Deleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity

Abstract

Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.

Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency

“…The cohort investigated here included only a limited number of hyper-IgM syndrome patients, and none carried any of the five reported APDS mutations. Autoimmune phenomena, enteropathies and blood dyscrasias feature strongly in lipopolysaccharideresponsive and beige-like anchor protein (LRBA) deficiency, another condition with a profile of combined immunodeficiency and autoimmunity [23,24], while massive EBV-driven B cell lymphoproliferation and possibly EBVassociated lymphoma is characteristic of deficiencies of interleukin 2-inducible T cell kinase (ITK) [25][26][27], CD27 [28,29] and X-linked lymphoproliferative disease caused by mutations in SH2D1A [30].…”

Infectious and Noninfectious Pulmonary Complications in Patients With Primary Immunodeficiency Disorders

“…No studies report GLILD in XLA, suggesting that T-cell dysfunction is the probable pathogenic mechanism. Hypomorphic mutations in recombination-activating gene 1 (RAG1), haploinsufficiency of cytotoxic T lymphocyte antigen-4 (CTLA4), and deficiency in lipopolysaccharide responsive beige-like anchor protein (LRBA) has been described in patients with GLILD [106].…”

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

“…15,16 In addition to these two entities, overlapping syndromes have been reported between CVID and ALPS (with ALPS-linked increased T-cell receptor a/b-positive CD4 17 One of the novel PIDs in this subgroup of autoantibody-mediated cytopenia is lipopolysaccharide-responsive beige-like anchor deficiency, a rare B-cell defect involving autophagy and apoptosis that, along with immune cytopenia, is often linked to inflammatory bowel disease, multiorgan autoimmune phenomena, severe infections, and hypogammaglobulinemia [18][19][20] [Markus G. Seidel, Tatjana Hirschmugl, Wolfgang Schwinger, Laura Gamez-Diaz, Nina Serwas, Andrea Deutschmann, Gregor Gorkiewicz, Werner Zenz, Christian Windpassinger, Bodo Grimbacher, Christian Urban, and Kaan Boztug; manuscript submitted July 2014]. Although the pathomechanism of this novel disease is incompletely understood, in vitro and in vivo immunologic analyses and human clinical data point toward a B-cell intrinsic defect in lipopolysaccharide-responsive beige-like anchor deficiency.…”

“…Although the pathomechanism of this novel disease is incompletely understood, in vitro and in vivo immunologic analyses and human clinical data point toward a B-cell intrinsic defect in lipopolysaccharide-responsive beige-like anchor deficiency. [18][19][20] An example of impaired T-cell-B-cell interaction is CD40/CD40L deficiency, in which the missing signal from T cells causes humoral autoimmunity as well as other severe immunologic symptoms; the phenotype for this deficiency is classified as combined immunodeficiency (CID). 3,21 In addition to these primary or secondary humoral defects, intrinsic defects in T-effector cells may lead to cellular autoimmunity.…”