Immune deficiencies, infection, and systemic immune disordersHuman CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation
Section snippets
Patients
Eight CD19-deficient and 8 CD40L-deficient patients suffering from an antibody deficiency were included in this study (see Table E1 in this article's Online Repository at www.jacionline.org). Seven CD19-deficient patients had biallelic genetic defects in the CD19 gene, and 1 patient had a homozygous mutation in the CD81 gene.17, 18, 19, 23, 24 Eight male patients suffered from a hyper-IgM syndrome because of the absence of CD40L expression on activated T cells and carried hemizygous mutations
Memory B-cell subsets in CD19 and CD40L deficiencies
To study the extent of impaired humoral immunity in CD19-deficient and CD40L-deficient patients (Table E1), we performed extensive flow cytometric immunophenotyping of their blood B-cell compartments. CD40L-deficient patients showed a nearly complete lack of primary (CD27+IgM-only and CD27−IgG+) and secondary GC-derived (CD27+IgG+ and CD27+IgA+) memory B cells, but had clearly detectable CD27+IgM+IgD+ “natural effector” B cells and normal numbers of CD27−IgA+ B cells (see Fig E1 in this
Discussion
Here, we analyzed antibody maturation in patients with CD19 and CD40L deficiencies to understand the absence of functional B-cell immunity in these patients. Although selection for superantigen binding was normal in CD19 deficiency, both patient groups showed decreased SHM and reduced selection strengths for antigen binding. Furthermore, selection against inherently autoreactive IGHV genes and IGH-CDR3 properties were impaired. Interestingly, SHM targeting and repair were differentially
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This work was supported by a grant from Erasmus University Rotterdam (EUR-Fellowship) to M.C.v.Z., and ZonMW Vidi grant 015.008.046 to M.v.d.B.
Disclosure of potential conflict of interest: M. C. van Zelm has received research support from Erasmus University Rotterdam (EUR) in the form of a fellowship, ZonMW, Sophia Children's Hospital Fund, and ACTA Amsterdam. G. J. Driessen has received research support from EUR in the form of a fellowship and has received the Baxter Grant. F. Mascart has received research support from the ECFP-7 program and FRSM. L. Boon has received consultancy fees from Fast Forward Therapeutics; is employed by Bioceros; and has stock/stock options in Fast Forward Therapeutics, Bioceros, Biocerox, and Broteio. M. van der Burg has received research support from ZonMW (Vidi grant no. 91712312). The rest of the authors declare that they have no relevant conflicts of interest.