Blog

Acta Med Port. 2024 Sep 2;37(9):666-667. doi: 10.20344/amp.21580. Epub 2024 Sep 2.

NO ABSTRACT

PMID:39226558 | DOI:10.20344/amp.21580

PLoS Pathog. 2024 Sep 3;20(9):e1012472. doi: 10.1371/journal.ppat.1012472. Online ahead of print.

ABSTRACT

Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome is a rare primary immunodeficiency disease in humans caused by a gain of function in CXCR4, mostly due to inherited heterozygous mutations in CXCR4. One major clinical symptom of WHIM patients is their high susceptibility to human papillomavirus (HPV) induced disease, such as warts. Persistent high risk HPV infections cause 5% of all human cancers, including cervical, anogenital, head and neck and some skin cancers. WHIM mice bearing the same mutation identified in WHIM patients were created to study the underlying causes for the symptoms manifest in patients suffering from the WHIM syndrome. Using murine papillomavirus (MmuPV1) as an infection model in mice for HPV-induced disease, we demonstrate that WHIM mice are more susceptible to MmuPV1-induced warts (papillomas) compared to wild type mice. Namely, the incidence of papillomas is higher in WHIM mice compared to wild type mice when mice are exposed to low doses of MmuPV1. MmuPV1 infection facilitated both myeloid and lymphoid cell mobilization in the blood of wild type mice but not in WHIM mice. Higher incidence and larger size of papillomas in WHIM mice correlated with lower abundance of infiltrating T cells within the papillomas. Finally, we demonstrate that transplantation of bone marrow from wild type mice into WHIM mice normalized the incidence and size of papillomas, consistent with the WHIM mutation in hematopoietic cells contributing to higher susceptibility of WHIM mice to MmuPV1-induced disease. Our results provide evidence that MmuPV1 infection in WHIM mice is a powerful preclinical infectious model to investigate treatment options for alleviating papillomavirus infections in WHIM syndrome.

PMID:39226327 | DOI:10.1371/journal.ppat.1012472

J Clin Invest. 2024 Jul 11;134(17):e169994. doi: 10.1172/JCI169994.

ABSTRACT

The ubiquitously expressed small GTPase Ras-related protein 1B (RAP1B) acts as a molecular switch that regulates cell signaling, cytoskeletal remodeling, and cell trafficking and activates integrins in platelets and lymphocytes. The residue G12 in the P-loop is required for the RAP1B-GTPase conformational switch. Heterozygous germline RAP1B variants have been described in patients with syndromic thrombocytopenia. However, the causality and pathophysiological impact remained unexplored. We report a boy with neonatal thrombocytopenia, combined immunodeficiency, neutropenia, and monocytopenia caused by a heterozygous de novo single nucleotide substitution, c.35G>A (p.G12E) in RAP1B. We demonstrate that G12E and the previously described G12V and G60R were gain-of-function variants that increased RAP1B activation, talin recruitment, and integrin activation, thereby modifying late responses such as platelet activation, T cell proliferation, and migration. We show that in our patient, G12E was a somatic variant whose allele frequency decreased over time in the peripheral immune compartment, but remained stable in bone marrow cells, suggesting a differential effect in distinct cell populations. Allogeneic hematopoietic stem cell transplantation fully restored the patient’s hemato-immunological phenotype. Our findings define monoallelic RAP1B gain-of-function variants as a cause for constitutive immunodeficiency and thrombocytopenia. The phenotypic spectrum ranged from isolated hematological manifestations in our patient with somatic mosaicism to complex syndromic features in patients with reported germline RAP1B variants.

PMID:39225097 | DOI:10.1172/JCI169994

Front Immunol. 2024 Aug 19;15:1444130. doi: 10.3389/fimmu.2024.1444130. eCollection 2024.

ABSTRACT

INTRODUCTION: Ataxia telangiectasia (AT) is a rare disorder characterized by neurodegeneration, combined immunodeficiency, a predisposition to malignancies, and high clinical variability. Profiling of microRNAs (miRNAs) may offer insights into the underlying mechanisms of complex rare human diseases, as miRNAs play a role in various biological functions including proliferation, differentiation, and DNA repair. In this study, we investigate the differential expression of miRNAs in samples from AT patients to identify miRNA patterns and analyze how these patterns are related to the disease.

METHODS: We enrolled 20 AT patients (mean age 17.7 ± 9.6 years old) and collected clinical and genetic data. We performed short non-coding RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and fibroblasts to compare the miRNA expression profile between AT patients and controls.

RESULTS: We observed 42 differentially expressed (DE)-miRNAs in blood samples and 26 in fibroblast samples. Among these, three DE-miRNAs, miR-342-3p, miR-30a-5p, and miR-195-5p, were further validated in additional AT samples, confirming their dysregulation.

DISCUSSION: We identified an AT-related miRNA signature in blood cells and fibroblast samples collected from a group of AT patients. We also predicted several dysregulated pathways, primarily related to cancer, immune system control, or inflammatory processes. The findings suggest that miRNAs may provide insights into the pathophysiology and tumorigenesis of AT and have the potential to serve as useful biomarkers in cancer research.

PMID:39224604 | PMC:PMC11366618 | DOI:10.3389/fimmu.2024.1444130

Front Immunol. 2024 Aug 19;15:1467284. doi: 10.3389/fimmu.2024.1467284. eCollection 2024.

NO ABSTRACT

PMID:39224594 | PMC:PMC11366648 | DOI:10.3389/fimmu.2024.1467284

J Allergy Clin Immunol. 2024 Aug 30:S0091-6749(24)00903-5. doi: 10.1016/j.jaci.2024.08.020. Online ahead of print.

ABSTRACT

BACKGROUND: Cytotoxic T-lymphocyte antigen-4 (CTLA-4) insufficiency causes a primary immune regulatory disorder characterised by lymphoproliferation, dysgammaglobulinaemia, and multi-organ autoimmunity including cytopenias and colitis.

OBJECTIVE: To examine the outcome of HSCT for CTLA-4 insufficiency and study the impact of pre-HSCT CTLA-4-Ig therapy and pre-HSCT immune dysregulation on survival and immunological outcome.

METHODS: Retrospective study of HSCT for CTLA-4 insufficiency and 2q33.2-3 deletion from the Inborn Errors Working Party of EBMT. Primary endpoints were overall survival (OS) and disease- and chronic GvHD-free survival (DFS). Secondary endpoint was immunological outcome assessed by Immune Dysregulation Disease Activity (IDDA) score.

RESULTS: Forty patients were included over a 25-year period. Pre-HSCT, 60% received CTLA-4-Ig and IDDA was 23.3 (3.9-84.0). Median age at HSCT was 14.2 (1.3-56.0) years. Patients received PBSC (58%) or marrow (43%) from MUD (75%), MMUD (12.5%) or MFD (12.5%). Median follow-up was 3 years (0.6-15 years) and 3-year OS was 76.7% (58-87%) and DFS was 74.4% (54.9-86.0%). At latest follow-up, 28/30 surviving patients are in disease-free remission with median IDDA reduction of 16. Probability of OS and DFS was greater in patients with lower disease activity pre-HSCT (IDDA<23, p=0.002 and p=0.006, respectively). CTLA-4-Ig receipt did not influence OS or DFS. Cause of death was transplant-related in 7/8 patients.

CONCLUSION: This is the largest retrospective study of HSCT for CTLA-4 insufficiency to date. HSCT is an effective therapy to prevent ongoing disease progression and morbidity, with improving survival rates over time and in patients with lower pre-HSCT disease activity.

PMID:39218359 | DOI:10.1016/j.jaci.2024.08.020

Eur J Med Genet. 2024 Aug 27:104968. doi: 10.1016/j.ejmg.2024.104968. Online ahead of print.

ABSTRACT

TAF1A, a gene encoding a TATA-box binding protein involved in ribosomal RNA synthesis, is a candidate gene for pediatric cardiomyopathy as biallelic TAF1A variants were reported in two families with affected individuals. Here, we report a third family with two siblings who presented with infantile restrictive cardiomyopathy and carried biallelic missense variants in TAF1A (NM_001201536.1: c.1021G>A p.(Gly341Arg) and c.781A>C p.(Thr261Pro)). Additional shared clinical features in the siblings included feeding intolerance, congenital leukoencephalopathy, ventriculomegaly and concern for primary immunodeficiency. The first-born sibling passed away at 6 months of age due to complications of hemophagocytic lymphohistiocytosis (HLH) whereas the second sibling underwent cardiac transplantation at 1 year of age and is currently well. We compare the clinical and molecular features of all the TAF1A associated cardiomyopathy cases. Our study adds evidence for the gene-disease association of TAF1A with autosomal recessive pediatric cardiomyopathy.

PMID:39209150 | DOI:10.1016/j.ejmg.2024.104968

Expert Rev Clin Immunol. 2024 Aug 29. doi: 10.1080/1744666X.2024.2398546. Online ahead of print.

ABSTRACT

INTRODUCTION: CVID is the commonest and most symptomatic primary immune deficiency of adulthood. NHLs are the most prevalent malignancies in CVID. The cross-talk between tumor cells and immune cells may be an important risk factor in lymphomagenesis.

AREAS COVERED: The present review highlights immune cell, genetic and histopathological alterations in the CVID-associated NHLs.

EXPERT OPINION: CVID patients exhibit some notable immune defects that may predispose to lymphomas. T/NK cell defects including reduced T cells, naïve CD4+T cells, T regs and Th17 cells, increased CD8+T cells with reduced T cell proliferative and cytokine responses and reduced iNKT and NK cell count and cytotoxicity. B cell defects include increased transitional and CD21^low B cells, clonal IgH gene rearrangements and increased BCMA levels. Increase in IL-9, sCD30 levels, and upregulation of BAFF-BAFFR signaling are associated with lymphomas in CVID. Increased expression of PFTK1, duplication of ORC4L, germline defects in TACI, NFKB1, and PIK3CD, and somatic mutations in NOTCH2 and MYD88 are reported in CVID-associated lymphomas. Upregulation of PD-L1-PD-1 pathway may also promote lymphomagenesis in CVID. These abnormalities need to be explored as prognostic or predictive markers of CVID-associated NHLs by large multi-centric studies.

PMID:39206944 | DOI:10.1080/1744666X.2024.2398546

Vaccines (Basel). 2024 Jul 25;12(8):843. doi: 10.3390/vaccines12080843.

ABSTRACT

BACKGROUND: The problem of identifying vaccine-specific T-cell responses is still a matter of debate. Currently, there are no universal, clearly defined, agreed upon criteria for assessing the effectiveness of vaccinations and their immunogenicity for the cellular component of immunity, even for healthy people. But for patients with inborn errors of immunity (IEI), especially those with antibody deficiencies, evaluating cellular immunity holds significant importance.

AIM: To examine the effect of one and two doses of inactivated adjuvanted subunit influenza vaccines on the expression of endosomal Toll-like receptors (TLRs) on the immune cells and the primary lymphocyte subpopulations in patients with common variable immunodeficiency (CVID).

MATERIALS AND METHODS: During 2018-2019, six CVID patients received one dose of a quadrivalent adjuvanted influenza vaccine; in 2019-2020, nine patients were vaccinated with two doses of a trivalent inactivated influenza vaccine. The proportion of key lymphocyte subpopulations and expression levels of TLRs were analyzed using flow cytometry with monoclonal antibodies.

RESULTS: No statistically significant alterations in the absolute values of the main lymphocyte subpopulations were observed in CVID patients before or after vaccination with the different immunization protocols. However, after vaccination, a higher expression of TLR3 and TLR9 in granulocytes, monocytes, and lymphocytes was found in those patients who received two vaccine doses rather than one single dose.

CONCLUSION: This study marks the first instance of using a simultaneous two-dose vaccination, which is associated with an elevated level of TLR expression in the immune cells. Administration of the adjuvanted vaccines in CVID patients appears promising. Further research into their impact on innate immunity and the development of more effective vaccination regimens is warranted.

PMID:39203969 | DOI:10.3390/vaccines12080843

Genes (Basel). 2024 Aug 10;15(8):1052. doi: 10.3390/genes15081052.

ABSTRACT

Genetic disorders arise from alterations in the hereditary information encoded in DNA, leading to potential detrimental effects on the well-being and vitality of organisms. Within the bovine population, genetic conditions inherited in an autosomal recessive manner are frequently associated with particular breeds. In recent years, several recessive haplotypes and a few causative mutations have been discovered in Holstein cattle: CDH (Holstein cholesterol deficiency), haplotypes with a homozygous deficiency in Holstein (HH1, HH3, HH4, HH5, HH6 and HH7), BLAD (bovine leukocyte adhesion deficiency) and DUMPS (deficiency of uridine monophosphate synthase). All of these diseases are inherited in an autosomal recessive manner. From a breeding perspective, recessive mutations specifically exhibit considerable detrimental effects and are a significant problem for breeders, exposing them to economic losses. Individual mutations can cause embryo death at any stage of pregnancy. Only genetic research and conscious selection of animals for mating will lead to a reduction in the number of carriers and elimination of mutations from the population.

PMID:39202412 | DOI:10.3390/genes15081052