Background/Purpose: IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder of uncertain etiology. Recognition of this disease as a distinct entity stemmed from investigation into autoimmune pancreatitis (AIP), which was ultimately found to be part of a larger, systemic process. Prior studies on AIP have revealed 8 associated autoantigens including carbonic anhydrase (CA) isoforms 1, 2 and 4, lactoferrin (LAF), trypsin (PRSS2), trypsin inhibitor (SPINK1), E3 ubiquitin protein ligase (UBR2) and amylase-2A (AMY). While many AIP patients have IgG4-RD, these studies did not exclude type 2 AIP (non-IgG4 related), did not include patients with other manifestations of IgG4-RD and did not fully explore the B cell response. Our aim was to examine these autoantigens among a large and diverse cohort of systemic IgG4-RD patients.

Methods: Six of these autoantigens were commercially available in a recombinant form (CA-1, CA-2, CA-4, LAF, PRSS2, SPINK1). IgG4-RD patients (n = 100) were recruited between January 2012 and June 2016 and plasma samples frozen at -20°C until use. All samples had active disease at the time of collection. Disease controls (n = 25) included ANCA-associated vasculitis, rheumatoid arthritis and systemic lupus erythematosus. Healthy donors (n = 40) were used as negative controls. All proteins were studied by ELISA using a series of secondary antibodies (IgG, IgG1, IgG2, IgG3, and IgG4). Our cohort was powered to evaluate the correlation between autoantibody positivity and the presence of salivary gland, lymph node, pancreatic, lacrimal gland, lung, and retroperitoneal involvement.

Results: Our IgG4-RD cohort consisted of over 26 different organ manifestations including 47% with salivary gland, 28% lymph node, 21% pancreatic, 20% lacrimal gland, 20% lung and 20% retroperitoneal involvement. 77% had biopsy-proven disease while the remaining 22% had compelling clinical phenotypes with elevated serum IgG4 concentrations. 72% of the cohort had elevated serum IgG4 concentrations and 35%, elevated IgG1 concentrations. Overall, we observed a positive B cell autoantibody response in 26% of our IgG4-RD cohort. Each autoantigen was individually seen at a lower frequency, in the range of 5-10% of the cohort. 60% of the disease control cohort (15 of 25) showed a response to at least 1 of the 6 autoantigens. The predominant autoantibody subclass was of IgG1 (61%) closely followed by IgG4 (58%). IgG2 and IgG3 were also seen but at a much lower frequencies (8% and 33%, respectively). Autoantibodies of each subclass correlated to serum elevations of that subclass. Taken as a group, the presence of one or more of these autoantibodies did not correlate to salivary gland, lymph node, pancreatic, lacrimal gland, lung, or retroperitoneal involvement.

Conclusion: Autoantibodies previously reported in association with AIP were observed among a large cohort of systemic IgG4-RD patients. The presence of these autoantibodies did not correlate to pancreatic involvement nor were they specific for IgG4-RD. This finding of promiscuous autoreactivity likely represents a breach in tolerance in IgG4-RD providing support for an autoimmune etiology to this disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoimmune-pancreatitis-associated-autoantigens-among-100-igg4-related-diseases-patients/