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Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
Mutations in LRBA and CTLA4 result in immune deficiencies with overlapping phenotypes since LRBA has been demonstrated to regulate CTLA4 by blocking endosomal trafficking of CTLA4 to lysosomes for degradation. CTLA4 is expressed on the surface of activated and regulatory T cells and is involved in blocking B7:CD28 interactions and delivering immunosuppressive signals in these cells. LRBA is a cytosolic protein expressed broadly and is involved in a variety of cellular processes including endosomal trafficking and cytoskeletal and transcriptional regulation. In addition to its role in regulating CTLA4 in T cells, LRBA regulates B-cell development and function. Patients with either CTLA4 or LRBA deficiencies present with a multitude of immunoregulatory dysfunctions including hypogammaglobulinemia, recurrent infections, organomegaly, enteropathy, neurologic involvement, and a variety of autoimmune diseases and malignancies. The most common autoimmune diseases include IBD, type I diabetes, polyarthritis, autoimmune thyroid disease, and Evan's syndrome. The most common malignancies include gastric cancer and lymphoma. Gastrointestinal involvement is common in both LRBA and CTLA4 deficiencies and can manifest as IBD-like inflammation, atrophic gastritis, celiac disease, acute pancreatitis, and pancreatic insufficiency. Currently, therapies for both LRBA and CTLA4 deficiencies focus on treatment of ongoing infections and treatment with either Abatacept (a CTLA4-Fc fusion protein) or mTOR inhibitors. In addition to therapy causing a reduction in autoimmune sequelae, responsive patients typically have a reduction in soluble CD25 and circulating follicular T-helper cells. HCT has been employed successfully for both CTLA4 and LRBA deficiency.
G2-lymphocyte chromosomal radiosensitivity in patients with LPS responsive beige-like anchor protein (LRBA) deficiency
Published in International Journal of Radiation Biology, 2019
Hossein Mozdarani, Fatemeh Kiaee, Saba Fekrvand, Gholamreza Azizi, Reza Yazdani, Majid Zaki-Dizaji, Sahar Mozdarani, Sohail Mozdarani, Hassan Nosrati, Hassan Abolhassani, Asghar Aghamohammadi
Lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency is a disease of immune dysregulation caused by a mutation in LRBA gene (Lopez-Herrera et al. 2012; Picard et al. 2018). The LRBA gene provides instructions for production of the LRBA protein participating in multiple cellular processes including cytoskeleton assembly, signal transduction, vesicular trafficking, transcriptional regulation, chromatin dynamics and apoptosis (Alkhairy et al. 2016; Yazdani, Abolhassani, et al. 2016; Yazdani, Ganjalikhani-Hakemi, et al. 2017). Patients with LRBA deficiency have a variety of clinical symptoms including hypogammaglobulinemia, recurrent infections, lymphoproliferation, autoimmunity and enteropathy (Azizi, Rezaei, et al. 2016; Azizi, Abolhassani, Mahdaviani, et al. 2017; Azizi, Abolhassani, Asgardoon, et al. 2017; Azizi, Hafezi, et al. 2017; Azizi, Abolhassani, Habibi, et al. 2018). The results of a study showed that neoplasms including lymphoma, gastric carcinoma, malignant melanoma and adenoma may present another feature of patients with LRBA deficiency [4 (4.2%) cases among all 95 reported patients] (Sharapova et al. 2018).
Evaluation of Expression of LRBA and CTLA-4 Proteins in Common Variable Immunodeficiency Patients
Published in Immunological Investigations, 2022
Fereshte Salami, Saba Fekrvand, Reza Yazdani, Sepideh Shahkarami, Gholamreza Azizi, Yasser Bagheri, Samaneh Delavari, Sahar Shariati, Seyed Alireza Mahdaviani, Mohammamd Nabavi, Afshin Shirkani, Hassan Abolhassani, Morteza Samadi, Asghar Aghamohammadi
CVID is a primary immunodeficiency disorder with a wide range of genetic underpinnings. LRBA deficiency is known as a separate entity and is characterized by immune dysregulation. According to the findings, a concurrent presence of autoimmunity, enteropathy, and early-onset occurrence in CVID patients could be indicative of LRBA deficiency and/or CTLA-4 deficiency in most of the cases. Applying this approach in the newly diagnosed CVID population without yet confirmed mutations could lead to earlier detection of deficient patients prior to the genetic evaluation, and therefore help to early management and treatment of these patients before the occurrence of irrecoverable sequels and may prioritize patients that should be sequenced for LRBA and CTLA4 genes.
Targeted next-generation sequencing revealed a novel homozygous mutation in the LRBA gene causes severe haemolysis associated with Inborn Errors of Immunity in an Indian family.
Published in Hematology, 2022
Prabhakar Kedar, Rashmi Dongerdiye, Shanmukhaiah Chandrakala, Umair Ahmed Bargir, Manisha Madkaikar
Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA) deficiency, is one of the causes of Inborn Errors of Immunity (IEI), and presenting with autoimmunity and/or auto-inflammation phenotype comes under the group of common variable immunodeficiency (CVID-8; OMIM #614700) [1–3]. LRBA is ubiquitously expressed and regulates endosomal trafficking in endocytosis of ligand-activated receptors. In humans, it encodes the LRBA protein, associated with autophagy or self-digestion, which leads to antigen deficiency [4]. LRBA protein acts as signaling enzymes (PKA and PKC) with an A-kinase anchoring protein (AKAP) in organelles and membranes [5]. LRBA also regulates the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) expressions on the post-translational stage. It has the potential to suppress receptor and immune checkpoints [6]. The clinical manifestations are not well known, but humoral immune deficiencies can lead to IgA deficiency, and some have hypogammaglobulinaemia [7]. In most patients, recurrent infections are presented in early childhood. Most likely respiratory infections are more severe, which ultimately affect growth and difficulty to maintain weight, and some also develop various types of autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura, and also chronic diarrhea. In some cases, it is reported that LRBA deficiency can cause interstitial lung disease (ILD). The variable phenotypic symptoms are reported in LRBA deficiency. The testing for LRBA deficiency should be considered in cases without overt immunodeficiency. The low serum IgG and IgA and normal may find on Immunologic analysis. A normal or decreased B cells were seen in peripheral blood smear with less count of switched memory B cells and CD4+ regulatory T cells (Tregs). Bone marrow transplantation is the most valuable therapeutic option, but some patients may benefit from immunoglobulin replacement therapy. The IG prophylaxis (IV or SC) can be used regularly at a minimum of 500–600 mg/dL to maintain plasma levels [8,9].