Evaluation of Expression of LRBA and CTLA-4 Proteins in Common Variable Immunodeficiency Patients

Salami, Fereshte; Fekrvand, Saba; Yazdani, Reza; Shahkarami, Sepideh; Azizi, Gholamreza; Bagheri, Yasser; Delavari, Samaneh; Shariati, Sahar; Mahdaviani, Seyed Alireza; Nabavi, M.; Shirkani, Afshin; Abolhassani, Hassan; Samadi, Morteza; Aghamohammadi, Asghar

doi:10.1080/08820139.2020.1833029

Cited by 8 publications

(4 citation statements)

References 32 publications

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“…However, the literature data on this issue are extremely poor. Few literature data emphasize the significantly higher expression of PD-1 and CTLA-4 on selected populations of immune system cells in the course of CVID compared to healthy volunteers, which is consistent with the results of our study [56][57][58][59][60]. The causes of malignant transformation in CVID are still being intensively investigated, but researchers suggest that it is largely due to impaired immune surveillance.…”

Section: Discussionsupporting

confidence: 92%

Immune Checkpoint Pathway Expression in Lymphocyte Subpopulations in Patients with Common Variable Immunodeficiency and Chronic Lymphocytic Leukemia

Mertowska,

Mertowski,

Smolak

et al. 2023

Cancers

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This study aims to gain a deeper understanding of chronic lymphocytic leukemia (CLL) and common variable immunodeficiency (CVID) by studying immune cells and specific immune checkpoint signaling pathways. The analysis of the percentage of selected immune points and their ligands (PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200) on peripheral blood lymphocyte subpopulations was performed using flow cytometry, and additional analyses determining the serum concentration of the above-mentioned molecules were performed using enzyme immunoassay tests. The obtained results indicate several significant changes in the percentage of almost all tested molecules on selected subpopulations of T and B lymphocytes in both CVID and CLL patients in relation to healthy volunteers and between the disease subunits themselves. The results obtained were also supported by the analysis of the serum concentration of soluble molecules tested. By uncovering valuable insights, we hope to enhance our comprehension and management of these conditions, considering both immunodeficiencies and hematological malignancies. Understanding the role of these signaling pathways in disease development and progression may lead to the development of modern, personalized diagnostic and therapeutic strategies. Ultimately, this knowledge may enable the monitoring of the immune system in patients with CVID and CLL, paving the way for improved patient care in the future.

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Section: Discussionsupporting

confidence: 92%

Immune Checkpoint Pathway Expression in Lymphocyte Subpopulations in Patients with Common Variable Immunodeficiency and Chronic Lymphocytic Leukemia

Mertowska,

Mertowski,

Smolak

et al. 2023

Cancers

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“…The reduction of available CTLA-4 on the T-cell surface is the common end point of (i) aberrant CTLA-4 protein (i.e., due to truncated CTLA-4 protein, defects in the ligand-binding domain, or homodimerization) caused by heterozygous mutations in CTLA-4 or (ii) enhanced CTLA-4 lysosomal degradation generated by biallelic mutations in LRBA or DEF6 ( Figure 1 ). Although some missense mutations in CTLA-4 do not affect the CTLA-4 protein expression, most mutations in CTLA-4, LRBA , and DEF6 reduce CTLA-4 protein levels by 50, 50–75, and 50%, respectively ( 9 , 16 , 27 , 28 ). In addition, regardless of the mutations in CTLA-4, LRBA , and DEF6 , Tregs and activated conventional T (Tcon) cells present with an overall but variable reduction in CTLA-4-dependent transendocytosis.…”

Section: Introductionmentioning

confidence: 99%

Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies

Gámez-Díaz

Seidel

2021

Front. Pediatr.

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Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a crucial immune checkpoint that is constitutively expressed in regulatory T (Treg) cells. Following T-cell activation, CTLA-4 is rapidly mobilized from its intracellular vesicle pool to the cell surface to control the availability of co-stimulatory B7 molecules, thereby maintaining immune homeostasis. Heterozygous mutations in CTLA-4 lead to defects in (i) CTLA-4 ligand binding, (ii) homo-dimerization, (iii) B7-transendocytosis, and (iv) CTLA-4 vesicle trafficking, resulting in an inborn error of immunity with predominant autoimmunity. CTLA-4 vesicle trafficking impairment is also observed in patients with lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency or the differentially expressed in FDCP6 homolog (DEF6) deficiency, caused by biallelic mutations in LRBA and DEF6, respectively. Therefore, patients with CTLA-4 insufficiency, LRBA deficiency, and—most recently reported—DEF6 deficiency present an overlapping clinical phenotype mainly attributed to a defective suppressive activity of Tregs, as all three diseases reduce overall surface expression of CTLA-4. In this paper, we describe the clinical phenotypes of these immune checkpoint defects, their patho-mechanisms, and visually compare them to other immune regulatory disorders (IPEX syndrome, CD27, and CD70 deficiencies) by using the immune deficiency and dysregulation (IDDA version 2.1) “kaleidoscope” score. This illustrates the variability of the degrees and manifestations of immune deficiency and dysregulation. Patients characteristically present with an increased risk of infections, autoimmune cytopenias, multi-organ autoimmunity, and inflammation, which are often severe and life-threatening. Furthermore, these patients suffer an increased risk of developing malignancies, especially Non-Hodgkin's lymphoma. Successful treatment options include regular administration of soluble CTLA-4-Ig fusion protein, Treg cell-sparing immune suppressants like sirolimus or mycophenolate mofetil, and hematopoietic stem cell transplantation. This mini-review highlights the most relevant biological and clinical features as well as treatment options for CTLA-4 insufficiency and LRBA and DEF6 deficiencies.

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“…Common variable immunodeficiency (CVID) is a multifactorial disease characterized by antibody deficiency, recurrent infections, autoimmunity, and malignancy[ 5 ]. High-resolution genetic analyses, especially in cases of CVID complicated by inflammatory bowel disease, have revealed that the underlying genetic defects are often CTLA4 haploinsufficiency and LRBA deficiency[ 5 , 6 ]. Most patients with these genetic defects experience diarrhea and weight loss.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of abatacept treatment in a patient with enteropathy carrying a variant of unsignificance in CTLA4 gene: A case report

Musabak,

Erdoğan,

Ceylaner

et al. 2023

World J Clin Cases

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Fasting during the month of Ramadan is one of the five fundamental principles of Islam, and it is obligatory for healthy Muslim adults and adolescents. During the fasting month, Muslims usually have two meals a day, suhur (before dawn) and iftar (after dusk). However, diabetic patients may face difficulties when fasting, so it is important for medical staff to educate them on safe fasting practices. Prolonged strict fasting can increase the risk of hypoglycemia and diabetic ketoacidosis, but with proper knowledge, careful planning, and medication adjustment, diabetic Muslim patients can fast during Ramadan. For this review, a literature search was conducted using PubMed and Google Scholar until May 2023. Articles other than the English language were excluded. Current strategies for managing blood sugar levels during Ramadan include a combination of patient education on nutrition, regular monitoring of blood glucose, medications, and insulin therapy. Insulin therapy can be continued during fasting if properly titrated to the patients’ needs, and finger prick blood sugar levels should be assessed regularly. If certain symptoms such as hypoglycemia, hyperglycemia, dehydration, or acute illness occur, or blood glucose levels become too high (> 300 mg/dL) or too low (70 mg/dL), the fast should be broken. New insulin formulations such as pegylated insulin and medications like tirzepatide, a dual agonist of gastric-inhibitory peptideand glucagonlike-peptide 1 receptors, have shown promise in managing blood sugar levels during Ramadan. Non-insulin-dependent medications like sodium-glucose-cotransporter-2 inhibitors, including the Food and Drug Administration-approved ertugliflozin, are also being used to provide additional cardiovascular benefits in patients with type 2 diabetes.

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Evaluation of Expression of LRBA and CTLA-4 Proteins in Common Variable Immunodeficiency Patients

Cited by 8 publications

References 32 publications

Immune Checkpoint Pathway Expression in Lymphocyte Subpopulations in Patients with Common Variable Immunodeficiency and Chronic Lymphocytic Leukemia

Immune Checkpoint Pathway Expression in Lymphocyte Subpopulations in Patients with Common Variable Immunodeficiency and Chronic Lymphocytic Leukemia

Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies

Efficacy of abatacept treatment in a patient with enteropathy carrying a variant of unsignificance in CTLA4 gene: A case report

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