**3. Autoimmunity in Severe Combined Immunodeficiency and Related Disorders**

The genetic and clinical variability among severe combined immunodeficiency (SCID) is remarkable and in some patients, the phenotype of early-onset severe infections can be associated with autoimmunity [61]. The case of Omenn syndrome (OS) is of particular interest, since in this condition the immune impairment coexists with a marked tendency towards lymphoproliferation and autoimmunity [62]. Children with OS develop severe invasive infections in the first months of life, and commonly show hepatosplenomegaly, diffuse lymphadenopathy, severe eczema, and alopecia [63]. Laboratory testing evidence peripheral eosinophilia, lymphopenia, and reduced serum immunoglobulin levels, associated with the peripheral expansion of self-reactive T cells, which represents the most peculiar aspect of OS [64].

The molecular basis underlying this clinical phenotype relies in most of the patients on a mutation of the recombinase activating genes (RAG) 1 and 2, which are central in the V(D)J recombination during T and B cell development. However, defects in other proteins (such as IL-7Ra, ZAP70, ARTEMIS, AK2, JAK3, and others) can be responsible for OS [61]. The pathogenesis of the autoimmune phenotype is not completely elucidated, but defects in central negative selection secondary to reduced AIRE expression and altered peripheral tolerance are implicated [65]. The prognosis of children with OS is severe [64], with death occurring in the first years of life unless they receive definitive treatment with HSCT [66]. The clinical expression of RAG mutations is not limited to OS. Mutations causing a partial loss of function of RAG cause an extremely variable clinical phenotype, with a wide spectrum of severity and clinical features of combined immunodeficiency, immune dysregulation with autoimmunity (mainly autoimmune cytopenia), and lymphoproliferation [62,67,68].

Among the non-OS phenotypic variants of SCID, patients with ARTEMIS deficiency show an ineffective DNA repair with genomic instability, with a consequent clinical picture of SCID associated with radiosensitivity and immune dysregulation with autoimmunity. Autoimmunity has also been described in a few cases of SCID carrying other molecular defects (i.e., IL-7Ra, ZAP70, ADA, and PNP deficiency) as the result of an altered central negative selection of T-cells [61]. Finally, mutations in the ORAI1 and STIM1 genes, encoding for calcium channels implicated in multiple cell functions (including B-cell receptor (BCR) and T-cell receptor (TCR) signaling), are responsible for a clinical phenotype featured by SCID-like manifestations, autoimmunity, hypotonia, and ectodermal dysplasia [65]. In all these conditions, HSCT represents the only curative therapeutic strategy.
