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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 Homo sapiens and of other jawed vertebrate species, based on the CLASSIFICATION axiom. The second major breakthrough has been the IMGT unique numbering and the IMGT Collier de Perles for the V and constant (C) domains of the IG and TR and other proteins of the IG superfamily (IgSF), based on the NUMEROTATION axiom. IMGT-ONTOLOGY axioms and concepts bridge genes, sequences, structures and functions, between biological and computational spheres in the IMGT® system (Web resources, databases and tools). They provide the IMGT Scientific chart rules to identify, to describe and to analyse the IG complex molecular data, the huge diversity of repertoires, the genetic (alleles, allotypes, CNV) polymorphisms, the IG dual function (paratope/epitope, effector properties), the antibody humanization and engineering.

The immunoglobulins (IG) or antibodies and the T cell receptors (TR) are the antigen receptors of the adaptive immune responses (AIR) of jawed vertebrates (Gnathostomata). IMGT®, the international ImMunoGeneTics information system®, was created in 1989 by Marie-Paule Lefranc (Laboratoire d’ImmunoGénétique Moléculaire (LIGM), Université de Montpellier and CNRS) to deal with and to manage the huge diversity of IG or antibodies and TR. The founding of IMGT® marked the advent of immunoinformatics, a new science which emerged at the interface between immunogenetics and bioinformatics. For the first time, the IG and TR variable (V), diversity (D), joining (J) and constant (C) genes were officially recognized as ‘genes’, as were the conventional genes. The IMGT-ONTOLOGY CLASSIFICATION axiom and the concepts of classification have generated the IMGT nomenclature and the IMGT Scientific chart rules for assigning IMGT names to IG and TR genes and alleles of Homo sapiens and of any other jawed vertebrate species. The IMGT nomenclature is used for genes in locus, in sequences (genomic or rearranged, expressed or not) and in structures enabling comparative immunology, evolutionary immunogenetics, standardized analysis and comparison of IG and TR repertoires analysis in normal or pathologic situations. IMGT nomenclature is used in basic, veterinary, and medical research, in clinical applications (mutation analysis in leukemia and lymphoma), and in therapeutic antibody design, engineering and humanization. By providing consistent and high standard biocuration for the description of the IG and TR loci, genes and alleles, and for the analysis of the IG or antibody and TR-expressed rearranged sequences and proteins and structures, the IMGT nomenclature is the common language for immunoinformatics and artificial intelligence (AI).

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. IMGT® reference directories are used for the analysis of the NGS high-throughput expressed IG and TR repertoires (natural, synthetic and/or bioengineered) and for bridging sequences, two-dimensional (2D) and three-dimensional (3D) structures. This manuscript focuses on the IMGT®Homo sapiens IG and TR loci, gene order, copy number variation (CNV) and haplotypes new concepts, as a paradigm for jawed vertebrates genome assemblies.

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.g, CH1, h, CH2 and CH3), the novel AA (single letter abbreviation) and IMGT position according to the IMGT unique numbering for the C-domain and between parentheses, the Eu numbering. IMGT engineered variants are described with detailed amino acid changes, visualized in motifs based on the IMGT numbering bridging genes, sequences, and structures for higher order description.

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). Results: Differential analysis of gene expression between the 15 women in the T21 without BC group and BC patients in the other groups (two women with T21 and fifteen control women, respectively) revealed 154 differentially expressed genes, of which 63 were found to have similar expression profile (up- or downregulated). Of those 63 genes, four were in the same family, namely GIMAP4 , GIMAP6 , GIMAP7 and GIMAP8 , and were strongly upregulated in the T21 without BC group compared to the other groups. A significant decrease in mRNA levels of these genes in BC tissues compared to non-tumor breast tissues was also noted. Conclusion: We found that the expression of some GIMAPs is significantly higher in women with T21 without BC than in patients with sporadic BC. Our findings support the hypothesis that GIMAPs may play a tumor-suppressive role against BC, and open the possibility that they may also have the same role for other solid tumors in T21 patients. The search for new prognostic factors and hopefully new therapeutic or preventive strategies against BC are discussed.

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. The accuracy and the consistency between genes and alleles, sequences, and three-dimensional (3D) structures are based on the IMGT Scientific chart rules generated from the IMGT-ONTOLOGY axioms and concepts: IMGT standardized keywords (IDENTIFICATION), IMGT gene and allele nomenclature (CLASSIFICATION), IMGT standardized labels (DESCRIPTION), IMGT unique numbering and IMGT Collier de Perles (NUMEROTATION). These concepts provide IMGT® immunoinformatics insights for antibody V and C domain structure and function, used for the standardized description in IMGT® web resources, databases and tools, immune repertoires analysis, single cell and/or high-throughput sequencing (HTS, NGS), antibody humanization, and antibody engineering in relation with effector properties.

Dermatophyte infections are unusual but can cause serious invasive disease. In this report, autosomal recessive CARD9 deficiency indicated a potential genetic susceptibility to deep dermatophytosis, a severe invasive fungal infection. Deep dermatophytosis is a rare, invasive, sometimes life-threatening, fungal infection caused by dermatophytes. 1 These filamentous fungi are ubiquitous and usually cause benign infections that are limited to keratinized tissues and lead to onychomycosis, tinea corporis, tinea cruris, tinea pedis, or tinea capitis. 2 In deep dermatophytosis, dermatophytes invade the dermis and hypodermis and disseminate to the skin, hair, nails, lymph nodes, and brain. 3 Deep dermatophytosis has been reported in patients with the human immunodeficiency virus and patients who are receiving immunosuppressive therapy. 3 It was first described in 1959 in otherwise apparently healthy persons as “dermatophytic disease.” 1 Forty-five cases have been reported . . .

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_003025.3:c.427delC; p.Leu143Serfs*9), detected by whole exome sequencing in a 14-year-old boy with predominantly antibody deficiency. The patient who is issued from a consanguineous Lebanese family, presents since the age of 18 months with recurrent respiratory tract infections, low peripheral B cell counts and pan-hypogammaglobulinemia, with no history of opportunistic infections. This defect is associated with decrease in switched memory B cells development, impaired in-vitro B cell proliferation and diminished in-vitro IgG production. The detected variant in SH3GL1 segregates with the disease in the family. It significantly decreases the expression of the protein in the patient’s peripheral blood compared to healthy controls, thus confirming its pathogenicity. Interestingly, endophilin A2-deficient Sh3gl1 −/− mice have been reported to present defects in germinal center B cell responses and in the production of high-affinity IgG. Our data suggests that endophilin A2 deficiency impairs antibody production in humans. Reporting further cases with mutations in SH3GL1 is needed to better characterize the inborn error of immunity linked to this gene.

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. Human primary breast cancer cells were either cultured alone or co-cultured with autologous MOs before treatment with MET. MET downregulated breast cancer cell proliferation and phagocytosis, while having no significant effect on the ratio of phosphorylated Akt (p-Akt) to total Akt. Additionally, we observed that, in the absence of MET treatment, the levels of lactate dehydrogenase (LDH)-based cytotoxicity, catalase, ifCa2+, IL-10 and arginase activity were significantly reduced in co-cultures compared to levels in MOs cultured alone whereas levels of inducible nitric oxide synthase (iNOS) activity were significantly increased. In contrast, MET treatment reduced the effects measured in co-culture on the levels of LDH-based cytotoxicity, arginase activity, catalase, ifCa2+, and IFN-γ. MET also induced upregulation of both iNOS and arginase in MO cells, although the increase did not reach significant difference for iNOS activity. Moreover, MET induced a robust increase of superoxide dismutase (SOD) activity in MOs, but not in MOs co-cultured with breast cancer cells. Furthermore, MET markedly upregulated the levels of IFN-γ production and downregulated those of IL-10 in isolated MOs, while inducing a slight opposing up-regulation of IL-10 production in co-cultures. Our results show that the biomarkers of phenotypic functional activities of MOs are modified after co-culturing with primary human breast cancer cells. Treatment of co-cultures with MET resulted in increased release of antitumor cytokine IFN-γ and ifCa2+, and increased cell necrosis during breast cancer cells-MOs crosstalk.

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, C10H12O2) 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. We found that TQ treatment resulted in a significant upregulation of phagocytic activity, respiratory burst, the production of interleukin-2 (IL-2), IL-6, and IL-17 in NecrJCL-pulsed Mϕ co-culture system, and, conversely, in downregulation of the production of IL-6, IL-17, nitric oxide (NO), and arginase activity in nonpulsed TQ-treated Mϕs co-culture system. In addition, TQ has also shown low upregulation effect on the production of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-1β, pathogen killing capacity and H2O2 in NecrJCL-pulsed Mϕs co-cultures. Moreover, TQ significantly downregulated arginase activity, and significantly upregulated inducible NO synthase (iNOS) activity-to-arginase activity ratio in NecrJCL-pulsed Mϕ co-cultures. Furthermore, TQ downregulated IL-10-to-IL-17 ratio and total cellular cholesterol content (ttcCHOL), but upregulated the ratios of IL-1β-to-IL-4, IL-1β-to-IL-10, IFN-γ-to-IL-4, IFN-γ-to-IL-10, TNF-α-to-IL-4, TNF-α-to-IL-10, and combined proinflammatory cytokines (PICs)-to-anti-inflammatory cytokines (AICs) in NecrJCL-pulsed Mϕs co-culture system, whereas significant differences were highlighted only for IL-10-to-IL-17, IFN-γ-to-IL-10, and PICs-to-AICs ratios. Our outcomes demonstrated that TQ can act as potent adjuvant for enhancing both the functional activities of NecrJCL-pulsed Mϕ and the production of ATCs during their interplay with CD4+ T cells.