Gene variation at immunomodulatory and cell adhesion molecules Loci impacts primary Sjögren's Syndrome

Primary Sjögren's syndrome (pSS) is an autoimmune disease triggered by a combination of environmental and host genetic factors, which results in the focal lymphocytic infiltration of exocrine glands causing eye and mouth dryness. Glandular infiltrates include T and B cell subsets positive for CD5 and/or CD6, two surface scavenger receptors involved in the fine-tuning of intracellular signals mediated by the antigen-specific receptor complex of T (TCR) and B (BCR) cells. Moreover, the epithelial cells of inflamed glands overexpress CD166/ALCAM, a CD6 ligand involved in homo and heterotypic cell adhesion interactions. All this, together with the reported association of functionally relevant single nucleotide polymorphisms (SNPs) of CD5, CD6, and CD166/ALCAM with the risk or prognosis of some immune-mediated inflammatory disorders, led us to investigate similar associations in a local cohort of patients with pSS. The logistic regression analyses of individual SNPs showed the association of CD5 rs2241002T with anti-Ro/La positivity, CD6 rs17824933C with neutropenia, and CD6 rs11230563T with increased leukopenia and neutropenia but decreased peripheral nervous system EULAR Sjögren's syndrome disease activity index (ESSDAI). Further analyses showed the association of haplotypes from CD5 (rs2241002T-rs2229177C) with anemia and thrombocytopenia, CD6 (rs17824933G-rs11230563C-rs12360861G) with cutaneous ESSDAI, and CD166/ALCAM (rs6437585C-rs579565A-rs1044243C and rs6437585C-rs579565G-rs1044243T) with disease susceptibility and several analytical parameters (anti-nuclear antibodies, neurological ESSDAI, and hematologic cytopenias). These results support the relevance of gene variation at loci coding for cell surface receptors involved in the modulation of T and B lymphocyte activation (CD5, CD6) and epithelial-immune cell adhesion (CD166/ALCAM) in modulating the clinical and analytical outcomes in patients with pSS.Peer ReviewedPostprint (published version

How hepatitis C virus modifies the immunological profile of Sjögren syndrome: analysis of 783 patients.

Introduction: We conducted a study to analyze how infection by hepatitis C virus (HCV) may influence the immunological serum pattern of patients with Sjögren syndrome (SS). Methods: Since 1994, we have tested serum HCV-IgG antibodies in 783 patients with SS diagnosed according to the 1993 European classification criteria. The immunological profile at diagnosis was compared according to the presence or absence of HCV. Results: Of the 783 patients with SS, 105 (13.4 %) tested positive for HCV-IgG antibodies (88 females, 17 males,mean age at SS diagnosis: 62.9 years). Multivariate analysis showed that patients with SS-HCV had a higher mean age and a higher frequency of low C3/C4 levels, cryoglobulins, and hematological neoplasia compared with patients without HCV. The frequency of anti-La antibodies compared with anti-Ro antibodies was higher in patients with SS-HCV (17 % vs. 15 %) and lower in patients without HCV infection (30 % vs. 43 %). The frequency of concomitant detection of the three main cryoglobulin-related markers (cryoglobulins, rheumatoid factor activity, and C4 consumption) was threefold higher in patients with SS-HCV compared with patients without HCV. SS-HCV patients with genotype 1b showed the highest frequencies of immunological abnormalities related to cryoglobulins and the lowest frequencies of anti-Ro/La antibodies. Conclusions: We found HCV infection in 13 % of a large series of Spanish patients with SS. The HCV-driven autoimmune response was characterized by a lower frequency of anti-Ro/La antibodies, an abnormal predominance of anti-La among anti-Ro antibodies, and a higher frequency of cryoglobulinemic-related immunological markers in comparison with patients without HCV infection. This immunological pattern may contribute to the poor outcomes found in patients with SS-HCV

How hepatitis C virus modifies the immunological profile of Sjögren syndrome: analysis of 783 patients

Abstract Introduction: We conducted a study to analyze how infection by hepatitis C virus (HCV) may influence the immunological serum pattern of patients with Sjögren syndrome (SS). Methods: Since 1994, we have tested serum HCV-IgG antibodies in 783 patients with SS diagnosed according to the 1993 European classification criteria. The immunological profile at diagnosis was compared according to the presence or absence of HCV. Results: Of the 783 patients with SS, 105 (13.4 %) tested positive for HCV-IgG antibodies (88 females, 17 males, mean age at SS diagnosis: 62.9 years). Multivariate analysis showed that patients with SS-HCV had a higher mean age and a higher frequency of low C3/C4 levels, cryoglobulins, and hematological neoplasia compared with patients without HCV. The frequency of anti-La antibodies compared with anti-Ro antibodies was higher in patients with SS-HCV (17 % vs. 15 %) and lower in patients without HCV infection (30 % vs. 43 %). The frequency of concomitant detection of the three main cryoglobulin-related markers (cryoglobulins, rheumatoid factor activity, and C4 consumption) was threefold higher in patients with SS-HCV compared with patients without HCV. SS-HCV patients with genotype 1b showed the highest frequencies of immunological abnormalities related to cryoglobulins and the lowest frequencies of anti-Ro/La antibodies. Conclusions: We found HCV infection in 13 % of a large series of Spanish patients with SS. The HCV-driven autoimmune response was characterized by a lower frequency of anti-Ro/La antibodies, an abnormal predominance of anti-La among anti-Ro antibodies, and a higher frequency of cryoglobulinemic-related immunological markers in comparison with patients without HCV infection. This immunological pattern may contribute to the poor outcomes found in patients with SS-HCV

Role Of The Innate Immunity In The Etiopathogenesis of Primary Sjögren Syndrome: Influence Of Viral And Immunogenetic Factors Related To Cell Adhesion Molecules In Systemic Disease And Autoantibody Profile

[eng] Sjögren Syndrome is a systemic autoimmune disease that affects the exocrine glands, most notably the salivary and lacrimal glands, although it can affect other mucosal surfaces. Inflammation at these sites leads to a spectrum of sicca symptoms, thereby the predominantly symptoms are dryness of the mouth and the eyes. It is not limited to exocrine gland dysfunction; it may involve any other extraglandular systems as well (kidneys, lungs, central and peripheral nervous systems, among others). It is called primary SjS when it exists as an isolated diagnosis, and associated SjS when it co-occurs with another systemic autoimmune disorder. It is characterized by the presence of anti-Ro/La antibodies and/or the presence of focal lymphocytic sialadenitis. SjS is a chronic, systemic autoimmune disease for which no cure currently exists and the management should be organ-specific. The etiopathogenetic factors contributing to SjS remain enigmatic. The development of SjS can be considered as occurring in three stages: 1) an environmental trigger incites autoimmunity against a specific genetic background, b) the autoimmune response becomes chronic due to aberrant regulatory mechanisms within the immune system, and c) lymphoepithelial lesions and subsequent tissue damage arise from persistent inflammation. The prevailing theory, termed 'autoimmune epithelitis,' posits that the epithelial cells of the exocrine glands are the primary sites of inflammation in SjS. According to this model, lymphocytic infiltrates develop in epithelial cells surrounding or invading organs. These epithelial cells act as central players in the autoimmune response by functioning as atypical antigen-presenting cells. Extensive research has been devoted to investigating the role of salivary gland epithelial cells and epithelial cells of the lacrimal glands in SjS. These studies have demonstrated that epithelial cells are capable of orchestrating both innate and acquired immune responses, thereby affirming their crucial role in the disease process. The study of innate immunity in the context of autoimmune diseases like SjS is still in its infancy. Emerging evidence suggests that innate immune components may play a critical role in SjS etiopathogenesis. In this thesis, we focus on the role of HCV and innate immunity components (pattern recognition receptor SP-D, scavenger receptors CD5 and CD6 and adhesion molecule ALCAM) in SjS etiopathogenesis. Individuals infected with HCV often present sicca symptoms that mimic those of SjS. The virus is known to be associated with autoimmune phenomena and histopathological evidence shows that HCV can be isolated in the salivary glands of infected individuals. SP-D is found in epithelial cells and luminar material in glandular tissues, potentially implicating it in the pathogenesis of primary SjS. CD5, CD6, and ALCAM/CD166 are expressed in inflamed tissues of SjS, and their SNPs have been linked to other immune-mediated inflammatory diseases. Based on the evidence, we believe that individuals with HCV infection and those with specific SNPs in innate immunity components (SP-D, CD5/CD6, and ALCAM/CD166) may exhibit altered disease expression and immunological profiles in SjS. Understanding the role of these factors could provide critical insights into the onset and perpetuation of autoimmune responses in SjS. The overarching goal is to advance our understanding of how innate immunity machinery and specific etiopathogenic factors contribute to the complex landscape of SjS, thereby providing new avenues for diagnosis, prognosis, and therapeutic intervention.[cat] La síndrome de Sjögren és una malaltia autoimmune sistèmica que afecta les glàndules exocrines, sobretot a les glàndules salivals i lacrimals, encara que pot afectar altres superfícies mucoses. La inflamació en aquests llocs desencadena un espectre de símptomes de sicca (queratoconjuntivitis seca), de manera que els símptomes predominants són la sequedat de boca i d’ulls. No es limita a la disfunció de les glàndules exocrines, sinó que també pot afectar altres sistemes extraglandulars (ronyons, pulmons, sistema nerviós central i perifèric, entre altres). Es denomina SjS primari quan existeix com a diagnòstic aïllat, i SjS secundari quan es associat (coexisteix) amb un altre trastorn autoimmune sistèmic. Es caracteritza per la presència d'anticossos anti-Ro/La i/o la presència de sialoadenitis limfocítica focal. El SjS es una malaltia autoimmune sistèmica crònica per a la qual ara per ara encara no existeix cura i on el tractament de la qual ha de ser específic per a l’òrgan. Els factors etiopatogènics que contribueixen al SjS continuen sent enigmàtics. Pot considerar-se que el desenvolupament del SjS es produeix en tres etapes: 1) un desencadenant ambiental incita a l'autoimmunitat contra un determinat antecedent genètic, b) la resposta autoimmune es cronifica a causa de mecanismes reguladors anòmals dins del sistema immunitari, i c) les lesions limfoepitelials i el dany tissular conseqüent sorgeixen de la inflamació persistent. La teoria que més s'ha imposat, denominada "epitelitis autoimmune", sosté que les cèl·lules epitelials de les glàndules exocrines són el principal focus d'inflamació en el SjS. Segons aquest enfocament, es desenvolupen limfòcits infiltrats en cèl·lules epitelials que envolten o envaeixen els òrgans. Aquestes cèl·lules epitelials tenen un paper central en la resposta autoimmune perquè funcionen com a cèl·lules presentadores d'antígens atípiques. S'han dut a terme nombroses recerques sobre el paper de les cèl·lules epitelials de les glàndules salivals i de les glàndules lacrimals en el SjS. Aquests estudis han demostrat que les cèl·lules epitelials estan capacitades per a crear respostes immunitàries tant innates com adquirides, afirmant així el seu paper crucial en el desenvolupament de la malaltia. L'estudi de la resposta immunitària innata en el context de malalties autoimmunitàries com el SjS es troba encara en els seus inicis. Cada vegada hi ha més proves que afirmen que els components immunitaris innats poden exercir un funció fonamental en l'etiopatogènia del SjS. En aquesta tesi, ens centrem en el paper del VHC i els components de la immunitat innata (receptors de reconeixement de patrons SP-D, receptors scavenger CD5 i CD6, i la molècula d'adhesió ALCAM) en l'etiopatogènia del SjS. Les persones infectades pel VHC acostumen a presentar símptomes de sicca (queratoconjuntivitis seca) que s'assemblen als del SjS. Se sap que el virus està associat a fenòmens autoimmunes i les proves histopatològiques demostren que el VHC pot aïllar-se en les glàndules salivals dels individus infectats. El SP-D es troba en les cèl·lules epitelials i en el material luminar dels teixits glandulars, la qual cosa podria implicar-lo en la patogènesi del SjS primari. Els CD5, CD6 i ALCAM/CD166 s'expressen en els teixits inflamats del SjS, i els seus SNP s'han relacionat amb altres malalties inflamatòries inmunomediades. Basant-nos en aquestes proves, creiem que els individus amb infecció pel VHC i aquells amb SNPs en components de la immunitat innata (SPD, CD5/CD6, i ALCAM/CD166) poden mostrar una manifestació alterada de la malaltia i perfils immunològics en el SjS. La comprensió del funcionament d'aquests factors podria aportar informació significativa sobre l'inici i la perpetuació de les respostes autoimmunes en el SjS. L'objectiu general és avançar en la nostra recerca sobre com l'estructura de la immunitat innata i els factors etiopatogènics específics contribueixen al complex marc del SjS, i proporcionar així noves vies per al diagnòstic, el pronòstic i la intervenció terapèutica

Cryoglobulinaemic vasculitis at diagnosis predicts mortality in primary Sj\uf6gren syndrome: analysis of 515 patients

To evaluate the fulfilment of classification criteria for cryoglobulinaemic vasculitis (CV) at diagnosis in a large cohort of patients with primary SS and their correlation with poor outcomes

How hepatitis C virus modifies the immunological profile of Sjögren syndrome: analysis of 783 patients.

Introduction: We conducted a study to analyze how infection by hepatitis C virus (HCV) may influence the immunological serum pattern of patients with Sjögren syndrome (SS). Methods: Since 1994, we have tested serum HCV-IgG antibodies in 783 patients with SS diagnosed according to the 1993 European classification criteria. The immunological profile at diagnosis was compared according to the presence or absence of HCV. Results: Of the 783 patients with SS, 105 (13.4 %) tested positive for HCV-IgG antibodies (88 females, 17 males,mean age at SS diagnosis: 62.9 years). Multivariate analysis showed that patients with SS-HCV had a higher mean age and a higher frequency of low C3/C4 levels, cryoglobulins, and hematological neoplasia compared with patients without HCV. The frequency of anti-La antibodies compared with anti-Ro antibodies was higher in patients with SS-HCV (17 % vs. 15 %) and lower in patients without HCV infection (30 % vs. 43 %). The frequency of concomitant detection of the three main cryoglobulin-related markers (cryoglobulins, rheumatoid factor activity, and C4 consumption) was threefold higher in patients with SS-HCV compared with patients without HCV. SS-HCV patients with genotype 1b showed the highest frequencies of immunological abnormalities related to cryoglobulins and the lowest frequencies of anti-Ro/La antibodies. Conclusions: We found HCV infection in 13 % of a large series of Spanish patients with SS. The HCV-driven autoimmune response was characterized by a lower frequency of anti-Ro/La antibodies, an abnormal predominance of anti-La among anti-Ro antibodies, and a higher frequency of cryoglobulinemic-related immunological markers in comparison with patients without HCV infection. This immunological pattern may contribute to the poor outcomes found in patients with SS-HCV