Macrophages, But Not T and B Lymphocytes, Are Critical for Subepidermal Blister Formation in Experimental Bullous Pemphigoid: Macrophage-Mediated Neutrophil Infiltration Depends on Mast Cell Activation

Abstract

Bullous pemphigoid (BP) is a subepidermal blistering disease associated with autoantibodies against two hemidesmosomal proteins, BP180 and BP230. Numerous inflammatory cells infiltrate the upper dermis in BP. We have previously shown by passive transfer studies that Abs to the ectodomain of murine BP180 are capable of triggering blisters in mice that closely mimic human BP. Experimental BP depends on complement activation and neutrophil infiltration. In the present study, we investigated the relative contribution of neutrophils, mast cells (MCs), macrophages (Mφ), and lymphocytes and their functional relationship in the immunopathogenesis of this disease model by using mice deficient in these cells. Wild-type, T cell-deficient, and T and B cell-deficient mice injected intradermally with pathogenic anti-murine BP180 IgG exhibited extensive subepidermal blisters. In contrast, mice deficient in neutrophils, MCs, and Mφ were resistant to experimental BP. MCs play a major role in neutrophil recruitment into the dermis. Furthermore, Mφ-mediated neutrophil infiltration depends on MC activation/degranulation.

The Pathophysiology of Bullous Pemphigoid

“…Mice deficient in mast cells, macrophages, or neutrophils are resistant to experimental BP, whereas pathogenic anti-mBP180 antibodies trigger BP skin disease in wild-type mice and mice deficient in T or B, or both T and B cells. Reconstitution with MCs restores the pathogenic activity of anti-mBP180 IgG [82]. It has been shown that complement activation-derived fragments C3a and C5a can induce MC degranulation and that C5 deficiency completely abolishes MC degranulation.…”

Conditional Macrophage Ablation Demonstrates That Resident Macrophages Initiate Acute Peritoneal Inflammation

“…Our data suggest that the initiation of PMN infiltration is mediated by resident peritoneal M-dependent production of chemokines previously documented to play a role in orchestrating PMN recruitment in BTG peritonitis (32,33) and in other inflammatory situations (34 -36). MC are also a rich source of proinflammatory and vasoactive mediators and have been documented to play an important role in PMN recruitment during inflammation of the peritoneum (8) as well as other sites such as the skin (24).…”

“…Previous studies of peritoneal and dermal inflammation have implicated the MC as playing an important role in the initiation of PMN infiltration (8,24). We therefore performed in vitro studies to determine the production of PMN chemokines by BTG-stimulated peritoneal cell populations that had been depleted of M or MC.…”

The C5a Receptor on Mast Cells Is Critical for the Autoimmune Skin-blistering Disease Bullous Pemphigoid

“…The complement system and MC activation are indispensable to the pathogenesis of experimental BP (18,40). Having demonstrated that p38 MAPK activation is also required for disease development, we next investigated the links between complement, MCs, and p38 MAPK.…”