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Examining the patients with a new variant of endemic pemphigus foliaceus (EPF) in El Bagre, Colombia, (El Bagre-EPF), we noted several polymorphic clinical lesions around their axillary areas. Based on our clinical findings and on previous histopathological studies on the skin of these patients that showed abnormalities in their sweat glands, and the presence of mercuric selenides and iodines by autometallography assay, we decided to investigate immunoreactivity to the sweat glands in these patients. We tested for autoreactivity utilizing direct and indirect immunofluorescence (DIF, IIF). To be able to distinguish between non-specific immune deposits and real autoimmune response, and knowing that sweat glands have some intrinsic autofluorescence for the presence of lipofuscin granules (that naturally fluoresce under the UV light microscope), as well as by the presence of secretory IgA, we used simultaneously immunohistochemistry (IHC). We tested ten El Bagre-EPF patients, ten healthy controls from the endemic area and ten healthy controls from the United States. We were able to visualize a specific autoreactivity to sweat glands in 8/10 cases of El Bagre-EPF by DIF, IIF and by IHC. In addition when using anti-human monoclonal antibodies to CD3, CD68, and CD20, we confirmed the presence of several specific immune responses in situ, an around the sweat glands. No healthy control cases yielded positive findings. In some chronic cases, decrease and sometimes a complete absence of sweat glands and other skin appendices was found. In addition to this, sclerodermoid changes or early sclerodermatous changes sometimes extending into the adipose tissue as a membranous lipodystrophy were observed. Autoreactivity to the neurovascular components around the sweat glands were also observed. Our data demonstrate for the first time that there is immunoreactivity toward sweat glands in El Bagre-EPF patients that seems to destroy some of these structures.