Causative mechanisms and clinical impact of immunoglobulin deficiencies in Ataxia Telangiectasia

Ataxia Telangiectasia (AT) is characterized by cerebellar ataxia, telangiectasia, immunodeficiency, and increased cancer susceptibility, caused by mutations in the ataxia telangiectasia mutated (ATM) gene. The immunodeficiency comprises predominantly immunoglobulin (Ig)-deficiency, mainly IgA and IgG2, with a variable severity. So far, the exact mechanisms underlying the Ig-deficiency, especially the variable severity, remain unelucidated.To characterize the clinical impact of Ig-deficiencies in AT and to elucidate the mechanisms of Ig-deficiencies in AT.We analyzed long-term Ig-levels, immunophenotyping, and survival time in our cohort (n=87, median age 16 years; maximum 64 years). Somatic hypermutation (SHM) and class-switch junctions in B-cells were analyzed by next-generation sequencing. Furthermore, an in vitro class-switching induction assay was performed followed by RNAseq, to assess the effect of ATM-inhibition.Only the hyper-IgM AT phenotype significantly worsened survival time, while IgA or IgG2-deficiencies did not. The Ig-levels showed predominantly decreased IgG2 and IgA. Moreover, flowcytometric analysis demonstrated reduced naïve B- and T-lymphocytes and a deficiency of class-switched IgG2 and IgA memory B-cells. SHM frequencies were lowered in IgA and IgG2-deficient patients, indicating a hampered germinal center (GC) reaction. In addition, the microhomology of switch junctions was elongated, suggesting alternative end-joining during class-switch DNA-repair. The in vitro class-switching and proliferation were negatively affected by ATM-inhibition. RNA-sequencing analysis showed that ATM-inhibitor influenced expression of GC reaction genes.Ig-deficiency in AT is caused by disturbed development of class-switched memory B-cells. This study suggests that ATM-deficiency affects both the GC reaction and the choice of DNA-repair pathways in class-switching.