Immune modulation in Pemphigus vulgaris: Role of CD28 and IL-10

Pemphigus vulgaris (PV) is an autoimmune bullous skin disease characterized by Abs to the desmosomal cadherin desmoglein-3, Although the autoantibodie s have been shown to be pathogenic, the role of the cellular immune system in the pathology of pemphigus-induced acantholysis is unclear, To further d elineate the potential role of T cell-signaling pathways in the pathogenesi s of PV, we performed passive transfer experiments with PV IgG in gene-targ eted mutant mice. Our results demonstrated that CD28-deficient mice (lackin g a costimulatory signal for T cell activation) are 5-fold more sensitive t o 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 cyt okine (IL-10) in CD28-/- mice, Lower levels of IL-10 mRNA were found in les ions from CD28(-/-) mice. To determine whether pemphigus susceptibility in CD28(-/-) was related to IL-10 deficiency, we performed passive transfer ex periments in IL-10(-/-) mice that demonstrated increased blisters compared with controls. To confirm that IL-10 is involved in the pathogenesis, rIL-1 0 was given with PV IgG, IL-10 significantly suppressed the disease activit y. These data suggest a potential role of IL-10 in PV.