LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency

Alangari, Abdullah; Alsultan, Abdulrahman; Adly, Nouran; Massaad, Michel J.; Kiani, Iram Shakir; Aljebreen, Abdulrahman; Raddaoui, Emad; Almomen, Abdulkareem; Al‐Muhsen, Saleh; Geha, Raif S.; Alkuraya, Fowzan S.

doi:10.1016/j.jaci.2012.05.043

Cited by 220 publications

(182 citation statements)

References 30 publications

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“…Lrba, a gene known to cause common variable immunodeficiency with autoimmunity-8 (CVID8) [Online Mendelian Inheritance in Man (OMIM) ID no. 614700] and IBD in humans (13)(14)(15), was also mapped by this method, validating our screen as a means to identify human disease genes and components…”

supporting

confidence: 56%

Creatine maintains intestinal homeostasis and protects against colitis

Turer

McAlpine

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Creatine, a nitrogenous organic acid, replenishes cytoplasmic ATP at the expense of mitochondrial ATP via the phosphocreatine shuttle. Creatine levels are maintained by diet and endogenous synthesis from arginine and glycine. Glycine amidinotransferase (GATM) catalyzes the rate-limiting step of creatine biosynthesis: the transfer of an amidino group from arginine to glycine to form ornithine and guanidinoacetate. We screened 36,530 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea–mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). Among 27 colitis susceptibility phenotypes identified and mapped, one was strongly correlated with a missense mutation in Gatm in a recessive model of inheritance, and causation was confirmed by CRISPR/Cas9 gene targeting. Supplementation of homozygous Gatm mutants with exogenous creatine ameliorated the colitis phenotype. CRISPR/Cas9-targeted (Gatmc/c) mice displayed a normal peripheral immune response and immune cell homeostasis. However, the intestinal epithelium of the Gatmc/c mice displayed increased cell death and decreased proliferation during DSS treatment. In addition, Gatmc/c colonocytes showed increased metabolic stress in response to DSS with higher levels of phospho-AMPK and lower levels of phosphorylation of mammalian target of rapamycin (phospho-mTOR). These findings establish an in vivo requirement for rapid replenishment of cytoplasmic ATP within colonic epithelial cells in the maintenance of the mucosal barrier after injury.

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supporting

confidence: 56%

Creatine maintains intestinal homeostasis and protects against colitis

Turer

McAlpine

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…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.…”

Section: Autoimmune-mediated Cytopenia In Pidmentioning

confidence: 99%

“…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.…”

Section: Autoimmune-mediated Cytopenia In Pidmentioning

confidence: 99%

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

Seidel

2014

Blood

124

137

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Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PIDs). Especially when cytopenia is the initial symptom of a PID, the order and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and will help exclude disorders such as systemic lupus erythematosus, common variable immunodeficiency, and autoimmune lymphoproliferative syndromes, hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, activated PI3KD syndrome (APDS), X-linked immunodeficiency with magnesium defect (MAGT1 deficiency), and others. Immunosuppressive treatment often needs to be initiated urgently, which impedes further relevant immunologic laboratory analyses aimed at defining the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial for identifying a certain proportion of PID phenotypes and genotypes among descriptive diagnoses such as autoimmune hemolytic anemia, chronic immune thrombocytopenia, Evans syndrome, severe aplastic anemia/refractory cytopenia, and others. A synopsis of pathomechanisms, novel differential diagnoses, and advances in treatment options for cytopenias in PID is provided to facilitate multidisciplinary management and to bridge different approaches.

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“…This disorder is characterized by early-onset hypogammaglobulinemia, chronic diarrhea and autoimmune manifestations (1)(2)(3)(4). Similar to common variable immune deficiency (CVID) patients, affected individuals show a reduced levels of immunoglobulin (Ig) isotypes and suffer from recurrent infections, hepatosplenomegaly, chronic pulmonary disorders as well as auto-inflammatory conditions including idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA) and enteropathy (1,(5)(6)(7)(8)(9). The enteropathy phenotype includes autoimmune enteropathy, inflammatory bowel disease (IBD)/IBD-like disease and non-infectious recurrent diarrhea.…”

Section: Introductionmentioning

confidence: 99%

“…This treatment led to a complete improvement of their symptoms including decrease in frequency and severity of diarrhea and impatients, chronic diarrhea is characterized by duodenal villous atrophy and large bowel lymphocytic infiltration (5). Recent studies have reported that the chronic and severe diarrhea in patients with LRBA deficiency may not improve despite intravenous Ig (IVIg) treatment (6,12). Medical therapy typically with corticosteroids (budesonide and prednisone), empiric antibiotic therapy and gluten free diets have been used commonly (13).…”

Section: Introductionmentioning

confidence: 99%