*4.4. Inborn Errors of Immunity with Immune Dysregulation*

Bi-allelic loss-of-function variants in *TET2* in humans have been associated with immunodeficiency and autoimmune lymphoproliferative syndrome (ALPS)-like phenotypes with remarkable predisposition to lymphoma [84]. TET2 is a crucial epigenetic regulatory factor in hematopoietic cells, facilitating demethylation by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and other oxidation products. Loss-of-function mutations in TET2 are responsible for DNA methylation increases in hematologic cells, thus accounting for the failure of the controlled development of B cells and the expansion of double-negative T cells [85]. In Tregs, TET is implicated in the stability of Foxp3 molecules. The haploinsufficiency of TET2 is related to hematological neoplasia. However, it should be mentioned that TET2 mutations also occur in healthy subjects with clonal hematopoiesis, implying that they are sufficient to induce cancer alone [86,87]. Extrinsic factors, namely infections through hyperinflammation, seem to be co-factors in carcinogenesis.

The activity of activation-induced cytidine deaminase (AID) is hampered in TET2-/ mice, leading to abnormal demethylation. Altogether, these changes impair the transcription of genes critical for germinal center exit, antigen presentation and the differentiation of germinal center B cells, concurring with the development of diffuse large B-cell lymphomas. Therefore, it is conceivable to presume that TET2 has a crucial role in cell proliferation and differentiation [87].

TET proteins are also essential for specific points of B cell development, such as the transition from pro-B to pre-B and the differentiation of plasma cells [88].
