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.

Case Report: Atypical Manifestations Associated With FOXP3 Mutations. The “Fil Rouge” of Treg Between IPEX Features and Other Clinical Entities?

“…In a minority of cases, IPEX syndrome can indeed present an atypical phenotype and without the classic triad, but the incidence may be underestimated. Overall, our cases are consistent with the increasing evidence of atypical presentations of IPEX and also suggest that clinical manifestations are likely influenced by epigenetic factors or modifying genes ( 20 ). The genotype–phenotype correlation in IPEX is not clear: mutations in the DNA-binding site of FOXP3 seem associated with poor outcomes ( 21 ), whereas there are mutations in the Fork-head domain and leucine-zipper domain ( 12 ) that are associated more frequently with mild phenotype or late onset.…”

Neuroinflammation Associated With Inborn Errors of Immunity

“…The Treg cell defect leads to loss of peripheral tolerance manifested as enteropathy, dermatitis, type I diabetes mellitus, hypoparathyroidism, autoimmune cytopenias, and other autoimmune diseases. IPEX-like syndromes may also arise due to defects in other Treg cell related genes such as loss-of-function variants in IL2RA2 , CTLA4 , and LRBA , or gain-of-function variants in STAT1 and STAT3 ( 214 ). A cohort of 173 patients with IPEX or IPEX-like syndrome have been reported and approximately 25% in both groups had neurological symptoms, which included seizures, ventriculomegaly, and developmental delay ( 46 ).…”

Cohesin-Mediated Chromatin Interactions and Autoimmunity

“…FOXP3 is called the master transcriptional regulator of T regulatory cells (T regs ), which implies its major contribution to differentiation of CD4 + T cells into T regulatory cells. Mutations or distortions of the Foxp3 locus in man and mouse leads to a multiple autoimmune disorder clinically presented as diarrhoea, diabetes, and eczema ( 92 ).…”