1.
Genetic determinants of the humoral immune response in MS.
Gasperi, C, Andlauer, TFM, Keating, A, Knier, B, Klein, A, Pernpeintner, V, Lichtner, P, Gold, R, Zipp, F, Then Bergh, F, et al
Neurology(R) neuroimmunology & neuroinflammation. 2020;(5)
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Abstract
OBJECTIVE In this observational study, we investigated the impact of genetic factors at the immunoglobulin heavy chain constant locus on chromosome 14 and the major histocompatibility complex region on intrathecal immunoglobulin G, A, and M levels as well as on B cells and plasmablasts in the CSF and blood of patients with multiple sclerosis (MS). METHODS Using regression analyses, we tested genetic variants on chromosome 14 and imputed human leukocyte antigen (HLA) alleles for associations with intrathecal immunoglobulins in 1,279 patients with MS or clinically isolated syndrome and with blood and CSF B cells and plasmablasts in 301 and 348 patients, respectively. RESULTS The minor alleles of variants on chromosome 14 were associated with higher intrathecal immunoglobulin G levels (β = 0.58 [0.47 to 0.68], lowest adjusted p = 2.32 × 10-23), and lower intrathecal immunoglobulin M (β = -0.56 [-0.67 to -0.46], p = 2.06 × 10-24) and A (β = -0.42 [-0.54 to -0.31], p = 7.48 × 10-11) levels. Alleles from the HLA-B*07:02-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype were associated with higher (lowest p = 2.14 × 10-7) and HLA-B*44:02 with lower (β = -0.35 [-0.54 to -0.17], p = 1.38 × 10-2) immunoglobulin G levels. Of interest, different HLA alleles were associated with lower intrathecal immunoglobulin M (HLA-C*02:02, β = -0.45 [-0.61 to -0.28], p = 1.01 × 10-5) and higher immunoglobulin A levels (HLA-DQA1*01:03-DQB1*06:03-DRB1*13:01 haplotype, β = 0.40 [0.21 to 0.60], p = 4.46 × 10-3). The impact of HLA alleles on intrathecal immunoglobulin G and M levels could mostly be explained by associations with CSF B cells and plasmablasts. CONCLUSION Although some HLA alleles seem to primarily drive the extent of humoral immune responses in the CNS by increasing CSF B cells and plasmablasts, genetic variants at the immunoglobulin heavy chain constant locus might regulate intrathecal immunoglobulins levels via different mechanisms.
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Opsonization-Enhanced Antigen Presentation by MR1 Activates Rapid Polyfunctional MAIT Cell Responses Acting as an Effector Arm of Humoral Antibacterial Immunity.
Boulouis, C, Gorin, JB, Dias, J, Bergman, P, Leeansyah, E, Sandberg, JK
Journal of immunology (Baltimore, Md. : 1950). 2020;(1):67-77
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Abstract
Mucosa-associated invariant T (MAIT) cells are innate-like antimicrobial T cells recognizing a breadth of important pathogens via presentation of microbial riboflavin metabolite Ags by MHC class Ib-related (MR1) molecules. However, the interaction of human MAIT cells with adaptive immune responses and the role they may play in settings of vaccinology remain relatively little explored. In this study we investigated the interplay between MAIT cell-mediated antibacterial effector functions and the humoral immune response. IgG opsonization of the model microbe Escherichia coli with pooled human sera markedly enhanced the capacity of monocytic APC to stimulate MAIT cells. This effect included greater sensitivity of recognition and faster response kinetics, as well as a markedly higher polyfunctionality and magnitude of MAIT cell responses involving a range of effector functions. The boost of MAIT cell responses was dependent on strongly enhanced MR1-mediated Ag presentation via increased FcγR-mediated uptake and signaling primarily mediated by FcγRI. To investigate possible translation of this effect to a vaccine setting, sera from human subjects before and after vaccination with the 13-valent-conjugated Streptococcus pneumoniae vaccine were assessed in a MAIT cell activation assay. Interestingly, vaccine-induced Abs enhanced Ag presentation to MAIT cells, resulting in more potent effector responses. These findings indicate that enhancement of Ag presentation by IgG opsonization allows innate-like MAIT cells to mount a faster, stronger, and qualitatively more complex response and to function as an effector arm of vaccine-induced humoral adaptive antibacterial immunity.
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The farther the better: Investigating how distance from human self affects the propensity of a peptide to be presented on cell surface by MHC class I molecules, the case of Trypanosoma cruzi.
Vergni, D, Gaudio, R, Santoni, D
PloS one. 2020;(12):e0243285
Abstract
More than twenty years ago the reverse vaccinology paradigm came to light trying to design new vaccines based on the analysis of genomic information in order to select those pathogen peptides able to trigger an immune response. In this context, focusing on the proteome of Trypanosoma cruzi, we investigated the link between the probabilities for pathogen peptides to be presented on a cell surface and their distance from human self. We found a reasonable but, as far as we know, undiscovered property: the farther the distance between a peptide and the human-self the higher the probability for that peptide to be presented on a cell surface. We also found that the most distant peptides from human self bind, on average, a broader collection of HLAs than expected, implying a potential immunological role in a large portion of individuals. Finally, introducing a novel quantitative indicator for a peptide to measure its potential immunological role, we proposed a pool of peptides that could be potential epitopes and that can be suitable for experimental testing. The software to compute peptide classes according to the distance from human self is free available at http://www.iasi.cnr.it/~dsantoni/nullomers.
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Conserved epitopes with high HLA-I population coverage are targets of CD8+ T cells associated with high IFN-γ responses against all dengue virus serotypes.
Adikari, TN, Di Giallonardo, F, Leung, P, Grifoni, A, Sette, A, Weiskopf, D, Bull, RA, Luciani, F
Scientific reports. 2020;(1):20497
Abstract
Cytotoxic CD8+ T cells are key for immune protection against viral infections. The breadth and cross-reactivity of these responses are important against rapidly mutating RNA viruses, such as dengue (DENV), yet how viral diversity affect T cell responses and their cross-reactivity against multiple variants of the virus remains poorly defined. In this study, an integrated analysis was performed to map experimentally validated CD8+ T cell epitopes onto the distribution of DENV genome sequences across the 4 serotypes worldwide. Despite the higher viral diversity observed within HLA-I restricted epitopes, mapping of 609 experimentally validated epitopes sequences on 3985 full-length viral genomes revealed 19 highly conserved epitopes across the four serotypes within the immunogenic regions of NS3, NS4B and NS5. These conserved epitopes were associated with a higher magnitude of IFN-γ response when compared to non-conserved epitopes and were restricted to 13 HLA class I genotypes, hence providing high coverage among human populations. Phylogeographic analyses showed that these epitopes are largely conserved in most of the endemic regions of the world, and with only some of these epitopes presenting distinct mutated variants circulating in South America and Asia.This study provides evidence for the existence of highly immunogenic and conserved epitopes across serotypes, which may impact design of new universal T-cell-inducing vaccine candidates that minimise detrimental effects of viral diversification and at the same time induce responses to a broad human population.
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HLA class I binding prediction via convolutional neural networks.
Vang, YS, Xie, X
Bioinformatics (Oxford, England). 2017;(17):2658-2665
Abstract
MOTIVATION Many biological processes are governed by protein-ligand interactions. One such example is the recognition of self and non-self cells by the immune system. This immune response process is regulated by the major histocompatibility complex (MHC) protein which is encoded by the human leukocyte antigen (HLA) complex. Understanding the binding potential between MHC and peptides can lead to the design of more potent, peptide-based vaccines and immunotherapies for infectious autoimmune diseases. RESULTS We apply machine learning techniques from the natural language processing (NLP) domain to address the task of MHC-peptide binding prediction. More specifically, we introduce a new distributed representation of amino acids, name HLA-Vec, that can be used for a variety of downstream proteomic machine learning tasks. We then propose a deep convolutional neural network architecture, name HLA-CNN, for the task of HLA class I-peptide binding prediction. Experimental results show combining the new distributed representation with our HLA-CNN architecture achieves state-of-the-art results in the majority of the latest two Immune Epitope Database (IEDB) weekly automated benchmark datasets. We further apply our model to predict binding on the human genome and identify 15 genes with potential for self binding. AVAILABILITY AND IMPLEMENTATION Codes to generate the HLA-Vec and HLA-CNN are publicly available at: https://github.com/uci-cbcl/HLA-bind . CONTACT xhx@ics.uci.edu. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.