In primary Sj�gren's syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response

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: 7.87). 08/2003; 48(8):2240-5. DOI: 10.1002/art.11103
Source: PubMed

ABSTRACT 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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    • "As T and B lymphocytes migrate into the gland, they themselves become activated by dendritic and epithelial cells, thereafter acting as antigen-presenting cells (Fox, 2005). Expressed antigens include SSA/Ro, SSB/La, alpha-fodrin and beta-fodrin, or cholinergic muscarinic receptors (Gottenberg et al., 2003). Recent studies suggest that the disease process of SS has a neuroendocrine component. "
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    • "Genes abbreviations: ABCA7, ATP-binding cassette, sub-family A (ABC1), member 7; APOE, apolipoprotein E (apoE); CCR5, chemokine (C –C motif) receptor 5; CTLA4, cytotoxic T-lymphocyteassociated protein 4; FAS, Fas (TNF receptor superfamily, member 6); FASLG, Fas ligand (TNF superfamily, member 6); HA-1, Minor hisocompatibility antigen; IFNG, interferon, gamma; IGHG, immunoglobulin heavy constant gamma; IGK, immunoglobulin kappa locus; IL10, interleukin 10; IL13, interleukin 13; IL1B, interleukin 1, beta; IL1RN, interleukin 1 receptor antagonist; IL4, interleukin 4; IL6, interleukin 6; MBL2, soluble mannose-binding lectin; MMP9, matrix metallopeptidase 9; PTPN22, protein tyrosine phosphatase, non-receptor type 22 (lymphoid); SSA1, Sjogren syndrome antigen A1 (52 kDa, ribonucleoprotein autoantigen SS-A/Ro); TAP1, transporter 1, ATP-binding cassette, sub-family B; TAP2, transporter 2, ATP-binding cassette, sub-family B; TGFB1, transforming growth factor, beta 1; TNF, tumor necrosis factor (TNF superfamily, member 2). Rischmueller et al. 1998; Gottenberg et al. 2003). Although selection bias could account for those results, HLA-DR2-DQA1 * 0102-DQB1 * 0602 (DR2-DQ1) haplotype has been found to be strongly associated with the presence of anti-Ro antibodies, whereas the risk of anti-Ro antibody spreading to produce precipitating anti-La antibodies might be higher in primary SS patients carrying the DR3-DQA1 * 0501- DQB1 * 02 (DR3-DQ2) haplotype (Rischmueller et al. 1998). "
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