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.

Advances in the diagnosis and management of IgG4 related disease

“…Finally, several autoantigens have been described in IgG4-RD, including prohibitin, annexin A11, laminin 511, and galectin-3, but autoantibodies against these proteins are found at low frequency in patients’ serum and can also be measured in some healthy donors and mimicker conditions, bearing low specificity and sensitivity for diagnostic purposes 37383940100Table 1. gives an overview of traditional and novel biomarkers used for diagnosing IgG4-RD.…”

“…In particular, patients with antibodies against two or more autoantigens (prohibitin, annexin A11, laminin 511-E8, and galectin-3) have marked IgG subclass elevations, complement consumption, and visceral organ involvement, indicating that severity of IgG4-RD is associated with an increased diversity of the autoantibody profile 100. Elevated serum concentrations of soluble interleukin 2 receptor, a surrogate marker of T cell activation, correlates with IgG4-RD activity and predicts response to glucocorticoids 169170.…”

Different Frequencies of Antibody Responses in IgG4‐Related Disease: Comment on the Article by Liu et al

“…All of the patients in our study population had AIP, whereas the population studied by Liu et al consisted of IgG4‐RD patients with involvement of various organs, including pancreatic involvement in only 32%. In this regard, we have found that the frequency of anti–laminin 511‐E8 autoantibody in patients with IgG4‐RD but without AIP was clearly low compared to the frequency in patients with AIP (Shiokawa M, et al: unpublished observations), whereas Liu and colleagues found no significant difference in laminin 511‐E8 autoantibody responses between patients with and those without pancreatic involvement . Finally, although the enzyme‐linked immunosorbent assay methods used for antibody measurement appear similar in both studies, some details might differ.…”

“…We read with interest the article by Liu et al describing their study evaluating relative frequencies of antibody responses against 3 autoantigens in order to explore the role of adaptive immune response in IgG4‐related disease (IgG4‐RD) .…”

“…In recent years, investigators have been trying to identify autoantigens in IgG4‐RD, and to date 4 different autoantigens have been reported: prohibitin, annexin A11, laminin 511‐E8, and galectin‐3 . In this study, Liu et al examined frequencies of antibody responses against 3 of the reported autoantigens, prohibitin, annexin A11, and laminin 511‐E8, in their cohort of 100 patients with IgG4‐RD , and compared those with autoantibodies against galectin‐3 in a subset of their cohort (n = 86) that they had previously analyzed . Liu and colleagues found that frequencies of IgG4 autoantibody responses against prohibitin, annexin 11, and laminin 511‐E8 in patients with IgG4‐RD were not significantly different from those in controls.…”