Dysregulation of mCD46 and sCD46 contribute to the pathogenesis of bullous pemphigoid

Abstract

Bullous pemphigoid (BP) is an autoimmune bullous disease caused by autoantibodies against BP180 in the epidermal basement membrane. Autoantibody-mediated complement activation is an important process in BP pathogenesis. CD46, a crucial complement regulatory protein in the complement activation, has been reported to be involved in several autoimmune diseases. In the present study, we investigated whether CD46 plays a role in BP development. We found that sCD46 expression was significantly increased in the serum and blister fluids of BP patients and correlated with the levels of anti-BP180 NC16A antibody and C3a. Otherwise, the level of mCD46 was decreased in lesions of BP patients, whereas the complement activation was enhanced. We also found that CD46 knockdown in HaCaT human keratinocytes enhanced autoantibody-mediated complement activation. Importantly, exogenous CD46 blocked complement activation in both healthy skin sections and keratinocytes induced by exposure to pathogenic antibodies from BP patients. These data suggest that CD46 deficiency is an important factor in BP pathogenesis and that increasing CD46 levels might be an effective treatment for BP.

BP180 Is Critical in the Autoimmunity of Bullous Pemphigoid

“…Passive transfer of rabbit antimurine IgG antibodies against BP180 can lead to the development of BP-like skin phenotype, in which the mechanisms involved are complement activation, mast cell degradation, neutrophil infiltration, production of reactive oxygen species and proteases, and BP180 degradation ( 14 , 79 ); and these mechanisms suggest a complement-dependent inflammatory pathway in BP development. The pathways induced by antimurine BP180 NC16A domain is further verified in studies using mast cell-deficient ( 80 ), C5-null ( 16 ), C4-null, alternative pathway component factor B-deficient ( 28 , 81 ), membrane CD46 upregulated ( 82 ), Fab-IgG-deficient ( 83 ), and FcγR-deficient ( 84 ) mice. All these studies were able to identify the complement-dependent inflammatory pathway of anti-BP180 NC16A IgG (Figure 3 A).…”

Bullous Pemphigoid

“…After antigen-antibody reaction, complement deposition and activation of both classical and alternative pathways are necessary for subepidermal bulla development [23]. IgG and IgE autoantibodies against BP180 activate the complement system, which triggers the onset of inflammatory events [1,5]. Therefore, mast cell degranulation and the release of TNF alpha, PAF and other cytokines, matrix metalloproteinase 9 and leukotrienes occur [1,5,11].…”

“…IgG and IgE autoantibodies against BP180 activate the complement system, which triggers the onset of inflammatory events [1,5]. Therefore, mast cell degranulation and the release of TNF alpha, PAF and other cytokines, matrix metalloproteinase 9 and leukotrienes occur [1,5,11]. Proteolytic enzymes released from eosinophils and neutrophil elastase breakdown various extracellular matrix proteins and BP180 [9,11].…”

“…Bullous pemphigoid (BP) is a chronic, acquired, autoimmune bullous disease characterized by subepidermal bullae [1][2][3][4]. It is the most common bullous disease, and its incidence has been gradually increasing [2,5].…”

Glucocorticoids: The mode of action in bullous pemphigoid

“…All these events together lead to subepidermal blister formation . Complement activation is a key event in the pathogenesis of BP, and downregulation of CD46, a key inhibitor of complement activation, may be involved in the pathogenesis of BP …”