Background/Purpose: The oligoclonal expansion in IgG4-related disease (IgG4-RD) of both plasmablasts and tissue-infiltrating CD4+ cytotoxic T lymphocytes, the identification of specific auto-antigens as B cell targets, and the consistent clinical responsiveness to B cell depletion all support the possibility that this disorder is an autoimmune disease in which adaptive immune responses contribute to the associated tissue fibrosis. Since 2015, four different auto-antigens have been described as potential triggers for IgG4-RD: prohibitin, annexin A11, laminin 511-E8 and galectin-3. However, validation of these findings using external patient cohorts and characterization of the relationship between these specific auto-antigens has yet to be achieved.

Methods: Autoantibody responses against prohibitin, annexin A11 and laminin 511-E8 were measured by ELISA among a clinically diverse cohort of IgG4-RD patients (n = 100). Idiopathic pulmonary fibrosis (IPF) plasma samples (n = 50) were used as a disease control and age- and sex-matched healthy donor plasma samples (n = 50) as healthy controls. We clustered our cohort into subsets of patients according to their number of autoantibody responses (no responses, 1 response, and ≥ 2 responses) and compared clinical parameters among these groups.

Results: The frequencies of IgG4 autoantibody responses against prohibitin (10%), annexin A11 (12%), and laminin 511-E8 (7%) were not significantly different from those of controls. Patients with pancreatobiliary disease did not enrich for annexin A11 or laminin 511-E8 autoantibodies. A portion of the cohort (n = 86) had been analyzed previously at our center for anti-galectin-3 antibody responses with 25 (29%) having IgG4 anti-galectin-3 antibodies. Among these 86 subjects, 32 (37%) had IgG4 antibodies to at least one of the 4 auto-antigens and 12 (14%) showed reactivity to ≥ 2 of the tested antigens. The subset of patients with ≥ 2 autoantibodies had higher total IgG1, IgG2, IgG4, and C-reactive protein levels; were more commonly hypocomplementemic; and were more likely to have visceral organ involvement.

Conclusion: Antibodies against prohibitin, annexin A11, and laminin 511-E8 were found in only a small portion of patients with IgG4-RD. A subset of IgG4-RD patients, however, had IgG4 antibodies against ≥ 2 autoantigens. Patients with antibodies against ≥ 2 autoantigens present with robust IgG subclass elevations, complement consumption, and visceral organ involvement. This broader break in immunological tolerance in IgG4-RD was associated with more severe disease. (Supported by NIH U19 AI 110495 and UM1 AI144295)

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/disease-severity-is-linked-to-an-increase-in-autoantibody-diversity-in-igg4-related-disease/