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 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.
Toto
P
P
Department of Dermatology, University G.d'Annunzio, Chieti, Italy.
Feliciani
C
C
Amerio
P
P
Suzuki
H
H
Wang
B
B
Shivji
G M
GM
Woodley
D
D
Sauder
D N
DN
D000051:Acantholysis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D019264:Adoptive Transfer; D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D000882:Haplorhini; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000096:biosynthesis / Q000097:blood; D007271:Injections, Intradermal; D016753:Interleukin-10 / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015603:Keratinocytes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010392:Pemphigus / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D012867:Skin / Q000276:immunology
D000276:Adjuvants, Immunologic; D018106:CD28 Antigens; D007074:Immunoglobulin G; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016753:Interleukin-10