*4.1. Autoimmune Polyendocrine Syndrome 1*

APS-1 is a rare monogenic disorder with autosomal recessive inheritance caused by mutations altering the function of the AIRE gene, expressed by thymic medullary cells and thymic dendritic cells (DCs) [70]. AIRE promotes the production of a wide range of proteins expressed in other tissues, thus causing their presentation to immature thymocytes and driving the process of central negative selection. Moreover, AIRE induces the production of Tregs, contributing to the elimination of self-reactive T cells [71]. As a consequence, defective AIRE function is associated with an expansion of self-reactive lymphocytes and the production of different specificities of autoantibodies, with high variability among APS-1 patients. Although there are no specific autoantibodies allowing the diagnosis of APS-1, a significant percentage of patients exhibit antibodies directed against cytokines implicated in the immune and inflammatory response, such as interferon (IFN), IL-17, and IL-22, contributing to the immune impairment and dysregulation observed in this disease [71]. The main clinical features of APS-1 are represented by chronic mucocutaneous candidiasis, Addison's disease, and primary hypoparathyroidism, but the phenotypic spectrum comprehends autoimmune enteropathy, hepatitis, pancreatitis, nephritis, and other clinical manifestations [70,71]. Treatment strategies are not uniformed, since they are strongly influenced by the prominent clinical manifestations observed in the individual patient [72]. Indeed, while endocrine complications are treated with hormonal replacement therapy, autoimmune organ involvement often requires the use of steroids, immunosuppressive agents (such as azathioprine), or rituximab [70].

#### *4.2. 22q11.2 Deletion Syndrome*

The wide clinical spectrum of 22q11.2DS, also known as DiGeorge syndrome (DGS), comprehends both congenital abnormalities (cardiac malformation, velo/palatal dysfunction, parathyroid insufficiency) and immunological alterations [73]. Children with 22q11.2DS show variable severity of immune impairment, ranging from complete athymia

to different degrees of combined immunodeficiency with reduced thymic function (low levels of naïve T cells and recent emigrants T (RTE) cells) and increased risk of autoimmunity, which is observed in about 10% of the patients [74,75]. The autoimmune manifestations more commonly evidenced in 22q11.2DS are ITP, juvenile idiopathic arthritis (JIA), and thyroiditis. Additionally, enteropathy and cutaneous autoimmunity (alopecia, psoriasis, vitiligo) have been described [76].

In 22q11.2DS, the pathogenesis of autoimmunity involves multiple mechanisms. The abnormal thymic environment [77] is associated with reduced expression of AIRE (Figure 1), thus impairing T cell negative selection, and reduced generation of Tregs [65,74,75,78]. Moreover, the ineffective immune response, with consequent persistence of microbial antigens, could lead to the phenomenon of molecular mimicry [2]. Recently, alterations in DCs subpopulations have also been described in 22q11.2DS, with reduced circulating numbers of both myeloid DCs (mDCs) and plasmacytoid DCs [79]. This could contribute to the development of autoimmunity, since pDCs have an important role in maintaining peripheral immune tolerance [79]. Interestingly, while the infectious phenotype is prevalent during early childhood, autoimmunity is commonly observed at a higher age. This partly reflects an evolution of the immunological phenotype of 22q11.2DS patients, with progressive reduction of Tregs and expansion of self-reactive T cells [79,80].

**Figure 1.** Pathogenesis of autoimmunity in immunodeficiency disorders. Figure legend: 22q11.2DS: chromosome 22q11.2 deletion syndrome; APC: antigen-presenting cells; APDS: Activated phosphoinositide 3-kinase d syndrome; APS-1: Autoimmune polyendocrine syndrome 1; CTLA-4: Cytotoxic lymphocyte antigen 4; CVID: Common variable immunodeficiency; LRBA: LPS-responsive beige-like anchor protein; PI3K: Phosphoinositide 3-kinase; PKCD: protein kinase C δ deficiency; PKCδ: protein kinase C δ; RAG: Recombinase activating genes; SCID: severe combined immunodeficiency; STAT: Signal Transducers and Activator of Transcription; WAS: Wiskott-Aldrich syndrome; XLA: X-linked agammaglobulinemia.

When the immune function is preserved and patients experience a low rate of infections, the use of corticosteroids and conventional immunosuppressive agents represents the initial therapeutic strategy to treat autoimmunity, while the therapeutic approach is more blurred in patients with severe infectious complications [73].
