Natural HLA Class I Polymorphism Controls the Pathway of Antigen Presentation and Susceptibility to Viral Evasion

HLA class I polymorphism creates diversity in epitope specificity and T cell repertoire. We show that HLA polymorphism also controls the choice of Ag presentation pathway. A single amino acid polymorphism that distinguishes HLA-B*4402 (Asp116) from B*4405 (Tyr116) permits B*4405 to constitutively acquire peptides without any detectable incorporation into the transporter associated with Ag presentation (TAP)-associated peptide loading complex even under conditions of extreme peptide starvation. This mode of peptide capture is less susceptible to viral interference than the conventional loading pathway used by HLA-B*4402 that involves assembly of class I molecules within the peptide loading complex. Thus, B*4402 and B*4405 are at opposite extremes of a natural spectrum in HLA class I dependence on the PLC for Ag presentation. These findings unveil a new layer of MHC polymorphism that affects the generic pathway of Ag loading, revealing an unsuspected evolutionary trade-off in selection for optimal HLA class I loading versus effective pathogen evasion

Ohio History 2015

https://kent-islandora.s3.us-east-2.amazonaws.com/node/10127/OH-v122-thumb.jpgOHIO HISTORY Contents for Volume 122, 2015 Contested Patriarchy: John Cleves Symmes and the Struggle for Family Control in the Post-revolutionary West Cathy Rodabaugh ...... 5 Ralph Keeler: A Delightful Arabesque of Invention and Sentiment Larry Lee Nelson ...... 29 Peace Be with You: Leftist Activism at John Carroll University, 1967–69 Michael Daniel Goodnough ...... 49 Water in the Shaping of Columbus, Ohio, 1812–1912 Mansel G. Blackford ......&nbsp; 65 &nbsp; Book Reviews ...... 89 &nbsp; On the cover: The Columbus water-treatment plant was one of the most modern in the world, and worked well in all weather. (Columbus Metropolitan Library)</p

Human leukocyte Antigen Class I-restricted activation of CD8+ T Cells provides the immunogenetic basis of a systemic drug hypersensitivity

The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behçet's disease (HLA-B51) and ankylosing spondylitis (HLA-B27) remain mysterious. Recently, however, even stronger HLA associations are reported in drug hypersensitivities to the reverse-transcriptase inhibitor abacavir (HLA-B57), the gout prophylactic allopurinol (HLA-B58), and the antiepileptic carbamazepine (HLA-B∗1502), providing a defined disease trigger and suggesting a general mechanism for these associations. We show that systemic reactions to abacavir were driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells. Recognition of abacavir required the transporter associated with antigen presentation and tapasin, was fixation sensitive, and was uniquely restricted by HLA-B∗5701 and not closely related HLA allotypes with polymorphisms in the antigen-binding cleft. Hence, the strong association of HLA-B∗5701 with abacavir hypersensitivity reflects specificity through creation of a unique ligand as well as HLA-restricted antigen presentation, suggesting a basis for the strong HLA class I-association with certain inflammatory disorders