Clonally expanded cytotoxic CD4+T cells and the pathogenesis of IgG4-related disease.
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.
a Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.
Hamid
H
Mattoo
a Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.
John H
JH
Stone
a Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.
Shiv
S
Pillai
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002450:Cell Communication; D060965:Clonal Evolution / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004198:Disease Susceptibility; D005355:Fibrosis; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology*; D008213:Lymphocyte Activation; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
D016207:Cytokines; D007074:Immunoglobulin G
CD4+ CTL; IgG4-RD; fibrosis; lymphoplasmacytic infiltrate