**3.3 Immunodeficiency and inflammation**

A-T patients can show low levels of at least one type of immunoglobulin, inadequate antibody responses to infections and abnormal T and B lymphocyte counts [123, 124]. These phenotypes can be attributed to the roles that ATM has in regulating NHEJ during V(D)J recombination and class-switch recombination (CSR), two recombination processes required to produce antibody diversity during adaptive immunity. Both V(D)J and CSR involve induction of programmed DSBs followed by ATM-aided NHEJ repair [125]. For instance, during V(D)J ATM localizes to break sites and regulate NHEJ components, while p53BP1 phosphorylation by ATM is a crucial event during CSR. The regulatory roles that ATM exerts on these two processes are likely to be extensive and involve other DDR pathways. In A-T patients with immunodeficiencies, programmed DSBs remain unrepaired, and their persistence can cause severe T and B-cell developmental problems [126–128].

There is growing evidence that the innate immune response may be tightly linked to several clinical manifestations observed in A-T patients. Lack of ATM creates high levels of ROS and oxidative damage, which is known to induce pro-inflammatory cytokines [111, 129, 130]. ATM-deficient cells cannot trigger pexophagy and other forms of autophagy to counteract the negatives effect of oxidative damage, further compounding the problem [91]. Persistent genotoxic stress can, therefore, create chronic inflammation in A-T patients, a condition linked to several A-T symptoms: increased levels of cardiovascular and autoimmune diseases, insulin resistance, and aging. Tellingly, the immune response contributes to neurodegeneration during Alzheimer's disease, possibly suggesting that in A-T patients, chronic inflammation may also contribute to neurodegeneration in cerebellar tissues suffering high levels of genotoxic stress [131].
