Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked–like disorder caused by loss-of-function mutations in LRBA

Abstract

Background A number of heritable immune dysregulatory diseases result from defects affecting T regulatory (TR) cell development and/or function. They include Immune dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX), due to mutations in FOXP3, and IPEX-like disorders caused by mutations in IL2RA, STAT5b and STAT1. However, the genetic defects underlying many cases of IPEX-like disorders remain unknown. Objective We sought to identify the genetic abnormalities in subjects with idiopathic IPEX-like disorders. Methods We performed whole exome and targeted gene sequencing, and phenotypic and functional analyses of TR cells. Results A child who presented with an IPEX-like syndrome and severe TR cell deficiency was found to harbor a nonsense mutation in the gene encoding LPS-responsive beige-like anchor (LRBA), previously implicated as cause of common variable immunodeficiency with autoimmunity. Analysis of subjects with LRBA deficiency revealed marked TR cell depletion, profoundly decreased expression of canonical TR cell markers, including FOXP3, CD25, Helios, and CTLA4 and impaired TR cell-mediated suppression. There was skewing in favor of memory T cells and intense autoantibody production with marked expansion of T follicular helper and contraction of T follicular regulatory cells. Whereas the frequency of recent thymic emigrants and the differentiation of induced TR cells were normal, LRBA-deficient T cells exhibited increased apoptosis and reduced activities of the metabolic sensors mammalian target of rapamycin 1 and 2 complexes. Conclusion LRBA deficiency is a novel cause of IPEX-like syndrome and TR cell deficiency associated with metabolic dysfunction and increased apoptosis of TR cells.

T-Cell Abnormalities in Common Variable Immunodeficiency

“…These molecules include lymphocytespecific protein tyrosine kinase (LCK) [83], inositol-1,4,5-trisphosphate (IP3) [80], Vav [84], phospholipase C gamma-1 (PLCγ-1) [85], calcium mobilization [76], protein kinase C-δ (PKCδ) [86], and LPS-responsive beige-like anchor (LRBA) [87]. Although these new monogenic defects share clinical phenotypes with CVID, they could be considered distinct entities that may occasionally be misdiagnosed as CVID [88].…”

Recessively InheritedLRBAMutations Cause Autoimmunity Presenting as Neonatal Diabetes

“…(CVID-8, MIM #614700)(7) which often includes early-onset autoimmunity, immune dysregulation, recurrent infections and hypogammaglobinaemia with variable penetrance (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)27). Neonatal diabetes had not been confirmed as a feature of this disorder.…”

“…Rarely, a mutation in a single gene is the aetiological cause and the identification of the underlying monogenic defect can give important insights into mechanisms of beta-cell autoimmunity and pathways of immune tolerance (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Due to significant clinical overlap, discriminating patients with causative mutations in a single gene from those with a polygenic aetiology remains a challenge.…”

“…Mutations in LRBA typically presents with severe autoimmune disease early in childhood and diabetes is a feature in 22% of patients, however neonatal diabetes has not been confirmed (2).…”

New therapeutic approach by sirolimus for enteropathy treatment in patients with LRBA deficiency

“…In patients refractory to corticosteroids, treatment with immunosuppressive drugs such as azathioprine, 6-mercaptopurine, tacrolimus, mycophenolate mofetil, infliximab, and rituximab have been reported. Side effects are commonly documented in administration of this group of medications, and maintaining remission has been reported to be unsuccessful in previous studies (5,(14)(15)(16). sirolimus, also known as rapamycin, is a macrocyclic lactone antibiotic which also has a profound immunosuppressive property on the cellular immune response, particularly on T cells.…”