*2.3. Hyper IgM Syndrome*

The HIGM syndromes are a group of primary immunodeficiency disorders in which defective Ig class switch recombination, with or without defects of somatic hypermutation, leads to deficiency of IgG, IgA, and IgE with preserved or elevated levels of IgM [38]. Among HIGM syndromes, there is a genetic heterogeneity supported by the existence of X-linked, autosomal recessive, and autosomal dominant inheritance. Among X-linked HIGM (XHIM), the most common form is caused by mutations in the gene encoding CD40 ligand (CD40L) a molecule transiently expressed on the surface of activated T cells [39]. Mutations of NEMO/IKKγ genes are implicated in the X-linked Anhidrotic Ectodermal Dysplasia with Immunodeficiency (EDA-ID), a syndrome associated with HIGM. Mutations of NEMO lead to an abnormal expression of multiple enzymes required for antibody switching, such as activation-induced cytidine deaminase (AIG) and uracil DNA glycosylase (UNG), while mutations in IKKγ gene result in blockage of NF-kB release into the nucleus interfering with NF-kB and downstream CD40 signaling [40]. Concerning autosomal recessive HIGM, mutations in the AID and UNG genes result in HIGM syndrome with pure humoral immunodeficiency associated with lymphoid hypertrophy [41,42]. The natural receptor of CD40L is CD40, which is expressed on antigenpresenting cells, including B cells (APCs), dendritic cells, and macrophages. Additionally, mutations in the CD40 gene have been described in patients with HIGM, who present a very similar clinical picture to boys with XHIM [43]. In addition to susceptibility to infections, HIGM patients are prone to develop autoimmune diseases, in particular those

with mutations in CD40L, CD40, AID, and NEMO [44]. The prevalence of autoimmune manifestations in X-linked HIGM has been reported to be 10–20% without considering neutropenia, whose etiology is not well understood, with seronegative arthritis, thyroiditis, and SLE being the most commonly observed manifestations [45,46]. Regarding recessive HIGM, autoimmunity is described in about 20% of the patients with AID deficiency, and the manifestations consist of AIHA, ITP, hepatitis, T1D, Chron's disease, and uveitis [47]. The mechanisms responsible for autoimmunity in HIGM are heterogeneous and depend on the genetic background. In the XHIM form, the defective CD40-CD40L-mediated interaction results in the failure of elimination of self-reactive B cells, reduction of Tregs [48], and altered cytokine secretion [49], while in the recessive form, AID deficiency could result in defective regulation of self-reactive B cells [50].
