Immune Modulation in Pemphigus Vulgaris: Role of CD28 and IL-10

Abstract

Pemphigus vulgaris (PV) is an autoimmune bullous skin disease characterized by Abs to the desmosomal cadherin desmoglein-3. Although the autoantibodies have been shown to be pathogenic, the role of the cellular immune system in the pathology of pemphigus-induced acantholysis is unclear. To further delineate the potential role of T cell-signaling pathways in the pathogenesis of PV, we performed passive transfer experiments with PV IgG in gene-targeted mutant mice. Our results demonstrated that CD28-deficient mice (lacking a costimulatory signal for T cell activation) are 5-fold more sensitive to the development of PV than wild-type mice. To evaluate whether the higher incidence of disease was due to an impairment in intercellular adhesion of keratinocytes, we performed an in vitro acantholysis, using CD28−/− mice keratinocytes. No alteration in in vitro adhesion was detected in CD28−/−-type keratinocytes. Because the CD28 molecule plays a pivotal role in the induction of Th2 cytokines, we examined the levels of a prototypic Th2 cytokine (IL-10) in CD28−/− mice. Lower levels of IL-10 mRNA were found in lesions from CD28−/− mice. To determine whether pemphigus susceptibility in CD28−/− was related to IL-10 deficiency, we performed passive transfer experiments in IL-10−/− mice that demonstrated increased blisters compared with controls. To confirm that IL-10 is involved in the pathogenesis, rIL-10 was given with PV IgG. IL-10 significantly suppressed the disease activity. These data suggest a potential role of IL-10 in PV.

Pemphigus Vulgaris Antibody Identifies Pemphaxin

“…In an attempt to identify the pathogenic PV antibody, we investigated the ability of different fractions of immunoaffinity-purified anti-keratinocyte PV IgGs to: 1) stain the stratified epithelial substrates in a fishnet-like, "intercellular" pattern, which is diagnostic of PV (1); and 2) induce acantholysis in keratinocyte monolayers, which has become a standard approach to test disease-causing ability of PV antibodies (29,30). Among tested PV IgG fractions, the antibody eluted from the horizontal strip excised from the 75-kDa area of the immunoblotting membrane produced intercellular epithelial staining of both normal human skin and monkey esophagus in IIF experiments (Fig.…”

Pemphigus Vulgaris IgG and Methylprednisolone Exhibit Reciprocal Effects on Keratinocytes

“…In pilot studies, we determined that an 8-h incubation provided a sufficient amount of time to observe early acantholytic changes in PV IgG-treated keratinocyte monolayers. According to different reports, acantholysis can develop as early as several hours and as late as several days after exposure of KC to PV IgG (2,50,60,69,70), which may reflect the "strength" of PV antibody used.…”

Tannic Acid Induces in vitro Acantholysis of Keratinocytes via IL-1α and TNF-α

“…To elucidate the role of different pathological mechanisms, apparently contrasting theories have been put forward (3). Complement activation (4)(5), plasminogen-plasmin system (6-7) and local cellular immune responses (8)(9) are all involved in the mechanism of acantholysis, but none of them playa pivotal role. Knock-out mice lacking the C5 complement still develop blisters in passive transfer experiments (10).…”