Case Report: FOXP3 Mutation in a Patient Presenting With ALPS

Abstract

ALPS and IPEX are two well-characterized inborn errors of immunity with immune dysregulation, considered as two master models of monogenic auto-immune diseases. Thus, with autoimmunity as their primary clinical manifestation, these two entities may show clinical overlap. Traditionally, immunological biomarkers are used to establish an accurate differential diagnosis. Herein, we describe a patient who presented with clinical features and biomarkers fulfilling the diagnostic criteria of ALPS. Severe apoptotic defect was also shown in the patient’s cell lines and PHA-activated peripheral blood lymphocytes. Sanger sequencing of the FAS gene did not reveal any causal mutation. NGS screening revealed a novel deleterious variant located in the N terminal repressor domain of FOXP3 but no mutations in the FAS pathway-related genes. TEMRA cells (terminally differentiated effector memory cells re-expressing CD45RA) and PD1 expression were increased arguing in favor of T-cell exhaustion, which could be induced by unrestrained activation of T effector cells because of Treg deficiency. Moreover, defective FOXP3 observed in the patient could intrinsically induce increased proliferation and resistance to apoptosis in T effector cells. This observation expands the spectrum of FOXP3 deficiency and underscores the role of NGS in detecting mutations that induce overlapping phenotypes among inborn errors of immunity with immune dysregulation. In addition, these findings suggest a potential link between FOXP3 and FAS pathways.

Clinical and immunological characteristics of five patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in China–expanding the atypical phenotypes

“…The incidence of IPEX syndrome is less than one in a million, and to date, more than seventy pathogenic mutations of FOXP3 have been described in over 200 patients (6,7,(9)(10)(11)(12). The correlation of FOXP3 genotype and clinical phenotype in IPEX syndrome is not straightforward because the same mutation in different individuals may result in different clinical presentations (7,13).…”

Molecular Markers of Blood Cell Populations Can Help Estimate Aging of the Immune System

“…It is also dangerous to disrupt the regulatory (suppressor) function of the immune system. Mutation in the Foxp3 gene, which is critical for the development of a suppressor population of T regulatory cells (T regs ), causes multi-organ autoimmunity and death of children in the first two years after birth [ 13 ].…”

“…In line with this, a mutation in the Foxp3 gene in humans disrupts immunotolerance and causes immune dysregulation, polyendocrinopathy, enteropathy, an X-linked (IPEX) disease characterized by multi-organ autoimmunity. Most affected children die within the first two years of life [ 13 ]. Knockout of IL-10, the main anti-inflammatory factor produced by T regs cells, leads to cell senescence, premature development of mouse frailty, impaired immunotolerance mechanisms, and reduced mice lifespan [ 58 ].…”