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

• Published in: Autoimmunity (Chur, Switzerland) Vol. 50; no. 1; pp. 19 - 24
• Main Authors: Mattoo, Hamid, Stone, John H., Pillai, Shiv
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.02.2017; Taylor & Francis Group
• Subjects: Animals; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; CD4; cd4+ ctl; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Communication; Clonal Evolution - immunology; CTL; Cytokines - metabolism; Cytotoxicity, Immunologic; Disease Susceptibility; Fibrosis; Humans; IgG4-RD; Immunoglobulin Class Switching - genetics; Immunoglobulin Class Switching - immunology; Immunoglobulin G - immunology; Lymphocyte Activation; lymphoplasmacytic infiltrate; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; fibrosis; CD4+ CTL; lymphoplasmacytic infiltrate; IgG4-RD
• ISSN: 0891-6934; 1607-842X
• DOI: 10.1080/08916934.2017.1280029

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.