Novel CD81 Mutations in a Chinese Patient Led to IgA Nephropathy and Impaired BCR Signaling

Purpose CD81 deficiency is an extremely rare primary immunodeficiency disease characterized by severe and recurrent infections, IgA-related nephropathy, and profound hypogammaglobulinemia. Only one patient has been reported so far, and the pathogenesis remains unclear. Here, we identified a new case of CD81 deficiency and described its pathogenesis. Methods We analyzed the clinical, genetic, and immunological features of the patient with CD81 deficiency, and explored the pathogenesis of her antibody deficiencies. Results The major manifestation of this patient was unexpectedly not recurrent infections but IgA nephropathy with aberrant serum galactose-deficient IgA1. Whole-exome sequencing revealed novel biallelic mutations in CD81 gene that abolished the surface expression of CD81. B cells from the patient lack membrane CD19 and showed reduced switched memory B cells and transitional B cells. Decreased expression of key molecules pY and pBTK in BCR signaling were demonstrated by confocal microscopy. RNA sequencing revealed that genes associated with BCR signaling and immunoglobulins were downregulated in CD81-deficient B cells. In addition, the patient showed increased frequency of T follicular helper cells that biased to Th1-like subsets. Conclusion We reported the second patient with CD81 deficiency in the world and illustrated aberrant BCR signaling in the patient, therefore helping to unravel the mechanism of antibody deficiency in CD81-deficient patients.