Basophils and IgE contribute to Mixed Connective Tissue Disease development

ABSTRACT Background Mixed Connective Tissue Disease (MCTD) is a rare and complex autoimmune disease that presents mixed features with other connective tissue diseases, like systemic lupus erythematosus (SLE), systemic sclerosis and myositis. It is characterized by high levels of anti-U1-snRNP 70k autoantibodies and a high incidence of life-threatening pulmonary involvement. The pathophysiology of MCTD is not well understood and no specific treatment is yet available for the patients. Basophils and IgE play a role in the development of SLE and thus represent new therapeutic targets for SLE and other diseases involving basophils and IgE in their pathogenesis. Objective Investigate the role of basophils and IgE in the pathophysiology of MCTD. Methods Basophil activation status and the presence of autoreactive IgE were assessed in peripheral blood of a cohort of MCTD patients and in a MCTD-like mouse model. Basophil depletion and IgE-deficient animals were used to investigate the contribution of basophils and IgE in the lung pathology development of this mouse model. Results MCTD patients have a peripheral basopenia and activated blood basophils overexpressing C-C chemokine receptor 3 (CCR3). Autoreactive IgE raised against the main MCTD autoantigen U1-snRNP 70k were found in nearly 80% of the patients from the cohort. Basophil activation and IgE anti-U1-snRNP 70k were also observed in the MCTD-like mouse model along with basophil accumulation in lymph nodes and lungs. Basophil depletion dampened lung pathology and IgE deficiency prevented its development. Conclusion Basophils and IgE contribute to MCTD pathophysiology and represent new candidate therapeutic targets for MCTD patients.