T cell autoimmunity and immune regulation to desmoglein 3, a pemphigus autoantigen

Abstract

Pemphigus is a life-threatening autoimmune bullous disease mediated by anti-desmoglein IgG autoantibodies. Pemphigus is mainly classified into three subtypes: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. The pathogenicity of autoantibodies has been extensively studied. Anti-human CD20 antibody therapy targeting B cells emerged as a more effective treatment option compared to conventional therapy for patients with an intractable disease. On the other hand, autoreactive T cells are considered to be involved in the pathogenesis based on the test results of human leukocyte antigen association, autoreactive T cell detection, and cytokine profile analysis. Research on the role of T cells in pemphigus has continued to progress, including that on T follicular helper cells, which initiate molecular mechanisms involved in antibody production in B cells. Autoreactive T cell research in mice has highlighted the crucial roles of cellular autoimmunity and improved the understanding of its pathogenesis, especially in paraneoplastic pemphigus. The mouse research has helped elucidate novel regulatory mechanisms of autoreactive T cells, such as thymic tolerance to desmoglein 3 and the essential roles of regulatory T cells, Langerhans cells, and other molecules in peripheral tissues. This review focuses on the immunological aspects of autoreactive T cells in pemphigus by providing detailed information on various related topics.

Keywords: T cells; desmoglein; human leukocyte antigen; pemphigus; tolerance.

FIGURE 1

Schematic overview of humoral and cellular immunity in pemphigus vulgaris and paraneoplastic pemphigus. Ab, antibody; APC, antigen presenting cells. HLA, human leukocyte antigen.

FIGURE 2

Schematic overview of central and peripheral tolerance against Dsg3‐specific T cells. When pre‐T cells express Dsg3‐specific TCR to be Dsg3‐specific T cells, the cells receive Dsg3‐antigen presentation from mTECs which express Dsg3 in an Aire‐dependent manner as negative selection in central tolerance mechanisms. Based on the TCR affinity to Dsg3, the cells usually either undergo deletion or might differentiate into Treg. If the cells escape the central tolerance, the cells distribute in the periphery, but additionally undergo peripheral tolerance mechanisms such as IL‐10‐producing Tr‐1 differentiation, and being deviated in Th1 with Th2 differentiation prohibited, as well as deletion due to reduced OX40 signal directed by Tregs; Tregs deprive OX40L of antigen‐presenting DCs.

FIGURE 3

Experimental models revealing the peripheral deletion of Dsg3‐specific T cells. After bone marrow transplantation from Dsg3H1‐Rag2 ^−/− mice into Dsg3 ^−/− thymus‐transplanted athymic mice and Dsg3 ^−/− mice, development of Dsg3‐specific CD4⁺ T cells is observed in thymus and skin‐draining lymph nodes. In Dsg3 ^−/− thymus‐transplanted athymic mice, Dsg3‐specific CD4⁺ T cells are developed in the transplanted Dsg3 ^−/− thymus and are deleted in the periphery (a, upper row). In Dsg3 ^−/− mice, they develop in the thymus and survive in the periphery (a, bottom row). When the surviving Dsg3H1‐Rag2 ^−/− T cells are adoptively transferred into wild‐type mice, they are deleted (b).

FIGURE 4

Treg‐mediated peripheral tolerance against Dsg3‐specific CD4⁺ T cells. Dsg3H1‐Rag2 ^−/− CD4⁺ T cells disappear after adoptive transfer into Treg‐intact wild‐type mice. On the other hand, after transfer into Treg‐deficient mice, they are activated and induce interface dermatitis by attacking Dsg3‐expressing keratinocytes.