Nasopharyngeal microbiota dysbiosis in HSC transplanted SCID patients with IL2RG/JAK3 deficiency and IVIg-treated patients with hypogammaglobulinemia.

Here we characterize mucosal immunity in a unique human severe combined immunodeficiency (SCID) cohort comprising patients receiving hematopoietic stem cell transplantation with or without myeloablation. We confirmed that pre-transplant conditioning impacted on innate (NK, ILC) and adaptive lymphocyte reconstitution in these SCID patients and now demonstrate that this further extends to generation of Th2 and Tc2 cells. Using an integrated approach to assess nasopharyngeal immunity, we identify a local mucosal defect in type 2 cytokines, mucus production and a selective local IgA deficiency in SCID patients with genetic defects in IL2RG/GC or JAK3 that received allogeneic hematopoietic stem-cell transplantation (HSCT) in the absence of myeloablation. These patients have a reduction in IgA-coated nasopharyngeal bacteria and exhibit microbial dysbiosis with increased pathobiont carriage. Interestingly, IVIG replacement therapy can partially normalize nasopharyngeal Ig profiles and restore microbial communities in this context.