Endophilin A2 Deficiency Impairs Antibody Production in Humans.

Endophilin A2, the sole endophilin A family member expressed in hematopoietic cells, regulates various aspects of membrane dynamics, including autophagy and endocytosis. Recent studies in rodents highlight the essential role of endophilin A2 in modulating immune responses. Here we report a homozygous frameshift variant in the SH3GL1 gene (NM_003025.

Next generation sequencing (NGS)-based approach to diagnosing Algerian patients with suspected inborn errors of immunity (IEIs).

The advent of next-generation sequencing (NGS) technologies has greatly expanded our understanding of both the clinical spectra and genetic landscape of inborn errors of immunity (IEIs). Endogamous populations may be enriched for unique, ancestry-specific disease-causing variants, a consideration that significantly impacts molecular testing and analysis strategies. Herein, we report on the application of a 2-step NGS-based testing approach beginning with targeted gene panels (TGPs) tailored to specific IEI subtypes and reflexing to whole exome sequencing (WES) if negative for Northwest Algerian patients with suspected IEIs.

POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment.

Combined immunodeficiency diseases (CID) represent the most severe forms of inborn errors of immunity. Defective T cell development and/or function, leading to an impairment in adaptive immunity are responsible for these diseases. The DNA polymerase δ complex is important for genome duplication and maintenance and consists of the catalytic subunit POLD1, and the accessory subunits POLD2 and POLD3 which stabilizes the complex.

Antibody Sequence and Structure Analyses Using IMGT: 30 Years of Immunoinformatics.

IMGT, the international ImMunoGeneTics information system, http://www.imgt.org , the global reference in immunogenetics and immunoinformatics, was created in 1989 by Marie-Paule Lefranc (Université de Montpellier and CNRS) to manage the huge diversity of the antigen receptors, immunoglobulins (IG) or antibodies, and T cell receptors (TR) of the adaptive immune responses.

IMGT Nomenclature of Engineered IGHG Variants Involved in Antibody Effector Properties and Formats.

The constant region of the immunoglobulin (IG) or antibody heavy gamma chain is frequently engineered to modify the effector properties of the therapeutic monoclonal antibodies. These variants are classified in regards to their effects on effector functions, antibody-dependent cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), complement-dependent cytotoxicity (CDC) enhancement or reduction, B cell inhibition by the coengagement of antigen and FcγR on the same cell, on half-life increase, and/or on structure such as prevention of IgG4 half-IG exchange, hexamerisation, knobs-into-holes and the heteropairing H-H of bispecific antibodies, absence of disulfide bridge inter H-L, absence of glycosylation site, and site-specific drug attachment engineered cysteine. The IMGT engineered variant identifier is comprised of the species and gene name (and eventually allele), the letter 'v' followed by a number (assigned chronologically), and for each concerned domain (e.

IMGT/3Dstructure-DB: T-Cell Receptor TR Paratope and Peptide/Major Histocompatibility pMH Contact Sites and Epitope.

T-cell receptors (TR), the antigen receptors of T cells, specifically recognize peptides presented by the major histocompatibility (MH) proteins, as peptide/MH (pMH), on the cell surface. The structure characterization of the trimolecular TR/pMH complexes is crucial to the fields of immunology, vaccination, and immunotherapy. IMGT/3Dstructure-DB is the three-dimensional (3-D) structure database of IMGT, the international ImMunoGenetics information system.

IMGT IG and TR Loci, Gene Order, CNV and Haplotypes: New Concepts as a Paradigm for Jawed Vertebrates Genome Assemblies.

IMGT, the international ImMunoGeneTics information system, created in 1989, by Marie-Paule Lefranc (Université de Montpellier and CNRS), marked the advent of immunoinformatics, a new science which emerged at the interface between immunogenetics and bioinformatics for the study of the adaptive immune responses. IMGT is based on a standardized nomenclature of the immunoglobulin (IG) and T cell receptor (TR) genes and alleles from fish to humans and on the IMGT unique numbering for the variable (V) and constant (C) domains of the immunoglobulin superfamily (IgSF) of vertebrates and invertebrates, and for the groove (G) domain of the major histocompatibility (MH) and MH superfamily (MhSF) proteins. IMGT comprises 7 databases, 17 tools and more than 25,000 pages of web resources for sequences, genes and structures, based on the IMGT Scientific chart rules generated from the IMGT-ONTOLOGY axioms and concepts.

A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort.

Background: Clinical and molecular data on the occurrence and frequency of inherited neuromuscular disorders (NMD) in the Lebanese population is scarce.

Objective: This study aims to provide a retrospective overview of hereditary NMDs based on our clinical consultations in Lebanon.

Methods: Clinical and molecular data of patients referred to a multi-disciplinary consultation for neuromuscular disorders over a 20-year period (1999-2019) was reviewed.

Metformin partially reverses the inhibitory effect of co-culture with ER-/PR-/HER2+ breast cancer cells on biomarkers of monocyte antitumor activity.

Background: Immune activities of monocytes (MOs) can be altered within the microenvironment of solid malignancies, including breast cancer. Metformin (1,1-dimethylbiguanide hydrochloride, MET), has been shown to decrease tumor cell proliferation, but its effects have yet to be explored with respect to MOs (monocytes) activity during their crosstalk with breast cancer cells. Here, we investigated the effects of MET on overall phenotypic functional activities, including cellular immunometabolism and protective redox signaling based-biomarkers, intracellular free calcium ions (ifCa2+), phagocytosis and co-operative cytokines (IFN-γ and IL-10) of autologous MOs before and during their interplay with primary ER-/PR-/HER2+ breast cancer cells.

Immunoglobulins or Antibodies: IMGT Bridging Genes, Structures and Functions.

IMGT, the international ImMunoGeneTics information system founded in 1989 by Marie-Paule Lefranc (Université de Montpellier and CNRS), marked the advent of immunoinformatics, a new science at the interface between immunogenetics and bioinformatics. For the first time, the immunoglobulin (IG) or antibody and T cell receptor (TR) genes were officially recognized as 'genes' as well as were conventional genes. This major breakthrough has allowed the entry, in genomic databases, of the IG and TR variable (V), diversity (D) and joining (J) genes and alleles of and of other jawed vertebrate species, based on the CLASSIFICATION axiom.

Transcriptomic study in women with trisomy 21 identifies a possible role of the GTPases of the immunity-associated proteins (GIMAP) in the protection of breast cancer.

Background: People with trisomy 21 (T21) are predisposed to developing hematological tumors, but have significantly lower-than-expected age-adjusted incidence rates of having a solid tumor.

Material And Methods: To identify novel genetic factors implicated in the lower breast cancer (BC) frequency observed in women with T21 than in the general population, we compared the transcriptome pattern of women with a homogeneous T21, aged more than 30 years, with or without BC, and tumoral BC tissue of control women with a normal karyotype from the study of Varley et al. (2014).

Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2).

Background: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable.

Objective: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation.

IMGT and 30 Years of Immunoinformatics Insight in Antibody V and C Domain Structure and Function.

At the 10th Human Genome Mapping (HGM10) Workshop, in New Haven, for the first time, immunoglobulin (IG) or antibody and T cell receptor (TR) variable (V), diversity (D), joining (J), and constant (C) genes were officially recognized as 'genes', as were the conventional genes. Under these HGM auspices, IMGT, the international ImMunoGeneTics information system, was created in June 1989 at Montpellier (University of Montpellier and CNRS). The creation of IMGT marked the birth of immunoinformatics, a new science, at the interface between immunogenetics and bioinformatics.

Combination of metformin with sodium selenite induces a functional phenotypic switch of human GM-CSF monocyte-derived macrophages.

Objectives: We evaluated the effects of metformin (Met, 1,1‑dimethylbiguanide hydrochloride) combined or not with sodium selenite (Ss, NaSeO) on the functional activities of LPS-activated GM-CSF monocyte-derived macrophages (GM-MDM).

Materials And Methods: Human GM-MDMs from three healthy donors were treated with Met or Ss alone, or with the combination of Met and Ss, and assayed for various biological activities and cytokines expression.

Results: Met alone and Ss alone had significantly different effects on phagocytosis and killing capacities and IL-β production, but had similar effects on the downregulation of inducible nitric oxide synthase (iNOS) activity, relative nicotinamide adenine dinucleotide reduced (NADH) dehydrogenase (Complex I), intracellular free calcium ions (Ca), and on the upregulation of arginase activity.

Thymoquinone Potently Enhances the Activities of Classically Activated Macrophages Pulsed with Necrotic Jurkat Cell Lysates and the Production of Antitumor Th1-/M1-Related Cytokines.

Antitumor activity of classically activated macrophage (Mϕ) may be impaired within the tumors, spleen, and bone marrow. Thus, it is possible to boost its antitumor activity after its pulsing with necrotic tumor cell lysates combined with an adjuvant. We set out to determine the potential adjuvant effects of thymoquinone (TQ; 2-isopropyl-5-methyl-1,4-benzoquinone, CHO) on both functional activities of classically activated Mϕs, pulsed or not with necrotic Jurkat T cell line lysates (NecrJCL), and the balance of antitumor cytokines (ATCs) versus immunosuppressive cytokines (ISCs) during crosstalk with autologous human CD4 T cells.

Facial cutaneo-mucosal venous malformations can develop independently of mutation of TEK gene but may be associated with excessive expression of Src and p-Src.

We aimed to search for mutations in the germline and somatic DNA of the TEK gene and to analyze the expression level of Src and phospho-Src (p-Src) in tumor and healthy tissues from patients with facial cutaneo-mucosal venous malformations (VMCM). Eligible patients from twelve families and thirty healthy controls were recruited respectively at the Departments of Stomatology and Oral Surgery, and Transfusion Medicine of Tlemcen University Medical Centre. Immunoblot analyses of Src and p-Src were performed after direct DNA sequencing.

Polymorphisms Associated with Rheumatoid Arthritis Susceptibility in Tunisian and French Female Populations: Influence of Geographic Origin.

Polymorphisms have been identified in the Xq28 locus as risk loci for rheumatoid arthritis (RA). Here, we investigated the association between three polymorphisms in the Xq28 region containing and (rs13397, rs1059703, and rs1059702) in two unstudied populations: Tunisian and French. The rs13397 G and rs1059703 T major alleles were significantly increased in RA patients ( = 408) compared with age-matched controls ( = 471) in both Tunisian and French women.

The Role of Recent Admixture in Forming the Contemporary West Eurasian Genomic Landscape.

Over the past few years, studies of DNA isolated from human fossils and archaeological remains have generated considerable novel insight into the history of our species. Several landmark papers have described the genomes of ancient humans across West Eurasia, demonstrating the presence of large-scale, dynamic population movements over the last 10,000 years, such that ancestry across present-day populations is likely to be a mixture of several ancient groups [1-7]. While these efforts are bringing the details of West Eurasian prehistory into increasing focus, studies aimed at understanding the processes behind the generation of the current West Eurasian genetic landscape have been limited by the number of populations sampled or have been either too regional or global in their outlook [8-11].

The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency.

Background: Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management.

Objectives: We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings.