Clonally expanded cytotoxic CD4⁺ T cells and the pathogenesis of IgG4-related disease

Abstract

IgG4-related disease (IgG4-RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions, with dense lymphoplasmacytic infiltrates containing a preponderance of IgG4-expressing plasma cells. CD4⁺ T cells and B cells constitute the major inflammatory cell populations in IgG4-RD lesions. IgG4-RD patients with active, untreated disease show a marked expansion of plasmablasts in the circulation. Although the therapeutic depletion of B cells suggests a role for these cells in the disease, a direct role for B cells or IgG4 in the pathogenesis of IgG4-RD is yet to be demonstrated. Among the CD4⁺ T-cell subsets, Th2 cells were initially thought to contribute to IgG4-RD pathogenesis, but many previous studies were confounded by the concomitant history of allergic diseases in the patients studied and the failure to use multi-color staining to definitively identify T-cell subsets in tissue samples. More recently, using an unbiased approach to characterize CD4⁺ T-cell subsets in patients with IgG4-RD – based on their clonal expansion and ability to infiltrate affected tissue sites – CD4⁺ CTLs have been identified as the major CD4⁺ T-cell subset in disease lesions as well as in the circulation. CD4⁺ CTLs in affected tissues secrete pro-fibrotic cytokines including IL-1β, TGF-β1, and IFN-γ as well as cytolytic molecules such as perforin and granzymes A and B. In this review, we examine possible mechanisms by which activated B cells and plasmablasts may collaborate with the expanded CD4⁺ CTLs in driving the fibrotic pathology of the disease and describe the lacunae in the field and in our understanding of IgG4-RD pathogenesis.

• IgG4-RD
• CD4⁺ CTL
• fibrosis
• lymphoplasmacytic infiltrate

Declaration of interest

The authors declare that they have no relevant conflicts of interest. This work was supported by an Autoimmune Center of Excellence Award to SP from the National Institutes of Health [U19 AI 110495].