BP180 Is Critical in the Autoimmunity of Bullous Pemphigoid

Abstract

Bullous pemphigoid (BP) is by far the most common autoimmune blistering dermatosis that mainly occurs in the elderly. The BP180 is a transmembrane glycoprotein, which is highly immunodominant in BP. The structure and location of BP180 indicate that it is a significant autoantigen and plays a key role in blister formation. Autoantibodies from BP patients react with BP180, which leads to its degradation and this has been regarded as the central event in BP pathogenesis. The consequent blister formation involves the activation of complement-dependent or -independent signals, as well as inflammatory pathways induced by BP180/anti-BP180 autoantibody interaction. As a multi-epitope molecule, BP180 can cause dermal-epidermal separation via combining each epitope with specific immunoglobulin, which also facilitates blister formation. In addition, some inflammatory factors can directly deplete BP180, thereby leading to fragility of the dermal-epidermal junction and blister formation. This review summarizes recent investigations on the role of BP180 in BP pathogenesis to determine the potential targets for the treatment of patients with BP.

Keywords: BP180; autoantibody; bullous pemphigoid; cytokine; dermal–epidermal junction.

Figure 1

The target sites of the BP180 molecule. BP180 is a multi-epitope protein with three major domains-the intracellular domain (ICD), the NC16A domain and the ectodomain outside NC16A domain. The ICD include five target sites, including aa 1–452, aa 1–133, aa 103–266, aa 234–398, aa 36–452 and a central region aa 112–199. The NC6A domain contain seven targeted sites, that is, NC16A1-5, 1-3, 1, 2, 2.5, 3, 3-4. The ectodomain domain also have eight functional sites, namely aa 567–1497, aa 809–1106, aa 1080–1107, aa 1280–1315, aa 1331–1404, aa 1352–1465, aa 1365–1413, and aa 1048–1465. Additionally, there are also target sites crossing more than one domain, such as aa 46–567, aa 490–812, and aa 490–1497.

Figure 2

A possible mechanism for the generation of anti-BP180 autoantibodies. Antibodies are generated for the breakage of self-tolerance which is caused by drugs, psoralen, and ultraviolet A therapy, infections, physical, or chemical insults. Autoactivated Th1 and Th2 and B cell can target different domains of BP180, leading to the generation of anti-BP180 autoantibodies via epitope spreading and Ig class-switch. Such autoantibodies could be present in the serum for a long time before occurrence of clinical features. Attacked BP180 can be a source of new antigens to initiate the further expansion of autoantibodies and acceleration of disease.

Figure 3

The possible pathogenic mechanism of the anti-BP180 NC16A autoantibodies. (A) The IgG1, IgG3, IgE, or IgA anti-BP180 NC16A autoantibodies-mediated pathways for blister formation in bullous pemphigoid (BP). The binding of IgG1, IgG3 with NC16A activates complements via FcγR followed by mast cell degradation and neutrophilic, eosinophilic, basophilic, and macrophage infiltration, which lead to the degradation of BP180 by releasing inflammatory factors and proteases. While the IgE anti-BP180 NC16A autoantibodies activate infiltration of mast cell, eosinophils, and basophils via FcεRI. (B) The immunoglobulin G (IgG) or IgE-mediated pathways for blister formation in BP. On the one hand, the binding of IgG or IgE with NC16A domain activates the protein kinase C followed by BP180 phosphorylation and degradation, which leads to the reduced adhesion. The binding, on the other hand, causes the release of interleukin (IL)-6 and IL-8 by keratinocytes, which prompts recruitment of neutrophils, release of inflammatory factors and neutrophil elastase (NE), and blister formation.

Figure 4

The potential pathogenesis of the anti-BP180 autoantibodies targeting the intracellular domain (ICD) or the ectodomain outside the NC16A. There are three possible mechanism associated the autoantibodies with ICD or ectodomain. (1) The autoantibodies penetrate cells, reach the ICD, and inhibit the interaction of BP180 with plectin, BP230, or β4. (2) The binding of autoantibodies with ectodomain interferes the interplay of BP180, α6, β4, and laminin-332. (3) The interaction between autoantibodies and ectodomain induces inflammatory and immune responses, which lead to the exposure of the ICD, initiating the effect of autoantibodies on ICD.

Figure 5

The crosstalk networks of the inflammatory cells and the proteases. (A) The autoactive Th2 cells secrete type II cytokines, which act on macrophages, keratinocytes, and fibroblasts and induce the chemotaxis of mast cells. The mast cells produce various cytokines and chemokines, which act on the regulatory T (Treg) cells, neutrophils, Th2, eosinophils, and macrophages. All these inflammatory cells can release interleukin (IL)-17, which not only act on neutrophils and Th2 but also prompt inflammatory response and proteases release. (B) The keratinocytes synthesize tissue plasmogen activator (tPA), which activates plasmin followed by the activation of matrix metalloproteinase (MMP)-9. The eosinophil cationic protein (ECP) and mast cell protease (MCP)-4 can also activate MMP-9. MMP-9 inhibits production of α1-proteinase inhibitor (α1-PI) while promote generation of neutrophil elastase (NE). All these proteases act on BP180 and dermal–epidermal junction (DEJ). The cleaved BP180 can release pro-gly-pro tripeptides and attract neutrophils.