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Alterations in Immunophenotype of Autoimmune-prone Hypomorphic RAG-deficient Patients with CID-G/AI Phenotype

Rationale: Patients with partial deficiency of recombination-activating genes 1 or 2 (RAG1/2) can present with a wide spectrum of primary immunodeficiencies including combined immunodeficiency with granuloma and/or autoimmunity (CID-G/AI). Prior case reports have highlighted alterations in B and T cell compartments; however comprehensive characterization of these cell populations with focus on autoreactive-prone subsets has not been reported.

Methods: Multiparametric flow cytometry approach was used to characterize B and T cell subsets of RAG CID-G/AI patients' peripheral blood. Major B cell subsets were identified based on CD19, CD21, CD24, CD27, CD38, CD138, IgD and IgM expression, while regulatory (Treg) and follicular helper T (Tfh) cells were determined as CD3+CD4+CD25highCD127low and CD3+CD4+PD-1+CXCR5+ cells, respectively.

Results: Based on the analysis of our cohort of six hypomorphic RAG-deficient patients with CID-G/AI phenotype, we noted significantly lower ratio of transitional and naïve mature B cells, while memory B cells were enriched as compared to healthy controls. Interestingly, marginal zone and CD21−/low anergic B cells were represented in significantly higher frequencies in our cohort compared to healthy controls. Furthermore, RAG-deficient patients had fewer Tregs and increased frequency of circulating Tfh cells.

Conclusions: Alterations among B cell subsets patients may be related to partial developmental block in bone marrow and peripheral clonal expansion of memory, marginal zone B cells or anergic autoreactive-prone CD21−/low B cells. Decreased frequency of Tregs and expansion of Tfh cells, may contribute to immune dysregulation and autoimmunity observed in these patients.