The Pathogenic Effect of IgG4 Autoantibodies in Endemic Pemphigus Foliaceus (Fogo Selvagem)

Endemic pemphigus foliaceus, or fogo selvagem, is an autoimmune blistering skin disease caused by IgG autoantibodies to a desmosome-associated glycoprotein. We studied the IgG subclasses with autoantibody activity in serum from 29 patients with active disease and in the skin lesions of 18 patients by immunofluorescence, using IgG-subclass–specific monoclonal antibodies. The predominant disease autoantibodies present in all patients were of the IgG4 subclass. IgG1 and IgG2 autoantibodies were detected in low titer in the 29 patients: IgG1 in 23 patients and IgG2 in 9. IgG3 autoantibodies were not detected in the serum of any patient. Direct immunofluorescence testing of skin lesions showed a preferential deposition of IgG4 on the keratinocyte surface. The pathogenic effect of IgG4 was demonstrated by the passive transfer of fractions containing IgG4 autoantibodies from the patients to neonatal BALB/c mice. The disease of the patients was reproduced clinically, histologically, and immunologically in these animals. Only IgG4 autoantibodies were detected by direct immunofluorescence, bound to the epidermis in the lesions of the mice, and by immunoelectron microscopy at the keratinocyte surface. IgG4 has previously been reported to be a blocking or protective antibody because it has poor effector functions in vitro, as compared with the other IgG subclasses. The finding that it is the pathogenic autoantibody in fogo selvagem raises the possibility that it may also be important in other autoimmune disease. FOGO SELVAGEM is an autoimmune blistering disorder endemic in certain rural areas of Brazil and Colombia.^1,2 It affects children and young adults of both sexes. It is distributed predominantly in regions bordering rivers within the flying range of certain Simuliidae (blackfly). The unique epidemiologic features of fogo selvagem strongly suggest that it has an environmental cause.¹ Clinically, patients with fogo selvagem have extensive superficial bullae and erosions. Histologically, there is superficial acantholysis (keratinocyte–keratinocyte detachment) and separation of the epidermis at the granular cell layer. Patients have antiepidermal autoantibodies that recognize a desmosomal glycoprotein, desmoglein I.³ These autoantibodies are detected in…