Добірка наукової літератури з теми "LIPOPOLYSACCHARIDE RESPONSIVE BEIGE-LIKE ANCHOR PROTEIN"

Neonatal diabetes mellitus (NDM) is characterised by onset of persistent hyperglycaemia within the first 6 months of life. NDM is frequently caused by a mutation in a single gene affecting pancreatic beta cell function. We report an infant, born to a non-consanguineous couple, who presented with osmotic symptoms and diabetic ketoacidosis. The genetic analysis showed a mutation in LRBA (lipopolysaccharide-responsive and beige-like anchor protein) gene. We highlight the importance of considering genetic analysis in every infant with NDM, to understand the nature of genetic mutation, associated comorbidities, response to glibenclamide and future prognosis.

Cyclic AMP-dependent protein kinase A (PKA) is a ubiquitous enzymatic complex that is involved in a broad spectrum of intracellular receptor signaling. The activity of PKA depends on A-kinase anchoring proteins (AKAPs) that attach to PKAs close to their substrates to control signaling. Although the relevance of PKA-AKAP signaling in the immune system is evident in T cells, its relevance in B and other immune cells remains relatively unclear. In the last decade, lipopolysaccharide-responsive and beige-like anchor protein (LRBA) has emerged as an AKAP that is ubiquitously expressed in B and T cells, specifically after activation. A deficiency of LRBA leads to immune dysregulation and immunodeficiency. The cellular mechanisms regulated by LRBA have not yet been investigated. Therefore, this review summarizes the functions of PKA in immunity and provides the most recent information regarding LRBA deficiency to deepen our understanding of immune regulation and immunological diseases.

BackgroundLPS-responsive beige-like anchor protein(LRBA) deficiency is an autosomal recessive disorder caused by biallelic mutations in the LRBA gene leading to a syndrome of autoimmunity, lymphoproliferation and humoral immune deficiency.LRBA protein plays a major immuno-regulatory role in the expression, function and trafficking of cytotoxic T lymphocyte-associated protein 4 (CTLA4) in Tregs which is an immune effector molecule that acts as an inhibitory checkpoint for the immune response.1,2,3ObjectivesWe report a 7 years old boy with LRBA deficiency who was presented with polyautoimmuity primarily affecting gut, pancreas & joints with recurrent infections.MethodsHe was born to a non-consanguineous Indian parents with uneventful birth, development and vaccination history.He had been unwell from the age of one with multiple episodes of lower respiratory tract infections warranting usage of prolonged antibiotics. 2.5 years of age, he had been diagnosed as Type 1 Diabetes Mellitus and he was commenced on insulin therapy. 3.5 years, he developed chronic diarrhoea.Evaluation revealed sterile blood, urine and stool cultures with normal abdominal imaging(USG & CT scan), elevated TTg-IgA & HTTP/DGP screen and negative HLADQ2-DQ8. He failed gluten-free diet. Gastrointestinal endoscopy showed duodenum and terminal ileum nodularity & biopsy was suggestive of non-celiac autoimmune enteropathy. 4 years, he developed two episodes of stridor, tetany and breathing difficulty which were promptly reversed by IV calcium infusion. He had low serum calcium, low parathyroid hormone with normal vitamin D level, serum phosphorous, magnesium, thyroid profile, anti-thyroid antibodies, renal and liver functions. 5.5 years, he first presented to us with chronic unexplained polyarthritis involving small and large joints in an additive pattern. Family history was significant for a death of the previous male sibling at 7 months of age due to chronic unexplained diarrhoea. Examination revealed facial dysmorphism and failure to thrive with no systmic findings.ResultsInvestigations showed HB 8.1gm%,TLC6700/cumm with normal differential counts and platelet counts 233000/ul. ESR was 39mm/hr and CRP was negative. Direct coomb’s test, RF, ANA were negative. He had a mild elevation in IgG levels with normal B-T cells populations. Genetic evaluation revelaed pathogenic homozygous splice site mutation in intron 11 of LRBA gene. Both the parents are heterozygous carriers. A largest systematic review3 of 212 cases of LRBA deficiency showed autoimmunity(70%), non malignanat lymphoproliferation(54%), enteropathy(41%), endocrinopathy(41%) and lower respiratory tract infections(41%) as the most common clinical manifestations with normal or abnormal immunoglobulin level and B-T cells populations. Arthritis(8%) was amongst the rare manifestations. Hypoparathyroidism was the rarest endocrine manifestations. No data available regarding prevalence of positive celiac disease antibodies. There was no haematological manifestations in our case.ConclusionLRBA deficiency should be strongly considered in a child recurrent infection and polyautoimmunity including arthritis. Abatacept could be used as a steroid sparing agent and as a bridging agent awaiting transplant.References[1]Am J Hum Genet.2012; Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Lopez-Herrera G, Tampella G, Hammarström Q, et al.[2]J Allergy Clin Immunol Pract Sep-Oct 2019; Clinical, Immunologic, and Molecular Spectrum of Patients with LPS-Responsive Beige-Like Anchor Protein Deficiency: A Systematic Review Sima Habibi, Majid Zaki-Dizaji, Hosein Rafiemanesh, Bernice Lo, Mahnaz Jamee[3]Clinical and Experimental Immunology, 31st March 2021, Comprehensive comparison between 222 CTLA-4 haploinsufficiency and 212 LRBA deficiency patients: a systematic review, M. Jamee, S. Hosseinzadeh, N. Sharifinejad, M. Zaki-DizajiAcknowledgementsDr Hitesh Bhambhani, Dr Nitin Trivedi, Dr Zalak Shah Upadhyay, Dr Chetan DaveDisclosure of InterestsNone declared

Bi-allelic mutations in LRBA (from Lipopolysaccharide-responsive and beige-like anchor protein) result in a primary immunodeficiency with clinical features ranging from hypogammaglobulinemia and lymphoproliferative syndrome to inflammatory bowel disease and heterogeneous autoimmune manifestations. LRBA deficiency has been shown to affect vesicular trafficking, autophagy and apoptosis, which may lead to alterations of several molecules and processes that play key roles for immunity. In this review, we will discuss the relationship of LRBA with the endovesicular system in the context of receptor trafficking, autophagy and apoptosis. Since these mechanisms of homeostasis are inherent to all living cells and not only limited to the immune system and also, because they are involved in physiological as well as pathological processes such as embryogenesis or tumoral transformation, we envisage advancing in the identification of potential pharmacological agents to manipulate these processes.