Anti-64 integrin autoantibodies inhibit the binding of laminins to 64 integrin in patients with pemphigoid and affect the gastrointestinal tract

Background: Anti-alpha 6 beta 4 integrin autoantibodies can be observed in some patients with mucous membrane pemphigoid. We have previously identified anti-alpha 6 beta 4 integrin extracellular domain autoantibodies together with anti-BP180 NC16A antibodies in a patient with DPP-4 inhibitor-induced bullous pemphigoid. However, the significance and impact of anti-alpha 6 beta 4 integrin antibodies are unknown.Objectives: To characterize anti-alpha 6 beta 4 integrin extracellular domain autoantibodies in pemphigoid patients, to determine whether these antibodies inhibit laminin-alpha 6 beta 4 integrin binding and to observe their systemic effects.Methods: Anti-alpha 6 beta 4 integrin autoantibodies were analysed by staining cells expressing the extracellular region of alpha 6 beta 4 integrin with sera from 20 patients with pemphigoid. The anti-alpha 6 beta 4 integrin autoantibodies were characterized using different transfectants. The binding of laminins to alpha 6 beta 4 integrin was studied using cells expressing the activated conformation of alpha 6 beta 4 integrin and the inhibitory effect of the autoantibodies on the binding of laminins to alpha 6 beta 4 integrin was tested. Trends in antibody titres and clinical symptoms were quantified and analysed.Results: IgG autoantibodies against the extracellular domain of anti-alpha 6 beta 4 integrin were found in some patients with pemphigoid. Laminin binding to alpha 6 beta 4 integrin was observed in the active conformation of alpha 6 beta 4 integrin, and serum from a patient with a high titre of anti-alpha 6 beta 4 integrin antibodies inhibited the binding of both laminin-511 and laminin-332 to alpha 6 beta 4 integrin. alpha 6 beta 4 integrin is expressed on the basement membrane of both skin and small intestine, and exfoliation was observed in the patient's epidermis and small intestinal epithelium. A reduction in the titre of the anti-alpha 6 beta 4 integrin antibody was associated with improvement in both skin and gastrointestinal symptoms.Conclusions: This study demonstrated the presence of anti-alpha 6 beta 4 integrin extracellular domain-specific autoantibodies in some patients with pemphigoid. In addition, these autoantibodies showed inhibitory activity on alpha 6 beta 4 integrin-laminin binding. Anti-alpha 6 beta 4 integrin antibodies can affect the gastrointestinal tract as well as the skin and oral mucosa.