*2.2. Selective IgA Deficiency*

sIgAD is defined, according to ESID and the International Union of Immunological Societies (IUIS), as serum levels of <7 mg/dL in individuals older than 4 years in the presence of normal levels of both IgG and IgM, normal IgG antibody response to vaccinations and exclusion of other causes of hypogammaglobulinemia and T-cell defects [6]. Although most of the patients with sIgAD are asymptomatic, some patients develop various clinical manifestations, such as minor recurrent sinopulmonary infections, allergies, and autoimmune manifestations [27]. A variety of autoimmune diseases may be overrepresented in patients with sIgAD than the normal population and sometimes autoimmunity could be the only clinical manifestation in these patients [27]. The prevalence of autoimmune disorders in patients with sIgAD varies from 5 to 30% [28–80], with celiac disease, ITP, AIHA, autoimmune thyroiditis, T1D, RA, and SLE being the most frequently observed manifestations [28,29,31,32].

Several mechanisms have been suggested in the development of autoimmunity in sIgAD [32], including the association with specific HLA haplotypes (particularly, the haplotype 8.1) [33], T and B cells or cytokine abnormalities, shared genetic susceptibility, or ineffective antigen clearance with molecular mimicry. Concerning immune dysfunction, Tregs deficiency is observed in 64% of the patients [34], and a lower number of CD4 + lymphocytes and switched memory B cells have been described in patients with sIgA [35]. Additionally, it has been observed that sIgAD patients with a lower number of switched memory B cells are more prone to infections and autoimmunity [30]. The monogenic hypothesis suggests that certain monogenic mutations predispose both to the development of sIgAD and autoimmune diseases. Interestingly, similar variants of CTLA4-ICOS have been found in celiac disease, sIgAD, and CVID [36]. Functionally, as IgA protect mucosal barriers from the entry of foreign antigens, in patients with sIgAD, pathogens can easily penetrate the mucosa and through a mechanism of molecular mimicry and cross-reaction with self-antigens might cause the formation of self-reactive antibodies [29,37]. Additionally, the lack of IgA may cause defective removal of immune complexes, thus propagating a state of persistent local and systemic inflammation, which may predispose to the sensitization of immune cells to self-antigen s [29]. Finally, IgA interact with cell receptors (as FcαRI) to downregulate immune pathways and protect against autoimmunity, and this function is impaired in patients with sIgAD [29].
