Increased IgG4 responses to multiple food and animal antigens indicate a polyclonal expansion and differentiation of pre-existing B cells in IgG4-related disease

Abstract

Background: IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition, characterised by an elevated serum IgG4 concentration and abundant IgG4-positive plasma cells in the involved organs. An important question is whether the elevated IgG4 response is causal or a reflection of immune-regulatory mechanisms of the disease.

Objectives: To investigate if the IgG4 response in IgG4-RD represents a generalised polyclonal amplification by examining the response to common environmental antigens.

Methods: Serum from 24 patients with IgG4-RD (14 treatment-naive, 10 treatment-experienced), 9 patients with primary sclerosing cholangitis and an elevated serum IgG4 (PSC-high IgG4), and 18 healthy controls were tested against egg white and yolk, milk, banana, cat, peanut, rice and wheat antigens by radioimmunoassay.

Results: We demonstrated an elevated polyclonal IgG4 response to multiple antigens in patients with IgG4-RD and in PSC-high IgG4, compared with healthy controls. There was a strong correlation between serum IgG4 and antigen-specific responses. Responses to antigens were higher in treatment-naive compared with treatment-experienced patients with IgG4-RD. Serum electrophoresis and immunofixation demonstrated polyclonality.

Conclusions: This is the first study to show enhanced levels of polyclonal IgG4 to multiple antigens in IgG4-RD. This supports that elevated IgG4 levels reflect an aberrant immunological regulation of the overall IgG4 response, but does not exclude that causality of disease could be antigen-driven.

Keywords: Autoimmunity; B cells; Corticosteroids; Inflammation.

Figure 1

The dot plots show IgG4 antigen-specific responses in treatment-naive patients with IgG4-RD, patients with PSC-high IgG4, and healthy controls. X-axis labels as shown in the figure . Antigens were rice and wheat, egg, milk, peanut, cat dander and serum, and banana. On the Y-axis is IgG4-specific antigen response, log 10 scale, in arbitrary units per mL. Error bars represent median and IQR; p values: *p<0.05, **p<0.005, ***p<0.001. HC, healthy controls; IgG4-RD, IgG4-related disease; PSC, primary sclerosing cholangitis.

Figure 2

The dot plots show the IgG4 antigen-specific responses in treatment-naive and treatment-experienced (on corticosteroids) patients with IgG4-related disease (IgG4-RD). Antigens were rice and wheat, egg, milk, peanut, cat dander and serum, and banana. Units as in figure 1. Error bars represent median and IQR. Mann–Whitney p values: *p<0.05, **p<0.005, ***p<0.001.