scholarly journals High-throughput prediction of MHC Class I and Class II neoantigens with MHCnuggets

2019 ◽  
Author(s):  
XM Shao ◽  
R Bhattacharya ◽  
J Huang ◽  
IKA Sivakumar ◽  
C Tokheim ◽  
...  
Keyword(s):  
Neural Network ◽  
Major Histocompatibility Complex ◽  
Positive Predictive Value ◽  
Mhc Class I ◽  
High Throughput ◽  
Predictive Value ◽  
In Silico ◽  
Data Sets ◽  
Missense Mutations ◽  
Histocompatibility Complex

AbstractComputational prediction of binding between neoantigen peptides and major histocompatibility complex (MHC) proteins is an emerging biomarker for predicting patient response to cancer immunotherapy. Current neoantigen predictors focus onin silicoestimation of MHC binding affinity and are limited by low positive predictive value for actual peptide presentation, inadequate support for rare MHC alleles and poor scalability to high-throughput data sets. To address these limitations, we developed MHCnuggets, a deep neural network method to predict peptide-MHC binding. MHCnuggets is the only method to handle binding prediction for common or rare alleles of MHC Class I or II, with a single neural network architecture. Using a long short-term memory network (LSTM), MHCnuggets accepts peptides of variable length and is capable of faster performance than other methods. When compared to methods that integrate binding affinity and HLAp data from mass spectrometry, MHCnuggets yields a fourfold increase in positive predictive value on independent MHC-bound peptide (HLAp) data. We applied MHCnuggets to 26 cancer types in TCGA, processing 26.3 million allele-peptide comparisons in under 2.3 hours, yielding 101,326 unique candidate immunogenic missense mutations (IMMs). Predicted-IMM hotspots occurred in 38 genes, including 24 driver genes. Predicted-IMM load was significantly associated with increased immune cell infiltration (p<2e−16) including CD8+ T cells. Notably, only 0.16% of predicted immunogenic missense mutations were observed in >2 patients, with 61.7% of these derived from driver mutations. Our results provide a new method for neoantigen prediction with high performance characteristics and demonstrate its utility in large data sets across human cancers.SynopsisWe developed a newin silicopredictor of Major Histocompatibility Complex (MHC) ligand binding and demonstrated its utility to assess potential neoantigens and immunogenic missense mutations (IMMs) in 6613 TCGA patients.

scholarly journals High throughput screening to identify inhibitors of the type I interferon – major histocompatibility complex class I pathway in skeletal muscle

2020 ◽  
Author(s):  
Travis B. Kinder ◽  
Patricia Dranchak ◽  
James Inglese
Keyword(s):  
Skeletal Muscle ◽  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
High Throughput ◽  
High Throughput Screening ◽  
Janus Kinase ◽  
Class I ◽  
Type I ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

AbstractImmunosuppressants used to treat autoimmunity are often not curative and have many side effects. Our purpose was to identify therapeutics for autoimmunity of the skeletal muscle termed idiopathic inflammatory myopathies (myositis). Recent evidence shows the pro-inflammatory type I interferons (IFN) and a down-stream product major histocompatibility complex (MHC) class I are pathogenic in myositis. We conducted quantitative high throughput screening on >4,500 compound titrations through a series of cell-based assays to identify those that inhibit the type I IFN-MHC class I pathway in muscle precursor cells (myoblasts). The primary screen utilized CRISPR/Cas9 genome-engineered human myoblast containing a pro-luminescent reporter HiBit fused to the C-terminus of endogenous MHC class I. Active compounds were counter-screened for cytotoxicity and validated by MHC class I immunofluorescence, Western blot, and RT-qPCR. Actives included Janus kinase inhibitors and epigenetic/transcriptional modulators. Testing in animal models and clinical trials is warranted to translate these therapies to myositis patients.

Transcription of non-classic major histocompatibility complex (MHC) class I in the bovine placenta throughout gestation and after Brucella abortus infection

2015 ◽  
Vol 167 (3-4) ◽  
pp. 166-170
Author(s):  
Larissa Sarmento dos Santos ◽  
Juliana Pinto da Silva Mol ◽  
Auricélio Alves de Macedo ◽  
Ana Patrícia Carvalho Silva ◽  
Diego Luiz dos Santos Ribeiro ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Brucella Abortus ◽  
Class I ◽  
Major Histocompatibility ◽  
Bovine Placenta ◽  
Histocompatibility Complex

scholarly journals Major histocompatibility complex class I molecules mediate association of SV40 with caveolae.

1997 ◽  
Vol 8 (1) ◽  
pp. 47-57 ◽  
Author(s):  
E Stang ◽  
J Kartenbeck ◽  
R G Parton
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Mammalian Cells ◽  
Simian Virus 40 ◽  
Class I ◽  
Major Histocompatibility ◽  
Surface Binding ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecule ◽  
Mhc Class I Molecules

Simian virus 40 (SV40) has been shown to enter mammalian cells via uncoated plasma membrane invaginations. Viral particles subsequently appear within the endoplasmic reticulum. In the present study, we have examined the surface binding and internalization of SV40 by immunoelectron microscopy. We show that SV40 associates with surface pits which have the characteristics of caveolae and are labeled with antibodies to the caveolar marker protein, caveolin-1. SV40 is believed to use major histocompatibility complex (MHC) class I molecules as cell surface receptors. Using a number of MHC class I-specific monoclonal antibodies, we found that both viral infection and association of virus with caveolae were strongly reduced by preincubation with anti-MHC class I antibodies. Because binding of SV40 to MHC class I molecules may induce clustering, we investigated whether antibody cross-linked class I molecules also redistributed to caveolae. Clusters of MHC class I molecules were indeed shown to be specifically associated with caveolin-labeled surface pits. Taken together, the results suggest that SV40 may make use of MHC class I molecule clustering and the caveolae pathway to enter mammalian cells.

Nonimmune thyroid destruction results from transgenic overexpression of an allogeneic major histocompatibility complex class I protein

1993 ◽  
Vol 13 (3) ◽  
pp. 1554-1564
Author(s):  
A G Frauman ◽  
P Chu ◽  
L C Harrison
Keyword(s):  
Major Histocompatibility Complex ◽  
Beta Cells ◽  
Mhc Class I ◽  
Pancreatic Beta Cells ◽  
Class I ◽  
General Mechanism ◽  
Major Histocompatibility ◽  
Cell Destruction ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecules

The overexpression of major histocompatibility complex (MHC) class I molecules in endocrine epithelial cells is an early feature of autoimmune thyroid disease and insulin-dependent diabetes mellitus, which may reflect a cellular response, e.g., to viruses or toxins. Evidence from a transgenic model in pancreatic beta cells suggests that MHC class I overexpression could play an independent role in endocrine cell destruction. We demonstrate in this study that the transgenic overexpression of an allogeneic MHC class I protein (H-2Kb) linked to the rat thyroglobulin promoter, in H-2Kk mice homozygous for the transgene, leads to thyrocyte atrophy, hypothyroidism, growth retardation, and death. Thyrocyte atrophy occurred in the absence of lymphocytic infiltration. Tolerance to allogeneic class I was revealed by the reduced ability of primed lymphocytes from transgenic mice to lyse H-2Kb target cells in vitro. This nonimmune form of thyrocyte destruction and hypothyroidism recapitulates the beta-cell destruction and diabetes that results from transgenic overexpression of MHC class I molecules in pancreatic beta cells. Thus, we conclude that overexpression of MHC class I molecules may be a general mechanism that directly impairs endocrine epithelial cell viability.

scholarly journals Porcine major histocompatibility complex (MHC) class I molecules and analysis of their peptide-binding specificities

2011 ◽  
Vol 63 (12) ◽  
pp. 821-834 ◽  
Author(s):  
Lasse Eggers Pedersen ◽  
Mikkel Harndahl ◽  
Michael Rasmussen ◽  
Kasper Lamberth ◽  
William T. Golde ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Peptide Binding ◽  
Class I ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecules

scholarly journals Efficient Targeting of Protein Antigen to the Dendritic Cell Receptor DEC-205 in the Steady State Leads to Antigen Presentation on Major Histocompatibility Complex Class I Products and Peripheral CD8+ T Cell Tolerance

2002 ◽  
Vol 196 (12) ◽  
pp. 1627-1638 ◽  
Author(s):  
Laura Bonifaz ◽  
David Bonnyay ◽  
Karsten Mahnke ◽  
Miguel Rivera ◽  
Michel C. Nussenzweig ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Steady State ◽  
T Cell ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Class I ◽  
Histocompatibility Complex ◽  
Dc Maturation

To identify endocytic receptors that allow dendritic cells (DCs) to capture and present antigens on major histocompatibility complex (MHC) class I products in vivo, we evaluated DEC-205, which is abundant on DCs in lymphoid tissues. Ovalbumin (OVA) protein, when chemically coupled to monoclonal αDEC-205 antibody, was presented by CD11c+ lymph node DCs, but not by CD11c− cells, to OVA-specific, CD4+ and CD8+ T cells. Receptor-mediated presentation was at least 400 times more efficient than unconjugated OVA and, for MHC class I, the DCs had to express transporter of antigenic peptides (TAP) transporters. When αDEC-205:OVA was injected subcutaneously, OVA protein was identified over a 4–48 h period in DCs, primarily in the lymph nodes draining the injection site. In vivo, the OVA protein was selectively presented by DCs to TCR transgenic CD8+ cells, again at least 400 times more effectively than soluble OVA and in a TAP-dependent fashion. Targeting of αDEC-205:OVA to DCs in the steady state initially induced 4–7 cycles of T cell division, but the T cells were then deleted and the mice became specifically unresponsive to rechallenge with OVA in complete Freund's adjuvant. In contrast, simultaneous delivery of a DC maturation stimulus via CD40, together with αDEC-205:OVA, induced strong immunity. The CD8+ T cells responding in the presence of agonistic αCD40 antibody produced large amounts of interleukin 2 and interferon γ, acquired cytolytic function in vivo, emigrated in large numbers to the lung, and responded vigorously to OVA rechallenge. Therefore, DEC-205 provides an efficient receptor-based mechanism for DCs to process proteins for MHC class I presentation in vivo, leading to tolerance in the steady state and immunity after DC maturation.

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