IPEX Syndrome: Improved Knowledge of Immune Pathogenesis Empowers Diagnosis

Abstract

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic autoimmune disease with variable clinical manifestations, ranging from early-onset severe autoimmunity, including enteropathy, eczema, and type 1 diabetes, to late-onset or atypical symptoms. Despite the clinical heterogeneity, the unifying feature of IPEX is mutation of the FOXP3 gene, which encodes a transcription factor essential for maintenance of thymus-derived regulatory T cells (Tregs). In IPEX patients, Tregs can be present, although unstable and impaired in function, unable to inhibit proliferation and cytokine production of effector T (Teff) cells. Mutated FOXP3 can also disrupt other compartments: FOXP3-deficient Teff cells proliferate more than the wild-type counterpart, display altered T-cell-receptor signaling response, a reduced T-naïve compartment and a skew toward a Th2 profile. Due to FOXP3 mutations, the frequency of autoreactive B cells is increased and the IgA and IgE production is altered, together with early emergence of tissue-specific autoantibodies. Recently, the awareness of the wide clinical spectrum of IPEX improved the diagnostic tools. In cases presenting with enteropathy, histological evaluation is helpful, although there are no pathognomonic signs of disease. On the other hand, the study of FOXP3 expression and in vitro Treg function, as well as the detection of specific circulating autoantibodies, is recommended to narrow the differential diagnosis. Nowadays, Sanger sequencing should be limited to cases presenting with the classical triad of symptoms; otherwise, next-generation sequencing is recommended, given the cost-effectiveness and the advantage of excluding IPEX-like syndromes. The latter approach could be time spearing in children with severe phenotypes and candidate to advanced therapies.

Keywords: FOXP3; IPEX syndrome; autoimmunity; diagnosis; immune tolerance; next generation sequencing; regulatory T cells.

Figure 1

Multiple alterations affecting the Treg, Teff, and B-cell compartments as a consequence of FOXP3 mutations. HAA, anti-harmonin autoantibodies; VAA, anti-villin autoantibodies; ANKS4B, ankyrin repeat and sterile alpha motif domain containing 4; ACSL5, acyl-CoA synthetase long chain family member 5; HNF4A, hepatic nuclear factor 4 alpha; OCR, oxygen consumption rate; Treg, regulatory T cell; Teff, effector T cell.

Figure 2

Diagnostic steps driving toward IPEX syndrome. Ig, immunoglobulin; HbA1c, glycated hemoglobin; FOXP3, forkhead box protein P3; CTLA4, cytotoxic T-lymphocyte protein 4; BACH2, BTB Domain And CNC Homolog 2; TNF, tumor necrosis factor alpha; IL-10, interleukin 10; STAT1, signal transducer and activator of transcription 1; STAT3, signal transducer and activator of transcription 3; IGF1, insulin-like growth factor I; STAT5b, signal transducer and activator of transcription 5b; TSDR, Treg cell-specific demethylated region; NGS, next-generation sequencing; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked.