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Humans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation.

ABSTRACT: The glycosphingolipid isoglobotrihexosylceramide, or isogloboside 3 (iGb3), is believed to be critical for natural killer T (NKT) cell development and self-recognition in mice and humans. Furthermore, iGb3 may represent an important obstacle in xenotransplantation, in which this lipid represents the only other form of the major xenoepitope Galalpha(1,3)Gal. The role of iGb3 in NKT cell development is controversial, particularly with one study that suggested that NKT cell development is normal in mice that were rendered deficient for the enzyme iGb3 synthase (iGb3S). We demonstrate that spliced iGb3S mRNA was not detected after extensive analysis of human tissues, and furthermore, the iGb3S gene contains several mutations that render this product nonfunctional. We directly tested the potential functional activity of human iGb3S by expressing chimeric molecules containing the catalytic domain of human iGb3S. These hybrid molecules were unable to synthesize iGb3, due to at least one amino acid substitution. We also demonstrate that purified normal human anti-Gal immunoglobulin G can bind iGb3 lipid and mediate complement lysis of transfected human cells expressing iGb3. Collectively, our data suggest that iGb3S is not expressed in humans, and even if it were expressed, this enzyme would be inactive. Consequently, iGb3 is unlikely to represent a primary natural ligand for NKT cells in humans. Furthermore, the absence of iGb3 in humans implies that it is another source of foreign Galalpha(1,3)Gal xenoantigen, with obvious significance in the field of xenotransplantation.

SUBMITTER: Christiansen D

PROVIDER: S-EPMC2459210 | biostudies-literature |

REPOSITORIES: biostudies-literature

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CD1d protein structure determines species-selective antigenicity of isoglobotrihexosylceramide (iGb3) to invariant NKT cells.

Project description:Isoglobotrihexosylceramide (iGb3) has been identified as a potent CD1d-presented self-antigen for mouse invariant natural killer T (iNKT) cells. The role of iGb3 in humans remains unresolved, however, as there have been conflicting reports about iGb3-dependent human iNKT-cell activation, and humans lack iGb3 synthase, a key enzyme for iGb3 synthesis. Given the importance of human immune responses, we conducted a human-mouse cross-species analysis of iNKT-cell activation by iGb3-CD1d. Here we show that human and mouse iNKT cells were both able to recognise iGb3 presented by mouse CD1d (mCD1d), but not human CD1d (hCD1d), as iGb3-hCD1d was unable to support cognate interactions with the iNKT-cell TCRs tested in this study. The structural basis for this discrepancy was identified as a single amino acid variation between hCD1d and mCD1d, a glycine-to-tryptophan modification within the α2-helix that prevents flattening of the iGb3 headgroup upon TCR ligation. Mutation of the human residue, Trp153, to the mouse ortholog, Gly155, therefore allowed iGb3-hCD1d to stimulate human iNKT cells. In conclusion, our data indicate that iGb3 is unlikely to be a major antigen in human iNKT-cell biology.

| S-EPMC3961145 | biostudies-literature

Lack of iGb3 and Isoglobo-Series Glycosphingolipids in Pig Organs Used for Xenotransplantation: Implications for Natural Killer T-Cell Biology.

Project description:?-1,3-Terminated galactose residues on glycoproteins and glycosphingolipids are recognized by natural anti-?-1,3-galactose antibodies in human serum and cause hyperacute rejection in pig-to-human xenotransplantation. Genetic depletion of ?-1,3-galactosyltransferase-1 in pigs abolishes the hyperacute rejection reaction. However, the isoglobotriosylceramide (iGb3) synthase in pigs may produce additional ?-1,3-terminated galactose residues on glycosphingolipids. In both ?-1,3-galactosyltranserase-1 knockout mice and pigs, cytotoxic anti-?-1,3-galactose antibodies could be induced; thus, a paradox exists that anti-?-1,3-galactose antibodies are present in animals with functional iGb3 synthases. Furthermore, iGb3 has been found to be an endogenous antigen for natural killer T (NKT) cells, an innate type of lymphocyte that may initiate the adaptive immune responses. It has been reasoned that iGb3 may trigger the activation of NKT cells and cause the rejection of ?-1,3-galactosyltransferase-1-deficient organs through the potent stimulatory effects of NKT cells on adaptive immune cells (see ref.([20])). In this study, we examined the expression of iGb3 and the isoglobo-series glycosphingolipids in pig organs, including the heart, liver, pancreas, and kidney, by ion-trap mass spectrometry, which has a sensitivity of measuring 1% iGb3 among Gb3 isomers, when 5 ?g/mL of the total iGb3/Gb3 mixture is present (see ref.([35])). We did not detect iGb3 or other isoglobo-series glycosphingolipids in any of these organs, although they were readily detected in mouse and human thymus and dendritic cells. The lack of iGb3 and isoglobo-series glycosphingolipids in pig organs indicates that iGb3 is unlikely to be a relevant immune epitope in xenotransplantation.

| S-EPMC3558945 | biostudies-literature

The NKT cell TCR repertoire can accommodate structural modifications to the lipid and orientation of the terminal carbohydrate of iGb3.

Project description:Isoglobotrihexosylceramide (iGb3) is a known NKT cell agonist, however the specific interactions required to trigger NKT cell TCR activation in response to this mammalian glycolipid are not fully understood. Here we report the synthesis of 1,3-β-Gal-LacCer (βG-iGb3) that displays a β-linked terminal sugar. βG-iGb3 activated NKT cells to a similar extent as iGb3 with a terminal α-linkage, indicating that the conformation of the terminal sugar residue of iGb3 is not essential to facilitate NKT cell TCR recognition. In addition, the immunological activity of four recently described iGb3 analogues with modifications to their terminal sugar or lipid backbone were also investigated. These iGb3 analogues all induced NKT cell proliferation, with IL-13 the predominate cytokine detected. This highlights the ability of the NKT cell TCR to accommodate variations in iGb3-based glycolipids and suggests that undiscovered NKT cell ligands may exist within the lacto-series of mammalian glycosphingolipids.

| S-EPMC9215340 | biostudies-literature

Functional implications of Neandertal introgression in modern humans.

Project description:BackgroundAdmixture between early modern humans and Neandertals approximately 50,000-60,000 years ago has resulted in 1.5-4% Neandertal ancestry in the genomes of present-day non-Africans. Evidence is accumulating that some of these archaic alleles are advantageous for modern humans, while others are deleterious; however, the major mechanism by which these archaic alleles act has not been fully explored.ResultsHere we assess the contributions of introgressed non-synonymous and regulatory variants to modern human protein and gene expression variation. We show that gene expression changes are more often associated with Neandertal ancestry than expected, and that the introgressed non-synonymous variants tend to have less predicted functional effect on modern human proteins than mutations that arose on the human lineage. Conversely, introgressed alleles contribute proportionally more to expression variation than non-introgressed alleles.ConclusionsOur results suggest that the major influence of Neandertal introgressed alleles is through their effects on gene regulation.

| S-EPMC5376702 | biostudies-literature

Sphingolipid dysregulation due to lack of functional KDSR impairs proplatelet formation causing thrombocytopenia.

Project description:Sphingolipids are fundamental to membrane trafficking, apoptosis, and cell differentiation and proliferation. KDSR or 3-keto-dihydrosphingosine reductase is an essential enzyme for de novo sphingolipid synthesis, and pathogenic mutations in KDSR result in the severe skin disorder erythrokeratodermia variabilis et progressiva-4 Four of the eight reported cases also had thrombocytopenia but the underlying mechanism has remained unexplored. Here we expand upon the phenotypic spectrum of KDSR deficiency with studies in two siblings with novel compound heterozygous variants associated with thrombocytopenia, anemia, and minimal skin involvement. We report a novel phenotype of progressive juvenile myelofibrosis in the propositus, with spontaneous recovery of anemia and thrombocytopenia in the first decade of life. Examination of bone marrow biopsies showed megakaryocyte hyperproliferation and dysplasia. Megakaryocytes obtained by culture of CD34+ stem cells confirmed hyperproliferation and showed reduced proplatelet formation. The effect of KDSR insufficiency on the sphingolipid profile was unknown, and was explored in vivo and in vitro by a broad metabolomics screen that indicated activation of an in vivo compensatory pathway that leads to normalization of downstream metabolites such as ceramide. Differentiation of propositus-derived induced pluripotent stem cells to megakaryocytes followed by expression of functional KDSR showed correction of the aberrant cellular and biochemical phenotypes, corroborating the critical role of KDSR in proplatelet formation. Finally, Kdsr depletion in zebrafish recapitulated the thrombocytopenia and showed biochemical changes similar to those observed in the affected siblings. These studies support an important role for sphingolipids as regulators of cytoskeletal organization during megakaryopoiesis and proplatelet formation.

| S-EPMC6518879 | biostudies-literature

The crystal structure of anthranilate synthase from Sulfolobus solfataricus: functional implications.

Project description:Anthranilate synthase catalyzes the synthesis of anthranilate from chorismate and glutamine and is feedback-inhibited by tryptophan. The enzyme of the hyperthermophile Sulfolobus solfataricus has been crystallized in the absence of physiological ligands, and its three-dimensional structure has been determined at 2.5-A resolution with x-ray crystallography. It is a heterotetramer of anthranilate synthase (TrpE) and glutamine amidotransferase (TrpG) subunits, in which two TrpG:TrpE protomers associate mainly via the TrpG subunits. The small TrpG subunit (195 residues) has the known "triad" glutamine amidotransferase fold. The large TrpE subunit (421 residues) has a novel fold. It displays a cleft between two domains, the tips of which contact the TrpG subunit across its active site. Clusters of catalytically essential residues are located inside the cleft, spatially separated from clustered residues involved in feedback inhibition. The structure suggests a model in which chorismate binding triggers a relative movement of the two domain tips of the TrpE subunit, activating the TrpG subunit and creating a channel for passage of ammonia toward the active site of the TrpE subunit. Tryptophan presumably blocks this rearrangement, thus stabilizing the inactive states of both subunits. The structure of the TrpE subunit is a likely prototype for the related enzymes 4-amino 4-deoxychorismate synthase and isochorismate synthase.

| S-EPMC22234 | biostudies-literature

Absence of functional fetal regulatory T cells in humans causes in utero organ-specific autoimmunity.

Project description: Not available

| S-EPMC8941979 | biostudies-literature

Leave of absence due to depression.

Project description:OBJECTIVE:to analyze the occurrence of leave of absence due to depression among workers. METHOD:census, descriptive-analytical study, with retrospective collection. Population composed of 2,267 workers on leave due to depression with data from the Unified Benefits Information System. The independent variables were: sex, age group, income; county, origin, number of leaves of absence and type of benefit. For data analysis, descriptive statistics were used and the chi-square and Fisher's exact tests were applied. The variables that presented a value of p?0.20 were submitted to logistic regression. RESULTS:there was a predominance of females, age ?50 years, from the capital, with income of one to two minimum wages, urban origin and single removal. Single leaves of absence occurred mainly due to a mild depressive episode and the benefit granted to the significant majority was social security sickness benefit. Among those who were on leave of absence more than once, the main cause was recurrent depressive disorder, a current mild episode and, in terms of benefit, social security sickness benefit. There was a statistical association between total time and absence from work. In logistic regression, it was found that the time ?60 days, was 3.1 times longer in recurrent depressive disorder. CONCLUSION:there were an expressive quantitative number of absences due to depression, in which it was observed, especially, that the absence time remained long.

| S-EPMC7266636 | biostudies-literature

Neutrophilic granulocytes modulate invariant NKT cell function in mice and humans.

Project description:Invariant NKT (iNKT) cells are a conserved ??TCR(+) T cell population that can swiftly produce large amounts of cytokines, thereby activating other leukocytes, including neutrophilic granulocytes (neutrophils). In this study, we investigated the reverse relationship, showing that high neutrophil concentrations suppress the iNKT cell response in mice and humans. Peripheral V?14 iNKT cells from spontaneously neutrophilic mice produced reduced cytokines in response to the model iNKT cell Ag ?-galactosyl ceramide and expressed lower amounts of the T-box transcription factor 21 and GATA3 transcription factor than did wild-type controls. This influence was extrinsic, as iNKT cell transcription factor expression in mixed chimeric mice depended on neutrophil count, not iNKT cell genotype. Transcription factor expression was also decreased in primary iNKT cells from the neutrophil-rich bone marrow compared with spleen in wild-type mice. In vitro, the function of both mouse and human iNKT cells was inhibited by coincubation with neutrophils. This required cell-cell contact with live neutrophils. Neutrophilic inflammation in experimental peritonitis in mice decreased iNKT cell T-box transcription factor 21 and GATA3 expression and ?-galactosyl ceramide-induced cytokine production in vivo. This was reverted by blockade of neutrophil mobilization. Similarly, iNKT cells from the human peritoneal cavity expressed lower transcription factor levels during neutrophilic peritonitis. Our data reveal a novel regulatory axis whereby neutrophils reduce iNKT cell responses, which may be important in shaping the extent of inflammation.

| S-EPMC3311698 | biostudies-literature

Sickness absence due to depressive symptoms.

Project description:OBJECTIVE: There is no information on the duration of absence of depressed Dutch workers. The aim of this study was to determine the duration of sickness absence due to depressive symptoms in the working population. METHODS: In this observational study of 15% of the Dutch working population, all absence episodes (n = 9,910) starting between April 2002 and November 2005 diagnosed as depression were selected. For these episodes, Kaplan-Meier survival curves were computed. RESULTS: The mean (and median) duration of sickness absence due to depressive symptoms was 200 (179) days in men and 213 (201) days in women. In both sexes, older employees had longer absence durations. Depressive symptoms had an estimated rate of chronicity (1 year of absence) of 24%. Employees in educational and public services (232 days in men and 242 days in women), commercial services (213 days in men and 219 days in women) and health care (212 days in men and 214 days in women) had the longest mean duration of absence with depressive symptoms. Men in the industrial sector (189 days) had the shortest absence periods. Employees in large sized companies (188 days in men and 208 days in women) had shorter absence episodes as compared to companies with less than 75 employees (214 days in men and 226 days in women). CONCLUSIONS: Workers with depressive symptoms were absent for a long time. Explanations for the long duration are discussed. It is recommended to develop and apply tools for recognizing employees at risk for chronic depression.

| S-EPMC2254471 | biostudies-other

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