Biology subjects

Luzuriaga, K.

Publications and source records attributed to Luzuriaga, K..

4 recordsLinked to original sources

bioRxiv2024

Acute infectious mononucleosis generates persistent, functional EBNA-1 antibodies with high cross-reactivity to alpha crystalline beta

Epstein-Barr Virus (EBV) infects over 95% of the worlds population and is the most common cause of infectious mononucleosis (IM). Epidemiologic studies have linked EBV with certain cancers or autoimmune conditions, including multiple sclerosis (MS). Recent studies suggest that molecular mimicry between EBV proteins, particularly EBV nuclear antigen 1 (EBNA-1), and self-proteins is a plausible mechanism through which EBV infection may contribute to the development of autoimmune disorders. We used a systems immunology approach to investigate the magnitude, specificity, and functional properties of EBNA-1 specific antibodies in a cohort of 97 young adults with IM from presentation through 1-year post-primary infection compared to a control cohort of EBV-seropositive individuals. Levels of EBNA-1 specific IgG1 and IgG3 binding antibodies increased over the course of infection. EBNA-1 antibodies capable of mediating antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent complement deposition (ADCD) were detected at or after 6 months. Binding and ADCP- and ADCD-leveraged antibodies primarily targeted a region of EBNA-1 known to elicit cross-reactive antibodies to several self-peptides in individuals with MS. Significantly higher binding and ADCD-active antibodies targeting EBNA-1 were observed in individuals with at least one HLA-DRB1*15:01 allele, a known genetic risk factor for MS; Importantly, high levels of antibodies capable of binding alpha crystalline beta (CRYAB) and mediating complement deposition were detected at 6 months and 1-year following IM; CRYAB antibodies were resistant to denaturing forces, indicating an affinity matured response. Blocking experiments confirmed that CRYAB antibodies were cross-reactive with EBNA-1. Altogether, these results demonstrate that high levels of functional antibodies targeting EBNA-1 are generated in early EBV infection, some of which are cross-reactive with CRYAB. Further investigation is warranted to determine how these antibody responses may contribute to the subsequent development of MS.

immunology↗

bioRxiv2020

SwarmTCR: a computational approach to predict the specificity of T Cell Receptors

MotivationComputationally predicting the specificity of T cell receptors can be a powerful tool to shed light on the immune response against infectious diseases and cancers, autoimmunity, cancer immunotherapy, and immunopathology. With more T cell receptor sequence data becoming available, the need for bioinformatics approaches to tackle this problem is even more pressing. Here we present SwarmTCR, a method that uses labeled sequence data to predict the specificity of T cell receptors using a nearest-neighbor approach. SwarmTCR works by optimizing the weights of the individual CDR regions to maximize classification performance. ResultsWe compared the performance of SwarmTCR against a state-of-the-art method (TCRdist) and showed that SwarmTCR performed significantly better on epitopes EBV-BRLF1300, EBV-BRLF1109, NS4B214-222 with single cell data and epitopes EBV-BRLF1300, EBV-BRLF1109, IAV-M158 with bulk sequencing data ( and {beta} chains). In addition, we show that the weights returned by SwarmTCR are biologically interpretable. AvailabilitySwarmTCR is distributed freely under the terms of the GPL-3 license. The source code and all sequencing data are available at GitHub (https://github.com/thecodingdoc/SwarmTCR) Contactdghersi@unomaha.edu

bioinformatics↗

bioRxiv2020

Epstein Barr virus epitope/MHC interaction combined with convergent recombination drive selection of diverse T cell receptor a and b repertoires

Recognition modes of individual T cell receptors (TCR) are well studied, but factors driving the selection of TCR repertoires from primary through persistent human virus infections are less well understood. Using deep sequencing, we demonstrate a high degree of diversity of EBV-specific clonotypes in acute infectious mononucleosis. Only 9% of unique clonotypes detected in AIM persisted into convalescence; the majority (91%) of unique clonotypes detected in AIM were not detected in convalescence and were seeming replaced by equally diverse "de-novo" clonotypes. The persistent clonotypes had a greater probability of being generated than non-persistent due to convergence recombination of multiple nucleotide sequences to encode the same amino acid sequence, as well as the use of shorter CDR3 regions with fewer nucleotide additions (i.e. sequences closer to germline). Moreover, the two most immunodominant HLA-A2-restricted EBV epitopes, BRLF1109 and BMLF1280, show highly distinct antigen-specific public (i.e. shared between individuals) features. In fact, TCR CDR3 motifs played a dominant role, while TCR{beta} played a minimal role, in the selection of TCR repertoire to an immunodominant EBV epitope, BRLF1. This contrasts with the majority of previously reported repertoires, which appear to be selected either on TCR{beta} CDR3 interactions with peptide/MHC or in combination with TCR CDR3. Understanding of how TCR/peptide/MHC complex interactions drive repertoire selection can be used to develop optimal strategies for vaccine design or generation of appropriate adoptive immunotherapies for viral infections in transplant settings or for cancer. ImportanceSeveral lines of evidence suggest that TCR and {beta} repertoires play a role in disease outcomes and treatment strategies during viral infections in transplant patients, and in cancer and autoimmune disease therapy. Our data suggests that it is essential that we understand the basic principles of how to drive optimum repertoires for both TCR chains, and {beta}. We address this important issue by characterizing the CD8 TCR repertoire to a common persistent human viral infection (EBV), which is controlled by appropriate CD8 T cell responses. The ultimate goal would be to determine if the individuals who are infected asymptomatically develop a different TCR repertoire than those that develop the immunopathology of AIM. Here, we begin by doing an in depth characterization of both CD8 T cell TCR and {beta} repertoires to two immunodominant EBV epitopes over the course of AIM identifying potential factors that may be driving their selection.

immunology↗

bioRxiv2018

High diversity, turnover, and structural constraints characterize TCR α and β repertoire selection

Recognition modes of individual T-cell receptors (TCR) are well studied, but how TCR repertoires are selected during acute through persistent human virus infections is less clear. Here, we show that persistent EBV-specific clonotypes account for only 9% of unique clonotypes but are highly expanded in acute infectious mononucleosis, and have distinct antigen-specific public features that drive selection into convalescence. The other 91% of highly diverse unique clonotypes disappear and are replaced in convalescence by equally diverse \"de-novo\" clonotypes. These broad fluctuating repertoires lend plasticity to antigen recognition and potentially protect against T-cell clonal loss and viral escape.

immunology↗