**5. Autoimmunity in Disorders of T-Cell Peripheral Tolerance**

Among disorders of peripheral tolerance, conditions affecting Treg function (also called "Tregopathies") have a prominent relevance [3]. The most frequent disorder of Tregs is the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, which is featured by a classic clinical triad of eczema, enteropathy, and endocrine autoimmunity, without a significant increase in infectious morbidity [81]. Recent genetic advances allowed the identification of different monogenic disorders featured by an IPEXlike clinical phenotype accompanied with increased susceptibility to infections, placing them at a molecular, pathogenic, and clinical crossroad between immunodeficiency and autoimmunity [81,82].

## *5.1. CTLA-4 Deficiency*

Cytotoxic lymphocyte antigen 4 (CTLA-4) is a molecule expressed by Treg cells that has a central role in the induction of peripheral immune tolerance. Indeed, CTLA-4 reduces the expression of CD80 and CD86 on the surface of antigen-presenting cells. As CD80 and CD86 are essential proteins for the costimulatory signal in the immunologic synapsis between APC and T cells, their depletion causes a reduced activation of T cells and differentiation in effector cells [83].

Patients with CTLA-4 deficiency show a picture of combined immunodeficiency with lymphopenia (reduced naïve T cells, Tregs, CD19 cells), hypogammaglobulinemia, and susceptibility to viral and bacterial infections accompanied by a high rate of autoimmune and lymphoproliferative manifestations [2,83]. The autoimmune spectrum observed in CTLA-4 deficiency is variable, comprehending autoimmune cytopenia, arthritis, uveitis, endocrinopathies, and enteropathy. In this condition, lymphoproliferation is observed in about 50% of the patients and presenting with lymphadenopathy, hepatosplenomegaly, and, although in a reduced percentage of patients, with pulmonary involvement, in the form of GLILD [62,84]. In patients with CTLA-4 deficiency, surveillance for the risk of lymphomas is essential, and treatment of autoimmunity and lymphoproliferation comprehends the use of sirolimus and the biologic agent abatacept, a fusion molecule containing the extracellular domain of CTLA-4 [85].

#### *5.2. LRBA Deficiency*

LPS-responsive beige-like anchor protein (LRBA) is a protein implicated in intracellular trafficking, which acts by inhibiting the lysosome degradation of CTLA-4 [86]. Therefore, it is essential for maintaining adequate expression of CTLA-4 on the cellular surface, and its deficiency shares several common features with CTLA-4 deficiency. Indeed, patients with LRBA deficiency often present with recurrent sinopulmonary infections, hepatosplenomegaly, lymphadenopathy, and autoimmune cytopenia [87,88]. Among the other autoimmune manifestations observed in this condition, there are enteropathy, endocrinopathies (thyroiditis, T1D), hepatitis, and uveitis [89]. Therefore, patients can present with both an IPEX-like and a CVID-like clinical phenotype, and the immunological assessment commonly shows hypogammaglobulinemia and lymphopenia, with a reduced absolute number of Tregs and memory B cells [87]. Among classic immunosuppressive strategies, there is interest in the role of sirolimus and hydroxychloroquine, as this drug can potentially reduce CTLA-4 degradation. Although it has shown promising results on autoimmune manifestations and immune abnormalities, there are only a few reports of patients treated with abatacept and, similarly, the experience with HSCT in this condition is still limited [85,90,91].
