*5.3. STAT-Related Disorders*

The family of Signal Transducers and Activator of Transcription (STAT) molecules is involved in multiple signaling pathways activated by different cytokines and controls the transcription of genes implicated in the immune and inflammatory response [92]. In particular, the activation of STAT-1 is mostly mediated by IFN-α and IL-2, while STAT-3 is also influenced by IL-6. The molecular mechanism leading to STAT phosphorylation requires the presence of Janus kinase (JAK) molecules [92]. Impaired or enhanced function of the JAK/STAT-dependent molecular pathways can result in a wide spectrum of

immunological and clinical alterations, with immune dysregulation and susceptibility to infections being the most relevant features.

In STAT1 gain of function (GOF), patients show reduced proliferation of TH17 cells, causing increased susceptibility to different infections, and typically present with chronic mucocutaneous candidiasis [93]. Moreover, up to a third of the patients develop autoimmune manifestations, that are mainly represented by endocrinopathies, autoimmune cytopenia, and enteropathy [81].

STAT-3 GOF is also featured by an increased risk of severe infections, deriving from a combined immune defect, associated with a high incidence of autoimmunity (cytopenia, enteropathy, endocrinopathy, arthritis). In this condition, patients also frequently display lymphoproliferation with hepato-splenomegaly [94]. The molecular defect underlying this phenotype involves reduced Tregs and Th17 proliferation [95].

Finally, STAT5b deficiency causes impaired IL-2 signaling, with consequently reduced proliferation of Tregs. The disease presents with a picture of combined immunodeficiency, growth hormone insensitivity, and IPEX-like immune dysregulation [81,96].

Although the definitive treatment for STAT-related disorders is currently represented by HSCT, the use of JAK inhibitors has demonstrated promising responses in the management of autoimmunity, infections, and lymphoproliferation in STAT1 GOF and STAT3 GOF [85]. Additionally, given the role of IL-6 in the activation of STAT-3, the anti-IL-6 antibody tocilizumab is a promising alternative for this condition [85,97] (Figure 2).

**Figure 2.** Therapeutic strategies for autoimmunity in patients with PIDs. The figure shows the current therapeutic options for specific PIDs. The choice of the therapeutic strategy (immunosuppressive agents, biologic drugs, HSCT, gene therapy) depends on the clinical severity, comorbidities and also on the availability and physician's experience. \* In patients with refractory autoimmune cytopenia. APDS: Activated phosphoinositide 3-kinase d syndrome; APS-1: Autoimmune polyendocrine syndrome 1; CTLA-4: Cytotoxic lymphocyte antigen 4; CVID: Common variable immunodeficiency; HCQ: Hydroxychloroquine; HIGM: Hyper-IgM syndromes; HSCT: hematopoietic stem cell transplantation; JAK: Janus kinase; LRBA: LPS-responsive beige-like anchor protein; MMF: mycophenolate mofetil; PI3K: Phosphoinositide 3-kinase; PKCD: protein kinase C δ deficiency; SCID: severe combined immunodeficiency; sIgAD: selective IgA deficiency; STAT: Signal Transducers and Activator of Transcription; Tregs: regulatory T cells; WAS: Wiskott-Aldrich syndrome; XLA: X-linked agammaglobulinemia.

## *5.4. Other Disorders of Regulatory T Cells*

Recently, other molecular defects impairing Treg function have been described, each in a reduced number of patients. In CD25 (IL-2RA) deficiency, IL-2 signaling is significantly impaired, thus resulting in an IPEX-like clinical picture associated with infections, and lymphoproliferation [81]. The haploinsufficiency of the BACH2 transcription factor causes altered gem center reactions, reduced Tregs levels, and increased Th1 cell proliferation, finally causing hypogammaglobulinemia, sinopulmonary infections, enteropathy, and lymphoproliferation [98].

#### **6. Autoimmunity in Disorders of Lymphocyte Differentiation and Proliferation**

Altered lymphocyte proliferation and differentiation can be responsible for a heterogeneous range of clinical manifestations, ranging from severe infectious diseases to increased susceptibility to autoimmunity and lymphoproliferation. This pathogenic aspect has particular relevance in determining the clinical phenotype of the activated phosphoinositide 3-kinase d syndrome (APDS) and protein kinase C δ deficiency (PKCD).
