Disease Severity Linked to Increase in Autoantibody Diversity in IgG4-Related Disease

Abstract

Objective: Four autoantigens have been described recently in IgG4-related disease (IgG4-RD): prohibitin, annexin A11, laminin 511-E8, and galectin-3. However, no external validation has been performed, and the possibility that some individuals break tolerance to more than 1 autoantigen has not been explored. We undertook this study to evaluate the relative frequencies of antibody responses against these autoantigens in order to explore the role of adaptive immune response in IgG4-RD.

Methods: Autoantibody responses against prohibitin, annexin A11, and laminin 511-E8 were measured among a clinically diverse cohort of IgG4-RD patients (n = 100) using enzyme-linked immunosorbent assays. Autoantibody responses were correlated with disease severity and organ distribution.

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. A portion of the cohort (n = 86) had been analyzed previously at our center for anti-galectin-3 antibody responses, with 25 patients (29%) having IgG4 anti-galectin-3 antibodies. Of these 86 patients, 32 (37%) had IgG4 antibodies to ≥1 of the 4 autoantigens and 12 (14%) showed reactivity with ≥2 of the tested antigens. The subset of patients with ≥2 autoantibodies had higher total levels of IgG1, IgG2, IgG4, and C-reactive protein, 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. These patients presented with robust IgG subclass elevations, complement consumption, and visceral organ involvement. This broader break in immunologic tolerance in IgG4-RD was associated with more severe disease.

Figure 1:. Autoantibody responses against prohibitin, annexin A11 and laminin 511-E8 occur at a low frequency in systemic IgG4-RD.

Dot plots displaying means, standard deviations (error bars) and positivity cut-offs (dashed line representing the healthy donor mean + 2 standard deviations) show the IgG4 antibody frequencies for each studied auto-antigen among our cohort (A-C). Dot plot displaying IgG1 anti-laminin 511-E8 antibodies among our cohort (D).

Figure 2:. Pancreatobiliary involvement does not enrich for annexin A11 or laminin 511-E8 autoantibodies.

Dot plots display IgG4 anti-annexin A11 and anti-laminin 511-E8 antibody responses between patients with pancreatic or biliary involvement to those without such involvement among our cohort (A-B).

Figure 3:. A subset of IgG4-RD patients demonstrate B cell responses to a variety of auto-antigens.

Bar chart displaying percentages of subjects with IgG4 antibodies among all responders (n = 32) (A). Venn diagram showing overlap in antigen reactivity between annexin A11, laminin 511-E8, prohibitin and galectin-3 among all subjects with at least one IgG4 autoantibody response (n = 32) (B).

Figure 4:. Response to multiple autoantibodies is linked to disease severity in IgG4-RD.

Forest plot showing odds ratio and 95% confidence intervals of having multiple auto-antigen responses for categorical and continuous variables. Variables favoring one or no response (left of midline) and multiple responses (right of midline) are shown. CRP = C-reactive protein.