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Pemphigus is a group of autoimmune blistering diseases targeting the cell–cell adhesion molecules, desmogleins (Dsgs). Anti-Dsg antibodies, the hallmark of the disease, were not detected in normal individuals in many populations. In spite of the rarity of pemphigus vulgaris (PV) disease in many parts of the world, PV is not rare in Egypt. The purpose of the present study is to investigate the presence of anti-Dsg3 antibodies in normal Egyptians aiming to determine the reason for the increase in number of patients in Egypt with pemphigus.Anti-Dsg3 antibodies were evaluated in 200 normal human sera, 20 first-degree relatives with PV in comparison with 10 patients with PV as controls using the enzyme-linked immunosorbent assay technique.Fourteen of 200 (7%) normal individuals and two of 20 (10%) first-degree relatives with PV had anti-Dsg3 antibodies using enzyme-linked immunosorbent assay technique, and 11 of 16 were still positive after confirmation by indirect immunofluorescence. The sera were positive for IgG1, IgG3, and IgG4 subclasses. The presence of IgG4 subclass in normal individuals is suggestive that they may be in the preclinical stage and therefore are at higher risk to develop the PV disease.The study proved the presence of anti-Dsg3 antibodies in normal Egyptians with significant relation to some environmental factors. Follow-up of those individuals is necessary to determine who will develop the disease and the triggering factors.