Understanding CD4+ T cells in autoimmune bullous diseases

Abstract

Autoimmune bullous diseases (AIBDs) are a group of life-threatening blistering diseases caused by autoantibodies that target proteins in the skin and mucosa. Autoantibodies are the most important mediator in the pathogenesis of AIBDs, and various immune mechanisms contribute to the production of these pathogenic autoantibodies. Recently, significant progress has been made in understanding how CD4⁺ T cells drive autoantibody production in these diseases. Here, we review the critical role of CD4⁺ T cells in the production of pathogenic autoantibodies for the initiation and perpetuation of humoral response in AIBDs. To gain an in-depth understanding of CD4⁺ T-cell pathogenicity, antigen specificity, and mechanisms of immune tolerance, this review covers comprehensive mouse and human studies of pemphigus and bullous pemphigoid. Further exploration of pathogenic CD4⁺ T cells will potentially provide immune targets for improved treatment of AIBDs.

Keywords: CD4 T cells; autoimmune bullous disease; bullous pemphigoid; pathogenicity; pemphigus.

Figure 1

Schematic overview of immune mechanism of desmoglein (DSG)-specific CD4⁺ T cells in pemphigus. After recognizing DSG epitope expressed on major histocompatibility complex class II from medullary thymic epithelial cells under the control of AIRE, DSG-specific T cells undergo deletion in the thymus. When DSG-specific T cells escape from central tolerance, Tregs control tolerance in peripheral regions via OX40L-OX40 signaling. In a diseased state of pemphigus, tolerance is broken and DSG-specific CD4⁺ T cells become pathogenic. Of DSG-specific CD4⁺ T cells, ICOS⁺ Tfh cells interact with DSG-specific B cells to provide stimulatory signals including CD40L-CD40 interaction and cytokines. These signals lead to B-cell activation and proliferation, differentiation into plasma cells, and production of pathogenic DSG-specific IgG antibodies that induce acantholytic blister by loss of cell-cell adhesion in keratinocytes.

Figure 2

Schematic overview of immune mechanism of BPAG-specific CD4⁺ T cells in bullous pemphigoid (BP). The triggering factor for BP can be medication (e.g., immune checkpoint inhibitors and dipeptidyl peptidase-4 inhibitor) or neurologic diseases. The process begins with the presentation of a BPAG epitope by dendritic cells through MHC class II, including HLA-DQB*03:01, which activates BPAG-specific CD4⁺ T cells. Also, dysfunction of Treg cells play a role in the development of BP, as evidenced in patients with IPEX syndrome. This leads to interaction with BPAG-specific B cells through CD40-CD40L interaction, resulting in the differentiation of B cells and the epitope spreading of IgG and IgE autoantibodies. Among them, NC16A domain of BPAG2 is recognized as a major pathogenic epitope of autoantibodies. These autoantibodies bind to the basement membrane zone of the skin and mucous membranes, inducing subepidermal blistering in BP. The increased type 2 immunity was seen in BP and might contribute to the development of the diseases.