Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inherited mutations in lipopolysaccharide-responsive beige-like anchor (LRBA) cause a recessive human immune dysregulation syndrome with memory B-cell and antibody deficiency (common variable immunodeficiency), inflammatory bowel disease, enlarged spleen and lymph nodes, accumulation of activated T cells and multiple autoimmune diseases. To understand the pathogenesis of the syndrome, C57BL/6 mice carrying a homozygous truncating mutation in Lrba were produced using CRISPR/Cas9-mediated gene targeting. These mice revealed that LRBA has a critical, cell-autonomous role in promoting cytotoxic T-lymphocyte antigen-4 (CTLA-4) accumulation within CD4 effector T cells and FOXP3+ T-regulatory cells (Tregs). In young mice, or in chimeric mice where only half of the T cells are LRBA deficient, low CTLA-4 was the only detectable abnormality in Tregs, whereas in old mice FOXP3 was also decreased. Low CTLA-4 did not translate into increased CD86 on B cells unless the LRBA-deficient mice were immunised, and neither immunisation nor chronic lymphocytic choriomeningitis virus infection precipitated immune dysregulation. LRBA deficiency did not alter antigen-specific B-cell activation, germinal centre (GC) formation, isotype switching or affinity maturation. Paradoxically, CD86 was decreased on GC B cells in LRBA-deficient mice, pointing to compensatory mechanisms for controlling CD86 in the face of low CTLA-4. These results add to the experimental rationale for treating LRBA deficiency with the CTLA4-Ig fusion protein, Abatacept, and pose questions about the limitations of laboratory experiments in mice to reproduce human disease in natura.
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PMID:Murine LRBA deficiency causes CTLA-4 deficiency in Tregs without progression to immune dysregulation. 2892 82

The biological role of the lipopolysaccharide-responsive beige-like anchor (LRBA) protein associated with the immune system is not to date well known. However, it is thought to regulate the CTLA4 protein, an inhibitory immunoreceptor. Chronic diarrhea, autoimmune disorders, organomegaly, frequent recurrent infections, hypogammaglobulinemia, chronic lung manifestations, and growth retardation are some features of LRBA deficiency. This rare disease is observed as a result of homozygous mutations in the LRBA gene. An 11.3-year-old male patient presented because of short stature and high blood glucose level. He had a previous history of lymphoproliferative disease, chronic diarrhea, and recurrent infections. His parents were first-degree consanguineous relatives. A diagnosis of type 1 diabetes mellitus (T1DM) was added to the preexisting diagnoses of immunodeficiency, recurrent infection, enteropathy, chronic diarrhea, lymphadenopathy, hepatomegaly, and short stature. Genetic analysis revealed a homozygous mutation in the LRBA gene, c.5047C>T (p.R1683*) (p.Arg1683*). Abatacept treatment was started: the patient's hospital admission frequency decreased, and glucose regulation improved. At follow-up, growth hormone (GH) deficiency was diagnosed, although it was not treated because the underlying disease was not under control. Nevertheless, the patient's height improved with abatacept treatment. LRBA deficiency should be considered in the presence of consanguineous marriage, diabetes, immunodeficiency, and additional autoimmune symptoms. LRBA phenotypes are variable even when the same variants in the LRBA gene are present. Genetic diagnosis is important to determine optimal treatment options. In addition to chronic malnutrition and immunosuppressive therapy, GH deficiency may be one of the causes of short stature in these patients.
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PMID:LRBA deficiency: a rare cause of type 1 diabetes, colitis, and severe immunodeficiency. 3315 42