Gottenberg, J. E. et al. In primary Sjögren's syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response. Arthritis Rheum. 48, 2240-2245

Service de Rhumatologie, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), INSERM EMI 0109, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France.
Arthritis & Rheumatology (Impact Factor: 7.76). 08/2003; 48(8):2240-5. DOI: 10.1002/art.11103
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To reevaluate, in a large series of patients with Sjögren's syndrome (SS) recruited from 2 French centers, the question of whether HLA is associated with SS itself or with a pattern of secretion of autoantibodies.
One hundred forty-nine white patients fulfilling the American-European Consensus Group criteria for SS were divided into 3 subgroups, according to their anti-Ro/SSA and anti-La/SSB status, as follows: group 1 (n = 53), no antibody; group 2 (n = 46), anti-SSA only; group 3 (n = 50), both anti-SSA and anti-SSB. Patients were compared with 222 unrelated healthy subjects representative of the white population in France.
Comparisons between the 149 SS patients and 222 controls confirmed the association of SS with DRB1*03 (the frequency was 25% in patients versus 10% in controls) and DQB1*02 (32% versus 22%). The association between HLA and SS was restricted to patients with anti-SSA and/or anti-SSB; no association with HLA was observed in patients in group 1 (no antibody). The frequency of HLA-DRB1*15 was highest in group 2 (24%), compared with 11% in group 1 and 11% in controls, whereas the frequency of HLA-DRB1*03 was highest in group 3 (44%), compared with 12% in group 1, 19% in group 2, and 10% in controls. Group 2 and group 3 had more clinical and biologic markers of activity than did group 1 but were not clinically different. HLA alleles were not associated with clinical features of the disease, and were associated with only some biologic features: rheumatoid factor positivity, increased serum IgG, and thrombocytopenia were associated with HLA-DRB1*03, and neutropenia was associated with DQB1*01.
HLA class II markers confer genetic susceptibility to Sjögren's syndrome. The association between HLA and SS is restricted to patients with anti-SSA and/or anti-SSB antibodies; HLA is not associated with SS in patients without these autoantibodies. The absence of a difference in disease severity between groups 2 and 3, as well as the restricted association of HLA-DRB1*03 in group 3, strongly suggest that HLA alleles predispose to autoantibody secretion, without being associated with clinical outcome. HLA class II phenotype might support epitope spreading: HLA-DR15 favors anti-SSA synthesis, whereas HLA-DR3 is associated with both anti-SSA and anti-SSB production.

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Available from: Marc Busson, Mar 11, 2015
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    • "The CSF phenotype association signals in the MHC region we observe have been associated with susceptibility and antibody levels in other diseases. The HLA- DRB1*1501-DQB1*0601 haplotype has been associated with either the presence or increased quantity of immunoglobulins of the IgG, IgA and IgM families both in healthy controls and in disease, including total immunoglobulins (Ferreira et al., 2010), antibodies induced by viruses such as Epstein-Barr virus (Rubicz et al., 2013), and autoantibodies in type 1 diabetes (Ishii et al., 2005) and Sjö gren syndrome (Gottenberg et al., 2003) though an opposite correlation is seen for few other antibody responses (Sundqvist et al., 2014). HLA-DQA1*0301, highly correlated with SNP rs34083746, is associated with autoantibody negative disease in ketosis-prone diabetes (Oak et al., 2014). "
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    ABSTRACT: Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 x 10-16). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 x 10-7). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 x 10-37). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 x 10-22), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 x 10-6). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.
    Brain 01/2015; 138(3). DOI:10.1093/brain/awu405 · 9.20 Impact Factor
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    • "No such an association was observed with autoantibodies, since RF was not associated in univariate analysis and anti-SSA/SSB antibodies were not associated in multivariate analysis with the ESSDAI. In addition, positivity for anti-SSA/SSB is genetically determined [28] and a previous study showed that their quantitative levels were not associated with extraglandular involvement [29]. Of note, there was no association between the studied serum markers and unstimulated salivary flow or Schirmer's test or with the new international consensus patient-related outcome score, the ESSPRI, which evaluates patient's pain, fatigue and symptoms of dryness. "
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    ABSTRACT: To analyze the clinical and immunological characteristics at enrollment in a large prospective cohort of patients with primary Sjögren's syndrome (pSS) and to investigate the association between serum BAFF, beta2-microglobulin and free light chains of immunoglobulins and systemic disease activity at enrollment. Three hundred and ninety five patients with pSS according to American-European Consensus Criteria were included from fifteen centers of Rheumatology and Internal Medicine in the "Assessment of Systemic Signs and Evolution of Sjögren's Syndrome" (ASSESS) 5-year prospective cohort. At enrollment, serum markers were assessed as well as activity of the disease measured with the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). Patient median age was 58 (25(th)-75(th): 51-67) and median disease duration was 5 (2-9) years. Median ESSDAI at enrollment was 2 (0-7) with 30.9% of patients having features of systemic involvement. Patients with elevated BAFF, beta2-microglobulin and kappa, lambda FLCS had higher ESSDAI scores at enrollment (4 [2]-[11] vs 2 [0-7], P = 0.03; 4 [1]-[11] vs 2 [0-7], P< 0.0001); 4 [2]-[10] vs 2 [0-6.6], P< 0.0001 and 4 [2-8.2] vs 2 [0-7.0], P = 0.02, respectively). In multivariate analysis, increased beta2-microglobulin, kappa and lambda FLCs were associated with a higher ESSDAI score. Median BAFF and beta2-microglobulin were higher in the 16 patients with history of lymphoma (1173.3(873.1-3665.5) vs 898.9 (715.9-1187.2) pg/ml, P = 0.01 and 2.6 (2.2-2.9) vs 2.1 (1.8-2.6) mg/l, P = 0.04, respectively). In pSS, higher levels of beta2-microglobulin and free light chains of immunoglobulins are associated with increased systemic disease activity.
    PLoS ONE 05/2013; 8(5):e59868. DOI:10.1371/journal.pone.0059868 · 3.23 Impact Factor
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    • "Anti-La/SS-B antibodies share many features with anti-Ro/SS-A antibodies, and almost all anti-La/SS-B antibody-positive RA patients also have anti-Ro/SS-A antibodies, whereas about one fifth of anti-Ro/SS-A antibody-positive RA patients also have anti-La/SS-B antibodies. HLA-DR2 (DRB1*15 and *16) and DR3 are strongly associated with anti- Ro/SS-A or anti-La/SS-B antibodies in European primary SS populations [5], [6], [7], [8]. On the other hand, DRB1*08∶03 was reported to be associated with anti-La/SS-B antibodies and *15∶01 with anti-Ro/SS-A antibodies in primary SS, SLE, and asymptomatic individuals in the Japanese population [9]. "
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    ABSTRACT: Autoantibodies to ribonucleoprotein are associated with a variety of autoimmune diseases, including rheumatoid arthritis (RA). Many studies on associations between human leukocyte antigen (HLA) alleles and RA have been reported, but few have been validated in RA subpopulations with anti-La/SS-B or anti-Ro/SS-A antibodies. Here, we investigated associations of HLA class II alleles with the presence of anti-Ro/SS-A or anti-La/SS-B antibodies in RA. An association study was conducted for HLA-DRB1, DQB1, and DPB1 in Japanese RA and systemic lupus erythematosus (SLE) patients that were positive or negative for anti-Ro/SS-A and/or anti-La/SS-B antibodies. An increased prevalence of certain class II alleles was associated with the presence of anti-Ro/SS-A antibodies as follows: DRB1*08∶03 (Pc = 3.79×10(-5), odds ratio [OR] 3.06, 95% confidence interval [CI] 1.98-4.73), DQB1*06∶01 (Pc = 0.0106, OR 1.70, 95%CI 1.26-2.31), and DPB1*05∶01 (Pc = 0.0040, OR 1.55, 95%CI 1.23-1.96). On the other hand, DRB1*15∶01 (Pc = 0.0470, OR 3.14, 95%CI 1.63-6.05), DQB1*06∶02 (Pc = 0.0252, OR 3.14, 95%CI 1.63-6.05), and DPB1*05∶01 (Pc = 0.0069, OR 2.27, 95% CI 1.44-3.57) were associated with anti-La/SS-B antibodies. The DPB1*05∶01 allele was associated with anti-Ro/SS-A (Pc = 0.0408, OR 1.69, 95% CI 1.19-2.41) and anti-La/SS-B antibodies (Pc = 2.48×10(-5), OR 3.31, 95%CI 2.02-5.43) in SLE patients. HLA-DPB1*05∶01 was the only allele associated with the presence of both anti-Ro/SS-A and anti-La/SS-B antibodies in Japanese RA and SLE patients.
    PLoS ONE 01/2013; 8(1):e53910. DOI:10.1371/journal.pone.0053910 · 3.23 Impact Factor
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