used to investigate the mediating role of immune cells between IBD and PG. The chief method utilized was the inverse variance weighted (IVW) approach. Using the Cochran's Q test and the MR-Egger intercept, respectively, heterogeneity or pleiotropy was evaluated to support the findings. MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) were used to identify the outlier SNP. RESULTS IBD was found to raise the incidence of PG (IVW-FE: OR = 1.604, 95%CI = 1.308-1.966, p = 5.58 × 10- 6), according to MR findings. Moreover, UC or CD were strongly correlated with a greater risk of PG (OR = 1.339, 95%CI = 1.041-1.723, p = 0.023 for UC; OR = 1.339, 95%CI = 1.107-1.621, p = 0.003 for CD). The results of the reverse MR study did not suggest a connection between PG and IBD. CD4+ regulatory T cell is the mediator that particularly stood out in the interaction between UC and PG. There was evidence of neither heterogeneity nor horizontal pleiotropy. And the validity of these conclusions was verified. CONCLUSION In the European population, PG risk may be genetically elevated by IBD, including CD and UC, according to the current study. The effect of UC on PG may have been causally mediated by CD4+ regulatory T cells.
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Affiliation(s)
- Haoqi Zhu
- Department of Gastroenterology, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Jingyi Pan
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
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2
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Zhu H, Jiang Y, Ma G, Xu Y, Pan J. Causal relationship between inflammatory bowel disease and erythema nodosum: A two-sample bidirectional Mendelian randomization study. Skin Res Technol 2024; 30:e13600. [PMID: 38297958 PMCID: PMC10831198 DOI: 10.1111/srt.13600] [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: 12/16/2023] [Accepted: 01/16/2024] [Indexed: 02/02/2024]
Abstract
BACKGROUND Previous studies have demonstrated the coexistence of erythema nodosum (EN) and inflammatory bowel disease (IBD), while the exact etiology of the co-occurrence of the two disorders remains uncertain. METHODS A bidirectional two-sample Mendelian randomization (MR) design was employed to determine the causal link between EN and IBD. Genetic variations associated with Crohn's disease (CD) and ulcerative colitis (UC) were derived from accessible genome-wide association studies pertaining to European ancestry. The FinnGen database was used to find the genetic variations containing EN. In the forward model, IBD was identified as the exposure, whereas in the reverse model, EN was identified as the exposure. The causal link between IBD and EN was examined using a range of different analysis techniques, the primary one being the inverse variance weighted (IVW) method, including inverse variance weighted-fixed effects (IVW-FE) and inverse-variance weighted-multiplicative random effects (IVW-MRE). To strengthen the results, assessments of sensitivity, heterogeneity, and pleiotropy were also conducted. RESULTS MR results showed that IBD increased the risk of EN (IVW-MRE: OR = 1.242, 95% CI = 1.068-1.443, p = 0.005). Furthermore, there was a strong correlation found between CD and a higher risk of EN (IVW-FE: OR = 1.250, 95% CI = 1.119-1.396, p = 8.036 × 10-5 ). However, UC did not appear to be linked to EN (IVW-FE: OR = 1.104, 95% CI = 0.868-1.405, p = 0.421). The reverse MR analysis findings did not imply that EN was linked to IBD. Horizontal pleiotropy did not appear to exist, and the robustness of these findings was confirmed. CONCLUSION The current investigation found that in European populations, IBD and its subtype CD could raise the incidence of EN.
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Affiliation(s)
- Haoqi Zhu
- Department of GastroenterologyWenzhou Central HospitalWenzhouZhejiangChina
- Department of GastroenterologyThe Second Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
| | - Yi Jiang
- Department of AnesthesiologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
| | - Guolong Ma
- Department of AnesthesiologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
| | - Yuan Xu
- Department of AnesthesiologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
| | - Jingyi Pan
- Department of GastroenterologyWenzhou Central HospitalWenzhouZhejiangChina
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da Silva Júnior RT, Apolonio JS, de Souza Nascimento JO, da Costa BT, Malheiro LH, Silva Luz M, de Carvalho LS, da Silva Santos C, Freire de Melo F. Crohn's disease and clinical management today: How it does? World J Methodol 2023; 13:399-413. [PMID: 38229938 PMCID: PMC10789097 DOI: 10.5662/wjm.v13.i5.399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/11/2023] [Accepted: 10/25/2023] [Indexed: 12/20/2023] Open
Abstract
Crohn's Disease (CD) is an Inflammatory Bowel Disease and is characterized by an immune-mediated nature. Its etiology results from the interaction between genetic, enviromental and microbial factors. Regarding pathophysiology, it involves high levels of interleukin (IL)-12, IL-17, and Th1 profile, along with loss of tolerance mechanisms, an increase in pro-inflammatory interleukins, beyond the possibility to affect any part of the gastrointestinal tract. Its symptoms include abdominal pain, chronic diarrhea, weight loss, anorexia, and fatigue, as well as blood in the stool or rectum. Additionally, conditions comprising musculoskeletal, cutaneous, ocular, hepatic, and hematological alterations may be associated with this scenario and extra-intestinal presentation, such as erythema nodosum, anterior uveitis, osteoporosis, and arthritis can also occur. Today, clinical history, exams as fecal calprotectin, ileocolonocopy, and capsule endoscopy can be performed in the diagnosis investigation, along with treatments to induce and maintain remission. In this sense, anti-inflammatory drugs, such as corticosteroids, immunomodulators, and biological agents, as well as surgery and non-pharmacological interventions plays a role in its therapy. The aim of this review is to bring more current evidence to clinical management of CD, as well as to briefly discuss aspects of its pathophysiology, surveillance, and associated disorders.
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Affiliation(s)
| | - Jonathan Santos Apolonio
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Bruna Teixeira da Costa
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luciano Hasimoto Malheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Lorena Sousa de Carvalho
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Cleiton da Silva Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Jatana S, Ponti AK, Johnson EE, Rebert NA, Smith JL, Fulmer CG, Maytin EV, Achkar JP, Fernandez AP, McDonald C. A novel murine model of pyoderma gangrenosum reveals that inflammatory skin-gut crosstalk is mediated by IL-1β-primed neutrophils. Front Immunol 2023; 14:1148893. [PMID: 37475852 PMCID: PMC10354730 DOI: 10.3389/fimmu.2023.1148893] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 06/08/2023] [Indexed: 07/22/2023] Open
Abstract
Pyoderma gangrenosum (PG) is a debilitating skin condition often accompanied by inflammatory bowel disease (IBD). Strikingly, ~40% of patients that present with PG have underlying IBD, suggesting shared but unknown mechanisms of pathogenesis. Impeding the development of effective treatments for PG is the absence of an animal model that exhibits features of both skin and gut manifestations. This study describes the development of the first experimental drug-induced mouse model of PG with concomitant intestinal inflammation. Topical application of pyrimidine synthesis inhibitors on wounded mouse skin generates skin ulcers enriched in neutrophil extracellular traps (NETs) as well as pro-inflammatory cellular and soluble mediators mimicking human PG. The mice also develop spontaneous intestinal inflammation demonstrated by histologic damage. Further investigations revealed increased circulating low density IL-1β primed neutrophils that undergo enhanced NETosis at inflamed tissue sites supported by an increase in circulatory citrullinated histone 3, a marker of aberrant NET formation. Granulocyte depletion dampens the intestinal inflammation in this model, further supporting the notion that granulocytes contribute to the skin-gut crosstalk in PG mice. We anticipate that this novel murine PG model will enable researchers to probe common disease mechanisms and identify more effective targets for treatment for PG patients with IBD.
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Affiliation(s)
- Samreen Jatana
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - András K. Ponti
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Erin E. Johnson
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
- Department of Biology, John Carroll University, University Heights, OH, United States
| | - Nancy A. Rebert
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Jordyn L. Smith
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Clifton G. Fulmer
- Department of Pathology, Pathology & Laboratory Medicine, Cleveland Clinic, Cleveland, OH, United States
| | - Edward V. Maytin
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
- Department of Dermatology, Dermatology & Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Jean-Paul Achkar
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
- Department of Gastroenterology, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Anthony P. Fernandez
- Department of Pathology, Pathology & Laboratory Medicine, Cleveland Clinic, Cleveland, OH, United States
- Department of Dermatology, Dermatology & Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Christine McDonald
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States
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Zhang J, Sun L, Withanage M, Ganesan S, Williamson M, Marchesan J, Jiao Y, Teles F, Yu N, Liu Y, Wu D, Moss K, Mangalam A, Zeng E, Lei Y, Zhang S. TRAF3IP2-IL-17 Axis Strengthens the Gingival Defense against Pathogens. J Dent Res 2023; 102:103-115. [PMID: 36281065 PMCID: PMC9780753 DOI: 10.1177/00220345221123256] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Recent genome-wide association studies have suggested novel risk loci associated with periodontitis, which is initiated by dysbiosis in subgingival plaque and leads to destruction of teeth-supporting structures. One such genetic locus was the tumor necrosis factor receptor-associated factor 3 interacting protein 2 (TRAF3IP2), a gene encoding the gate-keeping interleukin (IL)-17 receptor adaptor. In this study, we first determined that carriers of the lead exonic variant rs13190932 within the TRAF3IP2 locus combined with a high plaque microbial burden was associated with more severe periodontitis than noncarriers. We then demonstrated that TRAF3IP2 is essential in the IL-17-mediated CCL2 and IL-8 chemokine production in primary gingival epithelial cells. Further analysis suggested that rs13190932 may serve a surrogate variant for a genuine loss-of-function variant rs33980500 within the same gene. Traf3ip2 null mice (Traf3ip2-/-) were more susceptible than wild-type (WT) mice to the Porphyromonas gingivalis-induced periodontal alveolar bone loss. Such bone loss was associated with a delayed P. gingivalis clearance and an attenuated neutrophil recruitment in the gingiva of Traf3ip2-/- mice. Transcriptomic data showed decreased expression of antimicrobial genes, including Lcn2, S100a8, and Defb1, in the Traf3ip2-/- mouse gingiva in comparison to WT mice prior to or upon P. gingivalis oral challenge. Further 16S ribosomal RNA sequencing analysis identified a distinct microbial community in the Traf3ip2-/- mouse oral plaque, which was featured by a reduced microbial diversity and an overabundance of Streptococcus genus bacteria. More P. gingivalis was observed in the Traf3ip2-/- mouse gingiva than WT control animals in a ligature-promoted P. gingivalis invasion model. In agreement, neutrophil depletion resulted in more local gingival tissue invasion by P. gingivalis. Thus, we identified a homeostatic IL-17-TRAF3IP2-neutrophil axis underpinning host defense against a keystone periodontal pathogen.
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Affiliation(s)
- J. Zhang
- Iowa Institute of Oral Health Research, University of Iowa College of Dentistry, Iowa City, IA, USA,Periodontics, University of Iowa College of Dentistry, Iowa City, IA, USA,S. Zhang, Iowa Institute of Oral Health Research, Periodontics Department, University of Iowa College of Dentistry, Room 401 Dental Science Building, 801 Newton Road, Iowa City, IA 52242, USA.
| | - L. Sun
- Department of Microbiology & Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA,Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - M.H.H. Withanage
- Division of Biostatistics and Computational Biology, University of Iowa College of Dentistry, Iowa City, IA, USA
| | - S.M. Ganesan
- Iowa Institute of Oral Health Research, University of Iowa College of Dentistry, Iowa City, IA, USA,Periodontics, University of Iowa College of Dentistry, Iowa City, IA, USA
| | - M.A. Williamson
- Iowa Institute of Oral Health Research, University of Iowa College of Dentistry, Iowa City, IA, USA,Periodontics, University of Iowa College of Dentistry, Iowa City, IA, USA
| | - J.T. Marchesan
- Department of Periodontology, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Y. Jiao
- Department of Periodontology, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - F.R. Teles
- Department of Basic & Translational Sciences, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA
| | - N. Yu
- The Forsyth Institute, Cambridge, MA, USA
| | - Y. Liu
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - D. Wu
- Department of Periodontology, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA,Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - K.L. Moss
- Department of Periodontology, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - A.K. Mangalam
- Department of Pathology, University of Iowa College of Medicine, Iowa City, IA, USA
| | - E. Zeng
- Division of Biostatistics and Computational Biology, University of Iowa College of Dentistry, Iowa City, IA, USA
| | - Y.L. Lei
- Department of Periodontics & Oral Medicine, University of Michigan School of Dentistry, Ann Harbor, MI, USA
| | - S. Zhang
- Iowa Institute of Oral Health Research, University of Iowa College of Dentistry, Iowa City, IA, USA,Periodontics, University of Iowa College of Dentistry, Iowa City, IA, USA
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Cobb CBC, Caravaglio JV, Qureshi AA, Robinson‐Bostom L. Concominant Bullous Pemphigoid and Cutaneous Crohn Disease. J Cutan Pathol 2022; 49:579-583. [DOI: 10.1111/cup.14206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 01/05/2022] [Accepted: 01/22/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Caryn B. C. Cobb
- Department of Dermatology Warren Alpert Medical School of Brown University, 593 Eddy Street, Ambulatory Patient Care Building, 10th Floor Providence Rhode Island
| | - Joseph V. Caravaglio
- Department of Dermatology Warren Alpert Medical School of Brown University, 593 Eddy Street, Ambulatory Patient Care Building, 10th Floor Providence Rhode Island
| | - Abrar A. Qureshi
- Department of Dermatology Warren Alpert Medical School of Brown University, 593 Eddy Street, Ambulatory Patient Care Building, 10th Floor Providence Rhode Island
| | - Leslie Robinson‐Bostom
- Department of Dermatology Warren Alpert Medical School of Brown University, 593 Eddy Street, Ambulatory Patient Care Building, 10th Floor Providence Rhode Island
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Pantic I, Jevtic D, Nordstrom CW, Madrid C, Milovanovic T, Dumic I. Clinical Manifestations of Leukocytoclastic Vasculitis, Treatment, and Outcome in Patients with Ulcerative Colitis: A Systematic Review of the Literature. J Clin Med 2022; 11:739. [PMID: 35160187 PMCID: PMC8836768 DOI: 10.3390/jcm11030739] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/26/2022] [Accepted: 01/28/2022] [Indexed: 12/30/2022] Open
Abstract
Leukocytoclastic vasculitis (LCV) is a rare extraintestinal manifestation (EIM) of ulcerative colitis (UC). Observations about its association with UC stem from case reports and small case series. Due to its rarity, more rigorous cross-sectional studies are scarce and difficult to conduct. The aim of this systematic review was to synthetize the knowledge on this association by reviewing published literature in the form of both case reports and case series; and report the findings according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In contrast to LCV in Chron disease (CD), which occurs secondary to biologic therapies used for its treatment, LCV in UC is a true reactive skin manifestation. Both genders are equally affected. Palpable purpura (41%) and erythematous plaques (27%) are the most common clinical manifestations. In 41% of patients, the rash is painful, and the lower extremities are most commonly involved (73%). Systemic symptoms such as fever, arthralgias, fatigue, and malaise are seen in 60% of patients. Unlike previous reports, we found that LCV more commonly occurs after the UC diagnosis (59%), and 68% of patients have active intestinal disease at the time of LCV diagnosis. Antineutrophil cytoplasmic antibody (ANCA) is positive in 41% of patients, and 36% of patients have other EIMs present concomitantly with LCV. The majority of patients were treated with corticosteroids (77%), and two (10%) required colectomy to control UC and LCV symptoms. Aside from one patient who died from unrelated causes, all others survived with their rash typically resolving without scarring (82%).
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Affiliation(s)
- Ivana Pantic
- Clinic of Gastroenterology and Hepatology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia; (I.P.); (T.M.)
| | - Djordje Jevtic
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Charles W. Nordstrom
- Department of Hospital Medicine, Mayo Clinic Health System, Eau Claire, WI 54702, USA; (C.W.N.); (C.M.)
- Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA
| | - Cristian Madrid
- Department of Hospital Medicine, Mayo Clinic Health System, Eau Claire, WI 54702, USA; (C.W.N.); (C.M.)
- Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA
| | - Tamara Milovanovic
- Clinic of Gastroenterology and Hepatology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia; (I.P.); (T.M.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Igor Dumic
- Department of Hospital Medicine, Mayo Clinic Health System, Eau Claire, WI 54702, USA; (C.W.N.); (C.M.)
- Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA
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8
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Mucocutaneous manifestations in patients with inflammatory bowel disease: a decade study from a Greek cohort. Eur J Gastroenterol Hepatol 2021; 33:1387-1393. [PMID: 33470697 DOI: 10.1097/meg.0000000000002053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND We sought to investigate the prevalence of mucocutaneous manifestations (MCM) and potential associations with clinical characteristics in Greek patients with IBD. METHODS This was a retrospective observational single-center study. Patients with IBD diagnosis attending a tertiary referral hospital in Heraklion, Crete, from January 2010 to January 2020 were included. Data were extracted with relevant medical information from the IBD registry. Standard statistical tests, descriptive statistics tests, chi-square, Pearson correlation and multivariate analysis tests were performed, using IBM SPSS Statistics 25. RESULTS A total of 806 IBD patients were included in the study: 463 (57.4%) males, 441 (54.7%) Crohn's Disease, 352 (43.7%) ulcerative colitis and 13 (1.6%) IBD unclassified (IBD-U). Mean age was 50.67 ± 17.67 years, mean age of IBD diagnosis 36.67 ± 16.53 years and mean disease duration 13.65 ± 9.89 years. The prevalence of MCM was 171/806 (21.2%), 9.65% in ulcerative colitis and 30.84% in CD. The presence of MCM was significantly correlated with younger age of IBD diagnosis, longer IBD duration, CD diagnosis, inflammatory behavior and ileal or ileocolonic location of CD, extensive colitis in ulcerative colitis, intestinal manifestations (EIMs) and treatment with immunosuppressant or anti-TNFa. The development of MCM was independently associated with the presence of other EIMs odds ratio (OR), 4.03 [95% confidence interval (CI), 2.60-6.24; P < 0.001] and treatment with immunosuppressant (OR, 1.87; 95% CI, 01.14-3.07; P = 0.013) or anti-TNFa (OR = 2.47; 95% CI, 1.59-3.84; P < 0.01). CONCLUSIONS In our study, about one-fifth of IBD patients developed MCM that was more frequently present in CD than in ulcerative colitis.
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Wei J, Yan T, Liang Y. Targeting TRAF3IP2 alleviates high glucose-induced cardiomyocyte inflammation and apoptosis. Drug Dev Res 2021; 83:167-175. [PMID: 34260107 DOI: 10.1002/ddr.21856] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/16/2021] [Accepted: 06/23/2021] [Indexed: 11/12/2022]
Abstract
To clarify the role of TRAF3IP2 in high glucose (HG)-stimulated cardiomyocyte inflammation and apoptosis and its action mechanism. SiRNA plasmid of TRAF3IP2 was constructed and transfected into HG-stimulated cardiomyocytes to silence TRAF3IP2. The expression of TRAF3IP2 was determined by quantitative polymerase chain reaction (qPCR) and western blot. Cell viability and cytotoxicity were first observed using cell counting kit-8 and lactate dehydrogenase assays. The inflammatory injury of the cardiomyocytes was then examined by real time-qPCR (RT-qPCR) and western blot. The oxidative stress of the cardiomyocytes was evaluated using reactive oxygen species assay kit, RT-qPCR, western blot and enzyme activity assay kit. Next, cell apoptosis was detected employing TUNEL and western blot. Finally, RT-qPCR and western blot were performed to investigate the effects of inhibitors of dipeptidyl peptidase-4, including saxagliptin, empagliflozin and linagliptin, on TRAF3IP2. TRAF3IP2 expression was found to be increased in HG-stimulated cardiomyocytes. TRAF3IP2 interference inhibited HG-induced cell viability loss, cytotoxicity, inflammatory response, oxidative stress and apoptosis of the cardiomyocytes. Moreover, saxagliptin, empagliflozin and linagliptin inhibited the expression of TRAF3IP2. TRAF3IP2 interference alleviates HG-induced inflammation and apoptosis of cardiomyocytes. The result suggests that TRAF3IP2 may be a promising therapeutic target in treating diabetic cardiomyopathy.
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Affiliation(s)
- Jing Wei
- Department of Endocrinology, People's Hospital Affiliated to Chongqing Three Gorges Medical College, Chongqing, China
| | - Tao Yan
- Department of Endocrinology, People's Hospital Affiliated to Chongqing Three Gorges Medical College, Chongqing, China
| | - Yuanhong Liang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong, Guangzhou, China.,Department of Cardiology, Linzhi people's Hospital, Linzhi, Tibet, China
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10
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Treatment of Pyoderma Gangrenosum in Pediatric Inflammatory Bowel Disease. ACTA ACUST UNITED AC 2020; 1:e008. [DOI: 10.1097/pg9.0000000000000008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 08/03/2020] [Indexed: 11/26/2022]
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11
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Alinaghi F, Tekin HG, Burisch J, Wu JJ, Thyssen JP, Egeberg A. Global Prevalence and Bidirectional Association Between Psoriasis and Inflammatory Bowel Disease-A Systematic Review and Meta-analysis. J Crohns Colitis 2020; 14:351-360. [PMID: 31504363 DOI: 10.1093/ecco-jcc/jjz152] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Epidemiological studies have established an association between psoriasis and inflammatory bowel disease [IBD], i.e. ulcerative colitis [UC] and Crohn's disease [CD], but results are inconsistent. The aim of this study was therefore to quantify the prevalences and association between IBD and psoriasis. METHODS PubMed, Web of Science, and EMBASE were searched from database inception through April 2018 for studies reporting data on psoriasis among patients with IBD and vice versa. Meta-analysis was performed to estimate, respectively, the prevalences and association between IBD and psoriasis. Data extraction was according to the PRISMA guideline, and quality assessment was made using the Newcastle-Ottawa Scale. The main outcomes were the proportion of psoriasis patients with IBD and vice versa, as well as the association (odds ratio [OR]) of IBD in psoriasis and psoriasis in IBD, respectively. RESULTS Based on quantitative analysis of 93 studies, the prevalence of psoriasis in CD and in UC was 3.6% (95% confidence interval [CI] 3.1%-4.6%) and 2.8% [95% CI 2.0%-3.8%] respectively. The prevalence of CD and UC was 0.7% [95% CI 0.2%-1.3%] and 0.5% [95% CI 0.3%-0.8%], respectively, among patients with psoriasis. Presence of CD or UC was significantly associated with psoriasis, with OR 2.0 [95% CI 1.4-2.9] and OR 1.5 [95% CI 1.2-2.0], respectively. Presence of psoriasis was significantly associated with CD: OR 2.2 [95% CI 1.6-3.1] and with UC: OR 1.6 [95% CI 1.3-2.0]. CONCLUSIONS We found significant bidirectional associations between psoriasis and IBD, warranting increased awareness among clinicians in the diagnostic process, especially in children and adolescents with IBD. Last, this study showed an increased frequency of paradoxical psoriasis in patients treated with biologics.
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Affiliation(s)
- Farzad Alinaghi
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Hasan Göcker Tekin
- Department of Plastic Surgery, Aalborg University Hospital, Aalborg, Denmark
| | - Johan Burisch
- Gastro-unit, Hvidovre Hospital, University of Copenhagen, Hidovre, Denmark
| | - Jashin J Wu
- Department of Dermatology, Dermatology Research and Education Foundation, Irvine, CA, USA
| | - Jacob P Thyssen
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Alexander Egeberg
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
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12
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Ribaldone DG, Pellicano R, Actis GC. The gut and the inflammatory bowel diseases inside-out: extra-intestinal manifestations. MINERVA GASTROENTERO 2019; 65:309-318. [PMID: 30994321 DOI: 10.23736/s1121-421x.19.02577-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
An increasing deal of attention is being conveyed on the extra-intestinal manifestations (EIM) of inflammatory bowel diseases (IBD). We compiled the present review in an attempt to upgrade the accuracy of the classification of such polymorphic entities. We focused on three patterns. First, the conventional EIM localized to bone and joints, to the eye, to the biliary tree and to the skin. Second, the so-called IBD-like syndromes accompanied by bone marrow-derived anomalies of innate or acquired immunity. Third, specific disorders of the skin and of the lungs. EIM are thought to derive from an altered gut permeability, the release of cross-reacting antigens, and subsequent peripheral inflammation; T helper 17 cells boosted by a polymorphic interleukin 23 circuitry would be the main effectors of this chain. Inflammatory bowel disease-like pictures would derive from inborn errors of the immune response causing undue inflammation home to the gut. Monogenic IBD belong to this subset, and are of specific pediatric interest. Psoriasis, chronic obstructive pulmonary disease, and IBD are all inflammatory disorders of the barrier organs: skin, lungs, and gut. The demonstration that specific antigen hyper- or hyporesponsiveness raised at any of the three districts can modulate the response of the other two sites, has led to the innovative concept of a system-wide mucosal immunological organ. An improved knowledge of these entities has not only a speculative importance, but can also bear a clinical impact, insofar as EIM prove often more disabling than the underlying IBD itself.
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Affiliation(s)
| | - Rinaldo Pellicano
- Unit of Gastroenterology, Molinette-S. Giovanni Antica Sede Hospital, Turin, Italy
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13
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Xu T, Jin P, Qin ZS. Regulatory annotation of genomic intervals based on tissue-specific expression QTLs. Bioinformatics 2019; 36:690-697. [PMID: 31504167 PMCID: PMC8215915 DOI: 10.1093/bioinformatics/btz669] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 05/14/2019] [Accepted: 08/23/2019] [Indexed: 01/31/2023] Open
Abstract
MOTIVATION Annotating a given genomic locus or a set of genomic loci is an important yet challenging task. This is especially true for the non-coding part of the genome which is enormous yet poorly understood. Since gene set enrichment analyses have demonstrated to be effective approach to annotate a set of genes, the same idea can be extended to explore the enrichment of functional elements or features in a set of genomic intervals to reveal potential functional connections. RESULTS In this study, we describe a novel computational strategy named loci2path that takes advantage of the newly emerged, genome-wide and tissue-specific expression quantitative trait loci (eQTL) information to help annotate a set of genomic intervals in terms of transcription regulation. By checking the presence or the absence of millions of eQTLs in a set of input genomic intervals, combined with grouping eQTLs by the pathways or gene sets that their target genes belong to, loci2path build a bridge connecting genomic intervals to functional pathways and pre-defined biological-meaningful gene sets, revealing potential for regulatory connection. Our method enjoys two key advantages over existing methods: first, we no longer rely on proximity to link a locus to a gene which has shown to be unreliable; second, eQTL allows us to provide the regulatory annotation under the context of specific tissue types. To demonstrate its utilities, we apply loci2path on sets of genomic intervals harboring disease-associated variants as query. Using 1 702 612 eQTLs discovered by the Genotype-Tissue Expression (GTEx) project across 44 tissues and 6320 pathways or gene sets cataloged in MSigDB as annotation resource, our method successfully identifies highly relevant biological pathways and revealed disease mechanisms for psoriasis and other immune-related diseases. Tissue specificity analysis of associated eQTLs provide additional evidence of the distinct roles of different tissues played in the disease mechanisms. AVAILABILITY AND IMPLEMENTATION loci2path is published as an open source Bioconductor package, and it is available at http://bioconductor.org/packages/release/bioc/html/loci2path.html. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Tianlei Xu
- Department of Mathematics and Computer Science, Emory University, Atlanta, GA 30322, USA
| | - Peng Jin
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
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14
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Roth N, Biedermann L, Fournier N, Butter M, Vavricka SR, Navarini AA, Rogler G, Scharl M, on behalf of the Swiss IBD Cohort Study Group. Occurrence of skin manifestations in patients of the Swiss Inflammatory Bowel Disease Cohort Study. PLoS One 2019; 14:e0210436. [PMID: 30682031 PMCID: PMC6347222 DOI: 10.1371/journal.pone.0210436] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 12/22/2018] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND/AIMS Extraintestinal cutaneous manifestations of IBD represent a severe disease complication and an early and accurate treatment might positively influence the disease course. Using the patient collective of the Swiss IBD Cohort Study (SIBDCS), we analysed epidemiological as well as clinical factors being associated with the onset of pyoderma gangrenosum, erythema nodosum and aphthous ulcers in IBD patients. METHODS We included 3266 SIBDCs patients, 1840 with Crohn's disease (CD) and 1426 with ulcerative colitis (UC) or IBD unclassified (IBDU) and analysed the association of cutaneous manifestations with age, age at diagnosis time, type of disease, gender, family history, HLA-allotype, smoking, intestinal disease activity, therapy and other extraintestinal manifestations (EIM). RESULTS 354 CD patients and 136 UC/IBDU patients presented with skin manifestations at any time during their disease course. In both, CD and UC, female gender and younger age at IBD diagnosis were significantly associated with extraintestinal skin manifestations. For CD, we also detected a positive family history as associated factor. As an indicator of more intensive intestinal disease activity, patients with cutaneous manifestations of IBD needed more frequently therapy with antibiotics, steroids, immunomodulators and anti-TNF. Multivariate analysis revealed female gender, younger age at diagnosis and presence of other extraintestinal manifestations as factors being associated with skin EIM in IBD patients and anti-TNF as well as immunomodulatory treatment in CD patients. CONCLUSION Our results suggest that young females with a positive family history of IBD might be at increased risk for the onset of skin manifestations and require a careful screening for such complications.
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Affiliation(s)
- Nina Roth
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Department of Internal Medicine, Buergerspital Solothurn, Solothurn, Switzerland
| | - Luc Biedermann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Nicolas Fournier
- Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne, Switzerland
| | - Matthias Butter
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Stephan R. Vavricka
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | | | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- * E-mail:
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15
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Chams S, Badran R, Sayegh SE, Chams N, Shams A, Hajj Hussein I. Inflammatory bowel disease: Looking beyond the tract. Int J Immunopathol Pharmacol 2019; 33:2058738419866567. [PMID: 31382828 PMCID: PMC6685113 DOI: 10.1177/2058738419866567] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 07/05/2019] [Indexed: 12/31/2022] Open
Abstract
Inflammatory bowel disease is a chronic inflammatory condition that encompasses Crohn's disease and ulcerative colitis. Inflammatory bowel disease is not exclusive to the gastrointestinal system, as it has been identified to be associated with extraintestinal manifestations that encompass every other organ system in the human body. This review article will comprehensively review the current knowledge on extraintestinal manifestations of inflammatory bowel disease. In addition, it will discuss the recommendations for screening and surveillance for extraintestinal manifestations in these patients since early appropriate diagnosis is imperative in preventing morbidity and cancer development.
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Affiliation(s)
- Sana Chams
- Division of Geriatric Medicine, Beaumont Health, Royal Oak, MI, USA
| | - Reina Badran
- Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI, USA
| | - Skye El Sayegh
- Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Nour Chams
- Division of Geriatric Medicine, Beaumont Health, Royal Oak, MI, USA
| | - Ali Shams
- Department of Emergency Medicine, Beaumont Health, Royal Oak, MI, USA
| | - Inaya Hajj Hussein
- Department of Foundational Medical Studies, Oakland University William Beaumont School of Medicine, Rochester, MI, USA
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16
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Plumptre I, Knabel D, Tomecki K. Pyoderma Gangrenosum: A Review for the Gastroenterologist. Inflamm Bowel Dis 2018; 24:2510-2517. [PMID: 29788368 DOI: 10.1093/ibd/izy174] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Indexed: 12/20/2022]
Abstract
Pyoderma gangrenosum (PG) is a rare ulcerative skin disease of unknown etiology often associated with systemic inflammatory conditions, most commonly inflammatory bowel disease (IBD). The most common presentation of PG is spontaneous rapid formation of an extremely painful ulcer on the extremities, associated with significant morbidity and mortality. Rarely, PG can also occur as a chronic peristomal complication or as an acute postoperative complication of a surgical wound. The clinical course is unpredictable; it may not correlate with IBD activity and may even precede a diagnosis of IBD. Pyoderma gangrenosum is a diagnosis of exclusion. Treatment is challenging, often involving a variety of immunosuppressive therapies. This review aims to provide an update for the gastroenterologist on the pathogenesis, presentation, diagnosis, and management of PG, a rare complication of IBD.
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Affiliation(s)
- Isabella Plumptre
- London North West University Healthcare NHS Trust, London, United Kingdom
| | - Daniel Knabel
- Department of Dermatology, Cleveland Clinic, Cleveland, Ohio
| | - Kenneth Tomecki
- Department of Dermatology, Cleveland Clinic, Cleveland, Ohio
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17
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Satta R, Pes GM, Rocchi C, Pes MC, Dore MP. Is probiotic use beneficial for skin lesions in patients with inflammatory bowel disease? J DERMATOL TREAT 2018; 30:612-616. [PMID: 30244616 DOI: 10.1080/09546634.2018.1527998] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background: Inflammatory bowel diseases (IBDs) are associated with extraintestinal manifestations including skin lesions. The intestinal microflora plays a key role in the development and course of IBD. Aim: To examine the efficacy of probiotics and the occurrence of skin lesions in patients with IBD. Methods: The occurrence of cutaneous lesions in IBD patients from Northern Sardinia was analyzed according to demographic, anthropometrics, clinical features, treatments, and probiotic use expressed as the ratio of disease duration under probiotic treatment and the total disease duration. Results: In 170 IBD patients (59.4% women; UC: 61.2%) at least one skin lesion was present (8.2%) at diagnosis and in 30.6% developed during the follow-up. Psoriasis, erythema nodosum, and pyoderma gangrenosum were the most frequent. An inverse trend was observed between probiotics use and skin lesions occurrence after adjusting for confounders, including conventional treatment for IBD. The risk of developing at least one skin lesion was 1.40 for probiotic use between 5-19% of disease duration and 0.3 for probiotic use > 50%. Body mass index, Crohn phenotype, marriage, and potency of IBD-treatment were significant predictors for developing skin lesions. Conclusion: These findings suggest that probiotics may be an additional tool in the treatment of IBD.
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Affiliation(s)
- Rosanna Satta
- a Dermatology Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari , Sassari , Italy
| | - Giovanni Mario Pes
- a Dermatology Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari , Sassari , Italy
| | - Chiara Rocchi
- a Dermatology Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari , Sassari , Italy
| | - Maria Chiara Pes
- a Dermatology Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari , Sassari , Italy
| | - Maria Pina Dore
- a Dermatology Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari , Sassari , Italy.,b Department of Medicine, Baylor College of Medicine , Houston , TX , USA
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18
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Alt EU, Barabadi Z, Pfnür A, Ochoa JE, Daneshimehr F, Lang LM, Lin D, Braun SE, Chandrasekar B, Izadpanah R. TRAF3IP2, a novel therapeutic target in glioblastoma multiforme. Oncotarget 2018; 9:29772-29788. [PMID: 30038719 PMCID: PMC6049871 DOI: 10.18632/oncotarget.25710] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 06/13/2018] [Indexed: 11/25/2022] Open
Abstract
Glioblastoma multiforme (glioblastoma) remains one of the deadliest cancers. Pro-inflammatory and pro-tumorigenic mediators present in tumor microenvironment (TME) facilitate communication between tumor cells and adjacent non-malignant cells, resulting in glioblastoma growth. Since a majority of these mediators are products of NF-κB- and/or AP-1-responsive genes, and as TRAF3 Interacting Protein 2 (TRAF3IP2) is an upstream regulator of both transcription factors, we hypothesized that targeting TRAF3IP2 blunts tumor growth by inhibiting NF-κB and pro-inflammatory/pro-tumorigenic mediators. Our in vitro data demonstrate that similar to primary glioblastoma tumor tissues, malignant glioblastoma cell lines (U87 and U118) express high levels of TRAF3IP2. Silencing TRAF3IP2 expression inhibits basal and inducible NF-κB activation, induction of pro-inflammatory mediators, clusters of genes involved in cell cycle progression and angiogenesis, and formation of spheroids. Additionally, silencing TRAF3IP2 significantly increases apoptosis. In vivo studies indicate TRAF3IP2-silenced U87 cells formed smaller tumors. Additionally, treating existing tumors formed by wild type U87 cells with lentiviral TRAF3IP2 shRNA markedly regresses their size. Analysis of residual tumors revealed reduced expression of pro-inflammatory/pro-tumorigenic/pro-angiogenic mediators and kinesins. In contrast, the expression of IL-10, an anti-inflammatory cytokine, was increased. Together, these novel data indicate that TRAF3IP2 is a master regulator of malignant signaling in glioblastoma, and its targeting modulates the TME and inhibits tumor growth by suppressing the expression of mediators involved in inflammation, angiogenesis, growth, and malignant transformation. Our data identify TRAF3IP2 as a potential therapeutic target in glioblastoma growth and dissemination.
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Affiliation(s)
- Eckhard U Alt
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Zahra Barabadi
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Andreas Pfnür
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Joana E Ochoa
- Department of Surgery, Tulane University Health Science Center, New Orleans, Louisiana, USA
| | - Fatemeh Daneshimehr
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Lea M Lang
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Dong Lin
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Stephen E Braun
- Division of Regenerative Medicine, Tulane National Primate Research Center, Covington, Louisiana, USA
| | - Bysani Chandrasekar
- Department of Medicine, University of Missouri School of Medicine and Harry S. Truman Veterans Memorial Hospital, Columbia, Missouri, USA
| | - Reza Izadpanah
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.,Department of Surgery, Tulane University Health Science Center, New Orleans, Louisiana, USA
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Vide J, Osório F, Costa-Silva M, Lopes S, Azevedo F, Camila Dias C, Magina S, Magro F. Cutaneous Morbidity Among Inflammatory Bowel Disease Patients: A Cohort Study. J Crohns Colitis 2018; 12:442-451. [PMID: 29300856 DOI: 10.1093/ecco-jcc/jjx178] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Accepted: 12/27/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Patients with inflammatory bowel diseases are prone to cutaneous manifestations. The aim of this study was to investigate their prevalence, type and association to demographic and clinical factors. METHODS This was a cross-sectional study. Information relative to patients of a central Portuguese hospital with a definitive diagnosis of an inflammatory bowel disease, who were prospectively recruited, was collected. RESULTS The final cohort included 342 patients, 62% of whom had Crohn's disease and 38% had ulcerative colitis. Cutaneous extraintestinal manifestations were present in 44.4% of all patients; this prevalence was lower [14.9%] when excluding cutaneous manifestations secondary to nutrition deficiency or drugs. These skin lesions were classified as granulomatous [0.3%], reactive [4.4%], immunologically associated [10.5%] and secondary to nutritional deficiencies [6.4%] or to bowel-related therapy [29.5%]. Excluding those secondary to nutrition or drugs, cutaneous manifestations were significantly associated with females (odds ratio [OR] 3.210 [1.625-6.340], p = 0.001) and younger patients (OR 0.954 [0.924-0.985], p = 0.004). Additionally, their occurrence was related to patients up to 16 years (OR 13.875 [1.332-144.484], p = 0.028) among the Crohn's disease sub-cohort, whereas in the ulcerative colitis sub-cohort they were more likely to occur in patients with extensive colitis (OR 5.317 [1.552-18.214], p = 0.008). CONCLUSIONS Nearly half of the patients analysed had at least one cutaneous extraintestinal manifestation. The fact that certain lesions tend to be more common among patients with defined characteristics should alert the physicians and allow an early diagnosis and, when pertinent, a reference to dermatology.
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Affiliation(s)
- Júlia Vide
- Department of Dermatology and Venereology, Centro Hospitalar de São João EPE, Porto, Portugal
| | - Filipa Osório
- Department of Community Medicine Health Information and Decision, Faculty of Medicine of Porto University, Porto, Portugal
| | - Miguel Costa-Silva
- Department of Dermatology and Venereology, Centro Hospitalar de São João EPE, Porto, Portugal
| | - Sofia Lopes
- Department of Dermatology and Venereology, Centro Hospitalar de São João EPE, Porto, Portugal
| | - Filomena Azevedo
- Department of Dermatology and Venereology, Centro Hospitalar de São João EPE, Porto, Portugal
| | - Cláudia Camila Dias
- Department of Community Medicine Health Information and Decision, Faculty of Medicine of Porto University, Porto, Portugal
| | - Sofia Magina
- Department of Biomedicine, Faculty of Medicine of Porto University, Porto, Portugal.,Department of Pharmacology, Faculty of Medicine of Porto University, Porto, Portugal
| | - Fernando Magro
- Department of Biomedicine, Faculty of Medicine of Porto University, Porto, Portugal.,Department of Pharmacology, Faculty of Medicine of Porto University, Porto, Portugal.,Department of Gastroenterology, Centro Hospitalar de São João EPE, Porto, Portugal
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Pordel S, Sajedi Khanian M, Karimi MH, Nikoo H, Doroudchi M. Plasma CXCL1 levels and TRAF3IP2 variants in patients with myocardial infarction. J Clin Lab Anal 2018; 32:e22402. [PMID: 29430728 DOI: 10.1002/jcla.22402] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 01/13/2018] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND IL-17A plays an important role in inflammatory responses in myocardial infarction (MI). IL-17A signals through its receptor, for which, Act1 (TRAF3IP2) functions as a key upstream adaptor in the pathway. AIM To compare frequencies of functional polymorphisms of TRAF3IP2 (rs13210247, rs33980500) between patients with MI and healthy controls. METHODS The selected SNPs were studied in 201 Iranian MI patients and 201 healthy blood donors from Fars Province by PCR-RFLP in association with clinicopathologic criteria of patients. CXCL1 plasma levels in 126 MI patients and 50 normal subjects were measured by ELISA. RESULTS A significant increase in the mutant (T) allele of TRAF3IP2 rs33980500 in patients with diastolic dysfunction of the heart (P = .01) was observed. The highest correlation, however, was observed between the TRAF3IP2 rs33980500 TT genotype and T allele with left main coronary artery stenosis (P = .01, P < .001; OR = 31.03). T allele of TRAF3IP2 rs33980500 was also associated with female gender, family history of cardiovascular disease, and mechanical complications of heart (P = .04, P = .02, and P = .01, respectively). Moreover, TRAF3IP2 rs13210247 (G) correlated with mechanical complications of the heart (P = .01). A significant increase in the plasma levels of CXCL1 chemokine in patients (P = .0006) associated with TT genotype of TRAF3IP2 (rs33980500) was observed (P = .04). CONCLUSION The gene variants of Act1 adaptor are associated with correlates of poor outcome in patients with MI and plasma CXCL1 levels.
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Affiliation(s)
- Safoora Pordel
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahdi Sajedi Khanian
- Department of Cardiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Hossein Nikoo
- Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehrnoosh Doroudchi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Garcovich S, De Simone C, Berti E, Marzano AV. Drug management of neutrophilic dermatoses. Expert Rev Clin Pharmacol 2017; 10:1119-1128. [PMID: 28715916 DOI: 10.1080/17512433.2017.1356719] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Neutrophilic dermatoses are a heterogenous group of chronic, cutaneous inflammatory conditions characterized by the accumulation of neutrophils in the skin and by systemic inflammation. Neutrophilic dermatoses can be idiopathic or associated with other inflammatory or systemic diseases, including the group of the hereditary, autoinflammatory syndromes. Clinical management is challenging, due to limited clinical evidence and lack of clinical practice guidelines. Areas covered: This review provides an overview of current therapeutic management of the three prototypical neutrophilic dermatoses, aseptic pustulosis of the folds, Sweet syndrome and pyoderma gangrenosum. In addition, we describe innovative, pathogenesis-oriented treatment approaches, which are based on recent advances in the pathophysiology of neutrophilic dermatoses and autoinflammatory syndromes. The increasing role of the IL-1 cytokine family in initiating neutrophilic inflammation in both idiopathic and syndromic disease opened the way for the use of targeted biological treatment. Another promising treatment strategy is aimed at blocking downstream effector cytokines, such as IL12/23 and IL-17, involved in the autoinflammatory immune cascade. Expert commentary: In chronic-recurrent and syndromic cases of neutrophilic dermatoses, there is an unmet clinical need for long-term, continuous disease control. Future controlled clinical studies will optimize the use of targeted-biological agents in sequential or combination treatment strategies.
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Affiliation(s)
- Simone Garcovich
- a Institute of Dermatology , Policlinico A. Gemelli University Hospital, Catholic University of the Sacred Heart , Rome , Italy
| | - Clara De Simone
- a Institute of Dermatology , Policlinico A. Gemelli University Hospital, Catholic University of the Sacred Heart , Rome , Italy
| | - Emilio Berti
- b UOC Dermatologia, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti , Università Degli Studi di Milano , Milan , Italy
| | - Angelo Valerio Marzano
- b UOC Dermatologia, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti , Università Degli Studi di Milano , Milan , Italy
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Vallini V, Andreini R, Bonadio A. Pyoderma Gangrenosum: A Current Problem as Much as an Unknown One. INT J LOW EXTR WOUND 2017; 16:191-201. [DOI: 10.1177/1534734617710980] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pyoderma gangrenosum (PG) is a rare neutrophilic inflammatory skin disease, characterized by recurrent skin ulcers, which in almost 50% of cases are associated with systemic autoimmune disorders, including rheumatoid arthritis, chronic hepatitis, inflammatory bowel disease, paraproteinemias and hematological malignancies. A systematic search of literature for PG was carried out using the PubMed, Embase, and Google Scholar databases for the purpose of this review and 2780 articles were retrieved up to February 2017. Inflammation represents the predominant aspect of the disease, but its pathophysiological mechanisms are not completely clear yet, since there are many studies showing only one or more isolated findings of the disease. The goal of PG treatment is to reduce inflammation in order to promote ulcer healing by minimizing side effects of therapy. Several systemic and local treatments are available, but the lack of large randomized double-blind studies results in an absence of a uniform therapeutic standard: thus, more clinical studies are required in order to make head-to-head comparisons between combination and single-drug therapies and to identify specific combination therapies for distinctive clinical patterns of PG.
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Affiliation(s)
- Valerio Vallini
- Ospedale Santa Maria Maddalena–Volterra, Azienda Usl Nordovest, Toscana, Italy
| | - Roberto Andreini
- Ospedale Santa Maria Maddalena–Volterra, Azienda Usl Nordovest, Toscana, Italy
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Dual Role of Act1 in Keratinocyte Differentiation and Host Defense: TRAF3IP2 Silencing Alters Keratinocyte Differentiation and Inhibits IL-17 Responses. J Invest Dermatol 2017; 137:1501-1511. [PMID: 28274739 DOI: 10.1016/j.jid.2016.12.032] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 12/08/2016] [Accepted: 12/09/2016] [Indexed: 12/16/2022]
Abstract
TRAF3IP2 is a candidate psoriasis susceptibility gene encoding Act1, an adaptor protein with ubiquitin ligase activity that couples the IL-17 receptor to downstream signaling pathways. We investigated the role of Act1 in keratinocyte responses to IL-17 using a tetracycline inducible short hairpin RNA targeting TRAF3IP2. Tetracycline exposure for 7 days effectively silenced TRAF3IP2 mRNA and Act1 protein, resulting in 761 genes with significant changes in expression (495 down, 266 up; >1.5-fold, P < 0.05). Gene ontology analysis showed that genes affected by TRAF3IP2 silencing are involved in epidermal differentiation, with early differentiation genes (KRT1, KRT10, DSC1, DSG1) being down-regulated and late differentiation genes (SPRR2, SPRR3, LCE3) being up-regulated. AP1 binding sites were enriched upstream of genes up-regulated by TRAF3IP2 silencing. Correspondingly, nuclear expression of FosB and Fra1 was increased in TRAF3IP2-silenced cells. Many genes involved in host defense were induced by IL-17 in a TRAF3IP2-dependent fashion. Inflammatory differentiation conditions (serum addition for 4 days postconfluence) markedly amplified these IL-17 responses and increased basal levels and TRAF3IP2 silencing-dependent up-regulation of multiple late differentiation genes. These findings suggest that TRAF3IP2 may alter both epidermal homeostasis and keratinocyte defense responses to influence psoriasis risk.
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Conigliaro P, Ciccacci C, Politi C, Triggianese P, Rufini S, Kroegler B, Perricone C, Latini A, Novelli G, Borgiani P, Perricone R. Polymorphisms in STAT4, PTPN2, PSORS1C1 and TRAF3IP2 Genes Are Associated with the Response to TNF Inhibitors in Patients with Rheumatoid Arthritis. PLoS One 2017; 12:e0169956. [PMID: 28107378 PMCID: PMC5249113 DOI: 10.1371/journal.pone.0169956] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 12/27/2016] [Indexed: 11/29/2022] Open
Abstract
Objective Rheumatoid Arthritis (RA) is a progressive autoimmune disease characterized by chronic joint inflammation and structural damage. Remission or at least low disease activity (LDA) represent potentially desirable goals of RA treatment. Single nucleotide polymorphisms (SNPs) in several genes might be useful for prediction of response to therapy. We aimed at exploring 4 SNPs in candidate genes (STAT4, PTPN2, PSORS1C1 and TRAF3IP2) in order to investigate their potential role in the response to therapy with tumor necrosis factor inhibitors (TNF-i) in RA patients. Methods In 171 RA patients we investigated the following SNPs: rs7574865 (STAT4), rs2233945 (PSORS1C1), rs7234029 (PTPN2) and rs33980500 (TRAF3IP2). Remission, LDA, and EULAR response were registered at 6 months and 2 years after initiation of first line TNF-i [Adalimumab (ADA) and Etanercept (ETN)]. Results STAT4 variant allele was associated with the absence of a good/moderate EULAR response at 2 years of treatment in the whole RA group and in ETN treated patients. The PTPN2 SNP was associated with no good/moderate EULAR response at 6 months in ADA treated patients. Patients carrying PSORS1C1 variant allele did not reach LDA at 6 months in both the whole RA group and ETN treated patients. TRAF3IP2 variant allele was associated with the lack of LDA and remission achievement at 6 months in all RA cohort while an association with no EULAR response at 2 years of treatment occurred only in ETN treated patients. Conclusions For the first time, we reported that SNPs in STAT4, PTPN2, PSORS1C1, and TRAF3IP2 are associated with response to TNF-i treatment in RA patients; however, these findings should be validated in a larger population.
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Affiliation(s)
- Paola Conigliaro
- Clinic of Rheumatology, Allergology and Clinical Immunology, Department of “Medicina dei Sistemi”, University of Rome Tor Vergata, Rome, Italy
| | - Cinzia Ciccacci
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, Rome, Italy
| | - Cristina Politi
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, Rome, Italy
| | - Paola Triggianese
- Clinic of Rheumatology, Allergology and Clinical Immunology, Department of “Medicina dei Sistemi”, University of Rome Tor Vergata, Rome, Italy
- * E-mail:
| | - Sara Rufini
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, Rome, Italy
| | - Barbara Kroegler
- Clinic of Rheumatology, Allergology and Clinical Immunology, Department of “Medicina dei Sistemi”, University of Rome Tor Vergata, Rome, Italy
| | - Carlo Perricone
- Reumatologia, Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
| | - Andrea Latini
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, Rome, Italy
| | - Giuseppe Novelli
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, Rome, Italy
| | - Paola Borgiani
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, Rome, Italy
| | - Roberto Perricone
- Clinic of Rheumatology, Allergology and Clinical Immunology, Department of “Medicina dei Sistemi”, University of Rome Tor Vergata, Rome, Italy
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Ciccacci C, Perricone C, Politi C, Rufini S, Ceccarelli F, Cipriano E, Alessandri C, Latini A, Valesini G, Novelli G, Conti F, Borgiani P. A polymorphism upstream MIR1279 gene is associated with pericarditis development in Systemic Lupus Erythematosus and contributes to definition of a genetic risk profile for this complication. Lupus 2016; 26:841-848. [DOI: 10.1177/0961203316679528] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Recently, a study has shown that a polymorphism in the region of MIR1279 modulates the expression of the TRAF3IP2 gene. Since polymorphisms in the TRAF3IP2 gene have been described in association with systemic lupus erithematosus (SLE) susceptibility and with the development of pericarditis, our aim is to verify if the MIR1279 gene variability could also be involved. The rs1463335 SNP, located upstream MIR1279 gene, was analyzed by allelic discrimination assay in 315 Italian SLE patients and 201 healthy controls. Moreover, the MIR1279 gene was full sequenced in 50 patients. A case/control association study and a genotype/phenotype correlation analysis were performed. We also constructed a pericarditis genetic risk profile for patients with SLE. The full sequencing of the MIR1279 gene in patients with SLE did not reveal any novel or known variation. The variant allele of the rs1463335 SNP was significantly associated with susceptibility to pericarditis ( P = 0.017 and OR = 1.67). A risk profile model for pericarditis considering the risk alleles of MIR1279 and three other genes (STAT4, PTPN2 and TRAF3IP2) showed that patients with 4 or 5 risk alleles have a higher risk of developing pericarditis ( OR = 4.09 with P = 0.001 and OR = 6.04 with P = 0.04 respectively). In conclusion, we describe for the first time the contribution of a MIR1279 SNP in pericarditis development in patients with SLE and a genetic risk profile model that could be useful to identify patients more susceptible to developing pericarditis in SLE. This approach could help to improve the prediction and the management of this complication.
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Affiliation(s)
- C Ciccacci
- Department of Biomedicine and Prevention, Genetics Section, School of Medicine, University of Rome Tor Vergata, Italy
| | - C Perricone
- Lupus Clinic, Reumatologia, Dipartimento di Clinica e Terapia Medica, Sapienza Università di Roma, Italy
| | - C Politi
- Department of Biomedicine and Prevention, Genetics Section, School of Medicine, University of Rome Tor Vergata, Italy
| | - S Rufini
- Department of Biomedicine and Prevention, Genetics Section, School of Medicine, University of Rome Tor Vergata, Italy
| | - F Ceccarelli
- Lupus Clinic, Reumatologia, Dipartimento di Clinica e Terapia Medica, Sapienza Università di Roma, Italy
| | - E Cipriano
- Lupus Clinic, Reumatologia, Dipartimento di Clinica e Terapia Medica, Sapienza Università di Roma, Italy
| | - C Alessandri
- Lupus Clinic, Reumatologia, Dipartimento di Clinica e Terapia Medica, Sapienza Università di Roma, Italy
| | - A Latini
- Department of Biomedicine and Prevention, Genetics Section, School of Medicine, University of Rome Tor Vergata, Italy
| | - G Valesini
- Lupus Clinic, Reumatologia, Dipartimento di Clinica e Terapia Medica, Sapienza Università di Roma, Italy
| | - G Novelli
- Department of Biomedicine and Prevention, Genetics Section, School of Medicine, University of Rome Tor Vergata, Italy
| | - F Conti
- Lupus Clinic, Reumatologia, Dipartimento di Clinica e Terapia Medica, Sapienza Università di Roma, Italy
| | - P Borgiani
- Department of Biomedicine and Prevention, Genetics Section, School of Medicine, University of Rome Tor Vergata, Italy
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Extra-Gastrointestinal Manifestations of Inflammatory Bowel Disease May Be Less Common Than Previously Reported. Dig Dis Sci 2016; 61:2619-26. [PMID: 27193564 DOI: 10.1007/s10620-016-4195-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 05/05/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Extra-intestinal manifestations are well recognized in inflammatory bowel disease (IBD). To what extent the commonly recognized extra-intestinal manifestations seen in IBD patients are attributable to IBD is, however, not clear due to the limited number of controlled studies published. METHODS We have conducted a study of these manifestations using electronic primary care records. We have identified extra-intestinal manifestations in IBD and non-IBD patients and derived odds ratios (ORs) using conditional logistic regression. RESULTS A total of 56,097 IBD patients (32.5 % Crohn's disease, 48.3 % ulcerative colitis (UC) and 19.2 % not classified) were matched to 280,382 non-IBD controls. We found records of pyoderma gangrenosum (OR = 29.24), erythema nodosum (OR = 5.95), primary sclerosing cholangitis (OR = 188.25), uveitis (OR = 2.81), ankylosing spondylitis (OR = 7.07), sacroiliitis (OR = 2.79) and non-rheumatoid inflammatory arthritides (OR = 2.66) to be associated with IBD. One or more of these was recorded in 8.1 % of IBD patients and 2.3 % of controls. Non-specific arthritides were present in many more patients, affecting 30 % of IBD patients and 23.8 % of controls overall. We also found weaker associations with a number of conditions not generally considered to be extra-intestinal manifestations including psoriasis, ischemic heart disease, multiple sclerosis and hay fever. CONCLUSION Although "classical" extra-intestinal manifestations are strongly associated with IBD, most IBD patients remain unaffected. Arthropathies, perceived to be the commonest extra-intestinal manifestation, are not strongly associated with IBD, and the proportion of arthropathies attributable to IBD is likely to be small.
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Offenbacher S, Divaris K, Barros SP, Moss KL, Marchesan JT, Morelli T, Zhang S, Kim S, Sun L, Beck JD, Laudes M, Munz M, Schaefer AS, North KE. Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease. Hum Mol Genet 2016; 25:2113-2129. [PMID: 26962152 PMCID: PMC5062586 DOI: 10.1093/hmg/ddw069] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Revised: 02/19/2016] [Accepted: 02/26/2016] [Indexed: 12/12/2022] Open
Abstract
Genome-wide association studies (GWAS) of chronic periodontitis (CP) defined by clinical criteria alone have had modest success to-date. Here, we refine the CP phenotype by supplementing clinical data with biological intermediates of microbial burden (levels of eight periodontal pathogens) and local inflammatory response (gingival crevicular fluid IL-1β) and derive periodontal complex traits (PCTs) via principal component analysis. PCTs were carried forward to GWAS (∼2.5 million markers) to identify PCT-associated loci among 975 European American adult participants of the Dental ARIC study. We sought to validate these findings for CP in the larger ARIC cohort (n = 821 participants with severe CP, 2031-moderate CP, 1914-healthy/mild disease) and an independent German sample including 717 aggressive periodontitis cases and 4210 controls. We identified six PCTs with distinct microbial community/IL-1β structures, although with overlapping clinical presentations. PCT1 was characterized by a uniformly high pathogen load, whereas PCT3 and PCT5 were dominated by Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, respectively. We detected genome-wide significant signals for PCT1 (CLEC19A, TRA, GGTA2P, TM9SF2, IFI16, RBMS3), PCT4 (HPVC1) and PCT5 (SLC15A4, PKP2, SNRPN). Overall, the highlighted loci included genes associated with immune response and epithelial barrier function. With the exception of associations of BEGAIN with severe and UBE3D with moderate CP, no other loci were associated with CP in ARIC or aggressive periodontitis in the German sample. Although not associated with current clinically determined periodontal disease taxonomies, upon replication and mechanistic validation these candidate loci may highlight dysbiotic microbial community structures and altered inflammatory/immune responses underlying biological sub-types of CP.
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Affiliation(s)
- Steven Offenbacher
- Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
| | - Kimon Divaris
- Department of Pediatric Dentistry, UNC School of Dentistry, Chapel Hill, NC, USA Department of Epidemiology, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA
| | - Silvana P Barros
- Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
| | - Kevin L Moss
- Department of Dental Ecology, UNC School of Dentistry, Chapel Hill, NC, USA
| | - Julie T Marchesan
- Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
| | - Thiago Morelli
- Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
| | - Shaoping Zhang
- Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
| | - Steven Kim
- Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
| | - Lu Sun
- Department of Periodontology, UNC School of Dentistry, Chapel Hill, NC, USA
| | - James D Beck
- Department of Dental Ecology, UNC School of Dentistry, Chapel Hill, NC, USA
| | - Matthias Laudes
- Clinic of Internal Medicine I, University Clinic Schleswig-Holstein, Kiel, Germany
| | - Matthias Munz
- Department of Periodontology, Institute of Dental, Oral and Maxillary Medicine, Charité-University Medicine Berlin, Berlin, Germany Institute of Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany
| | - Arne S Schaefer
- Department of Periodontology, Institute of Dental, Oral and Maxillary Medicine, Charité-University Medicine Berlin, Berlin, Germany
| | - Kari E North
- Department of Epidemiology, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA
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The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity. Cell Mol Immunol 2016; 13:418-31. [PMID: 27018218 DOI: 10.1038/cmi.2015.105] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Revised: 11/21/2015] [Accepted: 11/21/2015] [Indexed: 01/12/2023] Open
Abstract
The mucosal immune system serves as our front-line defense against pathogens. It also tightly maintains immune tolerance to self-symbiotic bacteria, which are usually called commensals. Sensing both types of microorganisms is modulated by signalling primarily through various pattern-recognition receptors (PRRs) on barrier epithelial cells or immune cells. After sensing, proinflammatory molecules such as cytokines are released by these cells to mediate either defensive or tolerant responses. The interleukin-17 (IL-17) family members belong to a newly characterized cytokine subset that is critical for the maintenance of mucosal homeostasis. In this review, we will summarize recent progress on the diverse functions and signals of this family of cytokines at different mucosal edges.
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Braswell SF, Kostopoulos TC, Ortega-Loayza AG. Pathophysiology of pyoderma gangrenosum (PG): an updated review. J Am Acad Dermatol 2015; 73:691-8. [PMID: 26253362 DOI: 10.1016/j.jaad.2015.06.021] [Citation(s) in RCA: 163] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Revised: 06/05/2015] [Accepted: 06/10/2015] [Indexed: 12/11/2022]
Abstract
Pyoderma gangrenosum is a challenging skin condition to identify and treat because of its multifactorial pathogenesis. It is a rare cutaneous manifestation diagnosed clinically by exclusion of infection, neoplasia, thrombophilia, and other inflammatory conditions. Pathogenetic and treatment studies are scarce. Abnormalities in the function of inflammatory cytokines, the immune system, and neutrophils combined with specific genetic mutations predispose patients to develop this complex disease process. Early recognition of patients at risk for pyoderma gangrenosum, the necessity to improve its early diagnosis, and the future outlook of targeted and personalized therapies relies on the improved comprehension of the complex pathogenesis of pyoderma gangrenosum.
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Affiliation(s)
- Sara F Braswell
- Department of Dermatology, Virginia Commonwealth University, Richmond, Virginia
| | | | - Alex G Ortega-Loayza
- Department of Dermatology, Virginia Commonwealth University, Richmond, Virginia.
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Ciccacci C, Rufini S, Mancinelli S, Buonomo E, Giardina E, Scarcella P, Marazzi MC, Novelli G, Palombi L, Borgiani P. A pharmacogenetics study in Mozambican patients treated with nevirapine: full resequencing of TRAF3IP2 gene shows a novel association with SJS/TEN susceptibility. Int J Mol Sci 2015; 16:5830-8. [PMID: 25775161 PMCID: PMC4394508 DOI: 10.3390/ijms16035830] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Revised: 03/06/2015] [Accepted: 03/07/2015] [Indexed: 01/20/2023] Open
Abstract
Steven–Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are severe adverse drug reactions, characterized by extensive epidermal detachment and erosions of mucous membrane. SJS/TEN is one of the most serious adverse reactions to Nevirapine (NVP) treatment, commonly used in developing countries as first-line treatment of human immunodeficiency virus infection. In the last years TRAF3IP2 gene variants had been described as associated with susceptibility to several diseases such as psoriasis and psoriatic arthritis. We hypothesized that this gene, involved in immune response and in NF-κB activation, could also be implicated in the SJS/TEN susceptibility. We performed a full resequencing of TRAF3IP2 gene in a population of patients treated with NVP. Twenty-seven patients with NVP-induced SJS/TEN and 78 controls, all from Mozambique, were enrolled. We identified eight exonic and three intronic already described variants. The case/control association analysis highlighted an association between the rs76228616 SNP in exon 2 and the SJS/TEN susceptibility. In particular, the variant allele (C) resulted significantly associated with a higher risk to develop SJS/TEN (p = 0.012 and OR = 3.65 (95% CI 1.33–10.01)). A multivariate analysis by logistic regression confirmed its significant contribution (p = 0.027, OR = 4.39 (95% CI 1.19–16.23)). In conclusion, our study suggests that a variant in TRAF3IP2 gene could be involved in susceptibility to SJS/TEN.
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Affiliation(s)
- Cinzia Ciccacci
- Department of Biomedicine and Prevention, Genetics Section, University of Rome "Tor Vergata", Rome 00133, Italy.
| | - Sara Rufini
- Department of Biomedicine and Prevention, Genetics Section, University of Rome "Tor Vergata", Rome 00133, Italy.
| | - Sandro Mancinelli
- Department of Biomedicine and Prevention, Epidemiology Section, University of Rome "Tor Vergata", Rome 00133, Italy.
| | - Ersilia Buonomo
- Department of Biomedicine and Prevention, Epidemiology Section, University of Rome "Tor Vergata", Rome 00133, Italy.
| | - Emiliano Giardina
- Department of Biomedicine and Prevention, Genetics Section, University of Rome "Tor Vergata", Rome 00133, Italy.
- Laboratory of Molecular Genetics UILDM, Fondazione Santa Lucia, Rome 00179, Italy.
| | - Paola Scarcella
- Department of Biomedicine and Prevention, Epidemiology Section, University of Rome "Tor Vergata", Rome 00133, Italy.
| | - Maria C Marazzi
- Department of Human Sciences, LUMSA University, Rome 00193, Italy.
| | - Giuseppe Novelli
- Department of Biomedicine and Prevention, Genetics Section, University of Rome "Tor Vergata", Rome 00133, Italy.
| | - Leonardo Palombi
- Department of Biomedicine and Prevention, Epidemiology Section, University of Rome "Tor Vergata", Rome 00133, Italy.
| | - Paola Borgiani
- Department of Biomedicine and Prevention, Genetics Section, University of Rome "Tor Vergata", Rome 00133, Italy.
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DeFilippis E, Feldman S, Huang W. The genetics of pyoderma gangrenosum and implications for treatment: a systematic review. Br J Dermatol 2015; 172:1487-1497. [PMID: 25350484 DOI: 10.1111/bjd.13493] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/10/2014] [Indexed: 12/22/2022]
Affiliation(s)
- E.M. DeFilippis
- Center for Dermatology Research; Department of Dermatology; Wake Forest School of Medicine, Medical Center Boulevard; Winston-Salem NC 27157 U.S.A
| | - S.R. Feldman
- Center for Dermatology Research; Department of Dermatology; Wake Forest School of Medicine, Medical Center Boulevard; Winston-Salem NC 27157 U.S.A
- Department of Pathology; Wake Forest School of Medicine, Medical Center Boulevard; Winston-Salem NC 27157 U.S.A
- Department of Public Health Sciences; Wake Forest School of Medicine, Medical Center Boulevard; Winston-Salem NC 27157 U.S.A
| | - W.W. Huang
- Center for Dermatology Research; Department of Dermatology; Wake Forest School of Medicine, Medical Center Boulevard; Winston-Salem NC 27157 U.S.A
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Th17 differentiation and their pro-inflammation function. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 841:99-151. [PMID: 25261206 DOI: 10.1007/978-94-017-9487-9_5] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
CD4(+) T helper cells are classical but constantly reinterpreted T-cell subset, playing critical roles in a diverse range of inflammatory responses or diseases. Depending on the cytokines they release and the immune responses they mediate, CD4(+) T cells are classically divided into two major cell populations: Th1 and Th2 cells. However, recent studies challenged this Th1/Th2 paradigm by discovering several T-helper cell subsets with specific differentiation program and functions, including Th17 cells, Treg cells, and Tfh cells. In this chapter, we summarize the current understanding and recent progresses on the Th17 lineage differentiation and its effector impacts on variety of inflammatory responses or disease pathogenesis.
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A multilocus genetic study in a cohort of Italian SLE patients confirms the association with STAT4 gene and describes a new association with HCP5 gene. PLoS One 2014; 9:e111991. [PMID: 25369137 PMCID: PMC4219822 DOI: 10.1371/journal.pone.0111991] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2014] [Accepted: 10/10/2014] [Indexed: 12/12/2022] Open
Abstract
Background Systemic lupus erythematosus (SLE) is an autoimmune disease with complex pathogenesis in which genes and environmental factors are involved. We aimed at analyzing previously identified loci associated with SLE or with other autoimmune and/or inflammatory disorders (STAT4, IL10, IL23R, IRAK1, PSORS1C1, HCP5, MIR146a, PTPN2, ERAP1, ATG16L1, IRGM) in a sample of Italian SLE patients in order to verify or confirm their possible involvement and relative contribution in the disease. Materials and methods Two hundred thirty-nine consecutive SLE patients and 278 matched healthy controls were enrolled. Study protocol included complete physical examination, and clinical and laboratory data collection. Nineteen polymorphisms were genotyped by allelic discrimination assays. A case-control association study and a genotype-phenotype correlation were performed. Results STAT4 was the most associated gene [P = 3×10−7, OR = 2.13 (95% CI: 1.59–2.85)]. IL10 confirmed its association with SLE [rs3024505: P = 0.02, OR = 1.52 (95% CI: 1.07–2.16)]. We describe a novel significant association between HCP5 locus and SLE susceptibility [rs3099844: P = 0.01, OR = 2.06 (95% CI: 1.18–3.6)]. The genotype/phenotype correlation analysis showed several associations including a higher risk to develop pericarditis with STAT4, and an association between HCP5 rs3099844 and anti-Ro/SSA antibodies. Conclusions STAT4 and IL10 confirm their association with SLE. We found that some SNPs in PSORS1C1, ATG16L1, IL23R, PTPN2 and MIR146a genes can determine particular disease phenotypes. HCP5 rs3099844 is associated with SLE and with anti-Ro/SSA. This polymorphism has been previously found associated with cardiac manifestations of SLE, a condition related with anti-Ro/SSA antibodies. Thus, our results may provide new insights into SLE pathogenesis.
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Wu L, Wang C, Boisson B, Misra S, Rayman P, Finke JH, Puel A, Casanova JL, Li X. The differential regulation of human ACT1 isoforms by Hsp90 in IL-17 signaling. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2014; 193:1590-9. [PMID: 25024377 PMCID: PMC4119565 DOI: 10.4049/jimmunol.1400715] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
IL-17 is a proinflammatory cytokine implicated in the pathogenesis of autoimmune diseases including psoriasis. ACT1 is an essential adaptor molecule in the IL-17 signaling pathway. A missense single nucleotide polymorphism (rs33980500; SNP-D10N) that resulted in the substitution of an asparagine for an aspartic acid at position 10 of ACT1 (ACT1-D10N) is associated with psoriasis susceptibility. Due to alternative splicing in humans, SNP-D10N encodes two mutated ACT1 proteins, ACT1-D10N and ACT1-D19N. Although both ACT1 isoforms are Hsp90 client proteins, the nine additional amino acids in ACT1-D19N provide an additional Hsp90 binding site that is absent in ACT1-D10N. Therefore, whereas ACT1-D10N is a dead protein that is unable to transduce IL-17 signals for gene expression, ACT1-D19N is fully responsive to IL-17. Intriguingly, the two ACT1 isoforms are differentially expressed in ACT1(D10N/D10N) fibroblasts and T cells. Fibroblasts express both isoforms equally, enabling ACT1-D19N to compensate for the loss of ACT1-D10N function. ACT1(D10N/D10N) T cells, however, express predominantly ACT1-D10N. Lacking this compensatory mechanism, ACT1(D10N/D10N) T cells behave like ACT1-deficient T cells, exhibiting a dysregulated and hyperactive Th17 phenotype with overproduction of IL-22 and IL-17. The hyperactive Th17 response combined with fully responsive fibroblasts likely synergized to contribute to psoriasis susceptibility in SNP-D10N patients.
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Affiliation(s)
- Ling Wu
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106; Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
| | - Chenhui Wang
- Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065
| | - Saurav Misra
- Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
| | - Patricia Rayman
- Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
| | - James H Finke
- Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
| | - Anne Puel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; INSERM Unité Mixte de Recherche 1163, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris 75015, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris 75015, France; and
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; INSERM Unité Mixte de Recherche 1163, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris 75015, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris 75015, France; and Pediatric Hematology-Immunology Unit, Necker Hospital, Paris 75015, France
| | - Xiaoxia Li
- Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195;
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Faulkes RE. Upper limb erythema nodosum: the first presentation of Crohn's disease. Clin Case Rep 2014; 2:183-5. [PMID: 25614807 PMCID: PMC4302621 DOI: 10.1002/ccr3.87] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 01/10/2014] [Accepted: 05/10/2014] [Indexed: 12/28/2022] Open
Abstract
Key Clinical Message Inflammatory bowel disease can present with extraintestinal features as the patient's only complaint. The erythema nodosum (EN) initially affected the upper limbs only, reminding us that signs do not always present in a classical fashion. The presence of EN should prompt the clinician to look for any underlying cause.
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Affiliation(s)
- R E Faulkes
- Good Hope Hospital Rectory Road, Sutton Coldfield, West Midlands, B75 7RR
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Weizman A, Huang B, Berel D, Targan SR, Dubinsky M, Fleshner P, Ippoliti A, Kaur M, Panikkath D, Brant S, Oikonomou I, Duerr R, Rioux J, Silverberg M, Rotter JI, Vasiliauskas E, Haritunians T, Shih D, Li D, Melmed GY, McGovern DP. Clinical, serologic, and genetic factors associated with pyoderma gangrenosum and erythema nodosum in inflammatory bowel disease patients. Inflamm Bowel Dis 2014; 20:525-33. [PMID: 24487271 PMCID: PMC4046633 DOI: 10.1097/01.mib.0000442011.60285.68] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Pyoderma gangrenosum (PG) and erythema nodosum (EN) are the most common cutaneous manifestations of inflammatory bowel disease (IBD) but little is known regarding their etiopathogenesis. METHODS We performed a case-control study comparing characteristics between IBD patients with a documented episode of PG (PG+) and/or EN (EN+) with those without PG (PG-) and EN (EN-). Data on clinical features were obtained by chart review. IBD-related serology was determined using enzyme-linked immunosorbent assay and genome-wide data generated using Illumina technology. Standard statistical tests for association were used. RESULTS We identified a total of 92 cases of PG and 103 cases of EN with genetic and clinical characteristics, of which 64 PG and 55 EN cases were available for serological analyses. Fewer male subjects were identified in the PG(+) (odds ratio 0.6, P = 0.009) and EN(+) groups (odds ratio 0.31, P = 0 < 0.0001). Colonic disease, previous IBD-related surgery, and noncutaneous extra-intestinal manifestations were more common among both PG(+) and EN(+) patients compared with controls. PG(+) was associated with anti-nuclear cytoplasmic antibody seropositivity (P = 0.03) and higher anti-nuclear cytoplasmic antibody level (P = 0.02) in Crohn's disease. Genetic associations with PG included known IBD loci (IL8RA [P = 0.00003] and PRDM1 [0.03]) as well as with USP15 (4.8 × 10) and TIMP3 (5.6 ×10). Genetic associations with EN included known IBD susceptibility genes (PTGER4 [P = 8.8 × 10], ITGAL [0.03]) as well as SOCS5 (9.64 × 10), CD207 (3.14 × 10), ITGB3 (7.56 × 10), and rs6828740 (4q26) (P < 5.0 × 10). Multivariable models using clinical, serologic, and genetic parameters predicted PG (area under the curve = 0.8) and EN (area under the curve = 0.97). CONCLUSION Cutaneous manifestations in IBD are associated with distinctive genetic characteristics and with the similar clinical characteristics, including the development of other extra-intestinal manifestations suggesting shared and distinct etiologies.
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Affiliation(s)
- Adam Weizman
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Brian Huang
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dror Berel
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Stephan R. Targan
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Marla Dubinsky
- Departments of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars Sinai Medical Center, Los Angeles, California, USA
| | - Phillip Fleshner
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Andrew Ippoliti
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Manreet Kaur
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Deepa Panikkath
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Steve Brant
- Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, and Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Ioannis Oikonomou
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
| | - Rick Duerr
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - John Rioux
- Universite de Montreal and the Montreal Heart Institute, Research Center, Montreal, Quebec, Canada
| | - Mark Silverberg
- Mount Sinai Inflammatory Bowel Disease Center, University of Toronto, Toronto, Ontario, Canada
| | - Jerome I Rotter
- Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Eric Vasiliauskas
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Talin Haritunians
- Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - David Shih
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dalin Li
- Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Gil Y. Melmed
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dermot P.B. McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA,Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Ampuero J, Rojas-Feria M, Castro-Fernández M, Cano C, Romero-Gómez M. Predictive factors for erythema nodosum and pyoderma gangrenosum in inflammatory bowel disease. J Gastroenterol Hepatol 2014; 29:291-5. [PMID: 23927379 DOI: 10.1111/jgh.12352] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/21/2013] [Indexed: 01/21/2023]
Abstract
BACKGROUND AND AIM To identify predictive factors related to the development of erythema nodosum and pyoderma gangrenosum, in patients with inflammatory bowel disease (IBD). METHODS Epidemiological and clinical data from 270 patients with Crohn's disease (CD) and 125 patients with ulcerative colitis (UC) were collected between 2003 and 2011. The variables retrospectively analyzed were: gender, age at diagnosis, type of IBD (CD or UC), smoking habit, pattern of disease (IBD), location and extension, family history, previous IBD-related surgery, other extraintestinal manifestations (EIMs), and previous biological and immunosuppressive therapy. RESULTS Thirty-seven patients showed at least one cutaneous manifestation. These lesions were more frequent in women (15.4%) than in men (4.2%; P = 0.0001) and in CD (12.2%) than in UC patients (3.2%; P = 0.005). These manifestations were more frequently associated with other EIMs (25% vs 7.2%; P = 0.0001), and they were less frequent in patients who received a previous biological therapy for IBD (6.8% vs 11.2%; P = 0.1). Patients with skin manifestations were younger at diagnosis of IBD than those patients without them (26.3 ± 10 vs 32.9 ± 14.5, P = 0.008). Independent variables significantly associated with development of skin manifestations were: female (P = 0.008), previous biological therapy (P = 0.007), age at diagnosis (young, P = 0.026), type of IBD (CD, P = 0.043) and presence of other EIMs (P = 0.0001). CONCLUSION Predictive factors involved in the development of main cutaneous manifestations are: female, CD, young age at diagnosis of IBD, and presence of other EIMs. Early use of biological therapies prevents the development of cutaneous manifestations.
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Affiliation(s)
- Javier Ampuero
- Unit for Clinical Management of Digestive Diseases, Valme University Hospital, Sevilla, Spain
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Xiang Q, Chen L, Hou S, Fang J, Zhou Y, Bai L, Liu Y, Kijlstra A, Yang P. TRAF5 and TRAF3IP2 gene polymorphisms are associated with Behçet's disease and Vogt-Koyanagi-Harada syndrome: a case-control study. PLoS One 2014; 9:e84214. [PMID: 24416204 PMCID: PMC3885545 DOI: 10.1371/journal.pone.0084214] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 11/12/2013] [Indexed: 12/22/2022] Open
Abstract
Background TRAF5 and TRAF3IP2 have been reported to be associated with several autoimmune diseases. Behçet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome are two autoimmune uveitis entities whereby both genetic and environmental factors are thought to be involved. Objective The role of TRAF5 and TRAF3IP2 in BD and VKH has not yet been reported and was therefore the subject of this study. Methods The study included 789 BD patients, 940 VKH patients and 1601 healthy unrelated individuals. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or TaqMan® SNP Genotyping Assay. Real-Time PCR was used to detect mRNA expression from PBMCs obtained from healthy controls with (n = 22) or without (n = 79) stimulation. Levels of TNF-α, IL-6 and IL-8 in culture supernatants were measured by ELISA (n = 22). Results Three SNPs (rs6540679, rs12569232, rs10863888) of TRAF5 and rs13210247 of TRAF3IP2 were significantly associated with Behçet's disease and VKH syndrome (corrected P values ranging from 9.45×10−12 to 0.027). TRAF3IP2 rs33980500 and rs13190932 were not polymorphic in Han Chinese. Following stimulation by lipopolysaccharide (LPS), carriers of the GG genotype of rs6540679/TRAF5 had a higher TRAF5 mRNA expression (p = 0.004) and an increased TNF-α (p = 0.0052) and IL-6 (p = 0.0014) level compared with AA and AG genotype carriers. Conclusion This study provides evidence that TRAF5 and TRAF3IP2 genes are involved in the development of BD and VKH syndrome. Functional research suggested that TRAF5 gene polymorphisms may regulate TRAF5 expression and downstream inflammatory cytokines such as TNF-α and IL-6.
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Affiliation(s)
- Qin Xiang
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute; The First Affiliated Hospital of Chongqing Medical University, Chongqing, P. R. China
| | - Lu Chen
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute; The First Affiliated Hospital of Chongqing Medical University, Chongqing, P. R. China
| | - Shengping Hou
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute; The First Affiliated Hospital of Chongqing Medical University, Chongqing, P. R. China
| | - Jing Fang
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute; The First Affiliated Hospital of Chongqing Medical University, Chongqing, P. R. China
| | - Yan Zhou
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute; The First Affiliated Hospital of Chongqing Medical University, Chongqing, P. R. China
| | - Lin Bai
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute; The First Affiliated Hospital of Chongqing Medical University, Chongqing, P. R. China
| | - Yunjia Liu
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute; The First Affiliated Hospital of Chongqing Medical University, Chongqing, P. R. China
| | - Aize Kijlstra
- University Eye Clinic Maastricht, Maastricht, The Netherlands
| | - Peizeng Yang
- Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute; The First Affiliated Hospital of Chongqing Medical University, Chongqing, P. R. China
- * E-mail:
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Quoi de neuf en médecine interne? Ann Dermatol Venereol 2013; 140 Suppl 3:S263-72. [DOI: 10.1016/s0151-9638(13)70142-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Abstract
The interleukin 17 (IL-17) family, a subset of cytokines consisting of IL-17A-F, plays crucial roles in host defense against microbial organisms and in the development of inflammatory diseases. Although IL-17A is the signature cytokine produced by T helper 17 (Th17) cells, IL-17A and other IL-17 family cytokines have multiple sources ranging from immune cells to non-immune cells. The IL-17 family signals via their correspondent receptors and activates downstream pathways that include NFκB, MAPKs and C/EBPs to induce the expression of anti-microbial peptides, cytokines and chemokines. The proximal adaptor Act1 is a common mediator during the signaling of all IL-17 cytokines so far and is thus involved in IL-17 mediated host defense and IL-17-driven autoimmune conditions. This review will give an overview and recent updates on the IL-17 family, the activation and regulation of IL-17 signaling as well as diseases associated with this cytokine family.
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Affiliation(s)
- Chunfang Gu
- Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
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Song X, Qian Y. IL-17 family cytokines mediated signaling in the pathogenesis of inflammatory diseases. Cell Signal 2013; 25:2335-47. [PMID: 23917206 DOI: 10.1016/j.cellsig.2013.07.021] [Citation(s) in RCA: 122] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Accepted: 07/26/2013] [Indexed: 12/26/2022]
Abstract
Inflammation is the immediate protective response of the body to pathogen invasions, allergen challenges, chemical exposures or physical injuries. Acute inflammation usually accompanies with transient infiltration of leukocytes, removal of danger signals and eventually tissue repair, while persistent and uncontrolled inflammation becomes a major stimulator in the progression of many chronic diseases in human, including autoimmune diseases, metabolic disorders and cancer. Interleukin (IL)-17 family is a recent classified subset of cytokines, playing critical roles in both acute and chronic inflammatory responses. In this review, we will summarize recent progresses on the signalings of this family cytokines and their impacts on the inflammatory responses or disorders.
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Affiliation(s)
- Xinyang Song
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Perricone C, Ciccacci C, Ceccarelli F, Di Fusco D, Spinelli FR, Cipriano E, Novelli G, Valesini G, Conti F, Borgiani P. TRAF3IP2 gene and systemic lupus erythematosus: association with disease susceptibility and pericarditis development. Immunogenetics 2013; 65:703-9. [PMID: 23836313 DOI: 10.1007/s00251-013-0717-6] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 06/13/2013] [Indexed: 01/22/2023]
Abstract
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease. Although genetic factors confer susceptibility to the disease, only 15 % of the genetic contribution has been identified. TRAF3IP2 gene, associated with susceptibility to psoriatic arthritis and psoriasis, encodes for Act1, a negative regulator of adaptive immunity and a positive signaling adaptor in IL-17-mediated immune responses. The aim of this study was to assess the role of TRAF3IP2 gene variability in SLE susceptibility and disease phenotype in an Italian population. Two hundred thirty-nine consecutive SLE patients were enrolled. Study protocol included complete physical examination; the clinical and laboratory data were collected. Two hundred seventy-eight age- and ethnicity-matched healthy subjects served as controls. TRAF3IP2 polymorphisms (rs33980500, rs13190932, and rs13193677) were analyzed in both cases and controls. Genotype analysis was performed by allelic discrimination assays. A case-control association study and a genotype-phenotype correlation were performed. The rs33980500 and rs13193677 resulted significantly associated with SLE susceptibility (P = 0.021, odds ratio (OR) = 1.71, and P = 0.046, OR = 1.73, respectively). All three TRAF3IP2 single nucleotide polymorphisms resulted associated with the development of pericarditis; in particular, rs33980500 showed the strongest association (P = 0.002, OR 2.59). This association was further highlighted by binary logistic regression analysis. In conclusion, our data show for the first time the contribution of TRAF3IP2 genetic variability in SLE susceptibility, providing further suggestions that common variation in genes that function in the adaptive and innate arms of the immune system are important in establishing SLE risk. Our study also shows that this gene may affect disease phenotype and, particularly, the occurrence of pericarditis.
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Affiliation(s)
- Carlo Perricone
- Lupus Clinic, Reumatologia, Dipartimento di Clinica e Terapia Medica, Sapienza Università di Roma, Rome, Italy
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Song X, Qian Y. The activation and regulation of IL-17 receptor mediated signaling. Cytokine 2013; 62:175-82. [PMID: 23557798 DOI: 10.1016/j.cyto.2013.03.014] [Citation(s) in RCA: 155] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 02/27/2013] [Accepted: 03/08/2013] [Indexed: 12/19/2022]
Abstract
Interleukin-17 (IL-17), the signature cytokine produced by T helper 17 (Th17) cells, plays pivotal roles in host defense responses against microbial invasion, as well as in the pathogenesis of autoimmune diseases and allergic syndromes. IL-17 activates several downstream signaling pathways including NF-κB, MAPKs and C/EBPs to induce gene expression of antibacterial peptides, proinflammatory chemokines and cytokines and matrix metalloproteinases (MMPs). IL-17 can also stabilize mRNAs of genes induced by TNFα. Although the physiological and pathological functions of IL-17 have been studied for many years, the landscape of its signaling transduction has not been described until recently. The cytosolic adaptor molecule Act1 (also known as CIKS) is considered as the master mediator of IL-17 signaling. In this review, we will summarize recent progress on activation and regulation of IL-17 mediated signal transduction, especially on Act1 mediated regulation of the signaling.
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Affiliation(s)
- Xinyang Song
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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