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‐related disease: review of the histopathologic features, differential diagnosis, and therapeutic approach

“…Mattoo et al demonstrated oligoclonal expansions of CD4+ effector/memory CTLs within both the blood and the affected tissues of patients with IgG4-RD (87,88). These T cells demonstrated a cytolytic phenotype with expression of SLAMF7, granzyme A, IL-1b, TGF-b1, and IFN-c, cytokines (87). B-cell depletion therapy resulted in both clinical remission and decreased CD4+ CTLs, further implicating these cells in active IgG4-RD (88).…”

“…Recent studies have implicated CD4+ cytotoxic T lymphocytes (CTLs), rather than Th2 responses, in the pathophysiology of the disease (79,87,88). Mattoo et al demonstrated oligoclonal expansions of CD4+ effector/memory CTLs within both the blood and the affected tissues of patients with IgG4-RD (87,88). These T cells demonstrated a cytolytic phenotype with expression of SLAMF7, granzyme A, IL-1b, TGF-b1, and IFN-c, cytokines (87).…”

Comprehensive research on thyroid diseases associated with autoimmunity: autoimmune thyroid diseases, thyroid diseases during immune-checkpoint inhibitors therapy, and immunoglobulin-G4-associated thyroid diseases

“…IgG4 has neither antibody-dependent cellular cytotoxicity (ADCC) nor complement dependent cytotoxicity (CDC) [42]. Th2 cells and Tregs have been thought to contribute to the pathogenesis of IgG4-RD, but recently Mattoo et al showed that CD4 + cytotoxic T-cells (CD4 + CTLs), follicular helper 2 cells (Tfh2) are mainly associated with the progression of IgG4-RD [43] (Fig. 1).…”

“…1). IL-4 secreted from Tfh2 cells and possibly from Th2 cells promotes IgG class switching to IgG4, and tumor growth factor (TGF)β produced by immune-mediated cells promotes tissue fibrosis [43]. In the immune reaction, logically, APC should present antigens to T-cells, and thus they may play an important role in the development of IgG4-RD.…”

IgG4-Related Disease and the Spectrum of Mimics in Rheumatology

“…However, in AIP, an increased number of CD4+ and CD25+ Treg was observed [21,25]. In the most recent reports, attention has been paid to cytotoxic lymphocytes CD4+ (CTLs) [26][27][28][29] as well as the possibility of participation of annexin A11 in the pathogenesis of AIP [30].…”