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The human leukocyte antigen (HLA) system plays a pivotal role in the immune response to viral infections, mediating the presentation of viral peptides to T cells and influencing both the strength and specificity of the host immune response. Variations in HLA genotypes across individuals lead to differences in susceptibility to viral infection and severity of illness. This study uses observations from the early phase of the COVID-19 pandemic to explore how specific HLA class I molecules affect clinical responses to SARS-CoV-2 infection. By analyzing paired high-resolution HLA types and viral genomic sequences from 60 patients, we assess the relationship between predicted HLA class I peptide binding repertoires and infection severity as measured by the sequential organ failure assessment score. This approach leverages functional convergence across HLA-C alleles to identify relationships that may otherwise be inaccessible due to allelic diversity and limitations in sample size. Surprisingly, our findings show that severely symptomatic infection in this cohort is associated with disproportionately abundant binding of SARS-CoV-2 structural and non-structural protein epitopes by patient HLA-C molecules. In addition, the extent of overlap between a given patient's predicted HLA-C and HLA-A peptide binding repertoires correlates with worse prognoses in this cohort. The findings highlight immunologic mechanisms linking HLA-C molecules with the human response to viral pathogens that warrant further investigation.

Immune checkpoint inhibitors (ICI) are important treatment options for metastatic non-small cell lung cancer (mNSCLC). However, not all patients benefit from ICIs and can experience immune-related adverse events (irAEs). Limited understanding exists for germline determinants of ICI efficacy and toxicity, but Human Leukocyte Antigen (HLA) genes have emerged as a potential predictive biomarker. We performed HLA typing on 85 patients with mNSCLC, on ICI therapy and analyzed the impact of HLA Class II genotype on progression free survival (PFS), overall survival (OS), and irAEs. Most patients received pembrolizumab (83.5%). HLA-DRB4 genotype was seen in 34/85 (40%) and its presence correlated with improved OS in both univariate (p = 0.022; 26.3 months vs 10.2 months) and multivariate analysis (p = 0.011, HR 0.49, 95% CI [0.29, 0.85]). PFS did not reach significance (univariate, p = 0.12, 8.2 months vs 5.1 months). Eleven patients developed endocrine irAEs. HLA-DRB4 was the predominant genotype among these patients (9/11, 81.8%). Cumulative incidence of endocrine irAEs was higher in patients with HLA-DRB4 (p = 0.0139). Our study is the first to suggest that patients with metastatic NSCLC patients on ICI therapy with HLA-DRB4 genotype experience improved survival outcomes. Patients with HLA-DRB4 had the longest median OS (26.3 months). Additionally, we found a correlation between HLA-DRB4 and the occurrence of endocrine irAEs., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Infections have been associated with rejection episodes in solid organ transplant recipients. We report an association between COVID-19 infection and heart transplant (HT) rejection., Case Description: The patient was 14 years old and 6.5 years post-HT. He developed symptoms of rejection within 2 weeks of COVID exposure and presumed infection., Conclusions: In this case, COVID-19 infection closely preceded significant rejection and graft dysfunction. Further study is needed to establish a correlation between COVID-19 infection and rejection in HT patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Donor-recipient matching is a highly individualized and complex component of solid organ transplantation. Flowcytometry crossmatching (FC-XM) is an integral step in the matching process that is used to detect pre-formed deleterious anti-donor immunoglobulin. Despite high sensitivity in detecting cell-bound immunoglobulin, FC-XM is not able to determine the source or function of immunoglobulins detected. Monoclonal antibody therapeutic agents used in a clinic can interfere with the interpretation of FC-XM. We combined data from the prospectively maintained Antibody Society database and Human Protein Atlas with a comprehensive literature review of PubMed to summarize known FC-XM-interfering antibody therapeutics and identify potential interferers. We identified eight unique FC-XM-interfering antibody therapeutics. Rituximab (anti-CD20) was the most-cited agent. Daratumuab (anti-CD38) was the newest reported agent. We identified 43 unreported antibody therapeutics that may interfere with FC-XM. As antibody therapeutic agents become more common, identifying and mitigating FC-XM interference will likely become an increased focus for transplant centers.

Unrelated allogeneic hematopoietic cell transplant (HCT) is a critical modality to treat hematologic malignancies. The current objective of donor selection is to match donor and recipient at the HLA (human leukocyte antigen) peptide-binding region which should lower the risk of graft-versus-host disease. However, depending on the patient's ethnicity/race, finding a matched donor is challenging, especially for HLA-DPB1 which is due to the weak linkage disequilibrium between HLA-DPB1 and the other HLA class II loci. Recent evidence, on the molecular level, has shown that certain HLA mismatches carry lower clinical risk. More specifically, there is an increasing understanding of polymorphisms of the innate and adaptive immune systems and their impact on transplant outcomes, allowing us to expand our "toolkit" for optimization of donor selection in HCT. Therefore, in this review we discuss matching strategies based on comparing donor and recipient polymorphisms that may influence innate and adaptive immune response genes in allorecognition and the role of single nucleotide polymorphisms in non-HLA genes that have the potential for providing additional tools to refine risk stratification., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Chimerism testing provides informative clinical data regarding the status of a biological sample mixture. For years, this testing was achieved by measuring the peaks of informative short tandem repeat (STR) loci using capillary electrophoresis (CE). With the advent of next generation sequencing (NGS) technology, the quantification of the percentage of donor/recipient mixtures is more easily done using sequence reads in large batches of samples run on a single flow cell. In this study, we present data on using a FORENSIC NGS chimerism platform to accurately measure the percentage of donor/recipient mixtures. We were able to detect chimerism to a limit threshold of 1% using both STR and single nucleotide polymorphism (SNP) informative loci. Importantly, a significant correlation was observed between NGS and CE chimerism methods when compared at donor detection ranges from 1% to 10%. Furthermore, 100% accuracy was achieved through proficiency testing over six surveys. Its usefulness was expanded beyond this to help identify suitable donors for solid organ transplant patients using ancestry SNP profiles. In summary, the NGS method provides a sensitive and reliable alternative to traditional CE for chimerism testing of clinical samples., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

During simultaneous liver-kidney transplantation (SLK) in highly sensitized patients, donor specific anti-human leukocyte antigen antibodies (DSA, HLA) can be present prior to transplant leading to positive crossmatch, yet these recipients have relatively low incidences of acute rejection. The mechanisms and timing underlying immunologic changes that occur intra-operatively remain largely unknown. Therefore, we measured the intra- and peri-operative kinetics of anti-HLA antibodies in highly sensitized SLK recipients. In this study, pre- and post-operative blood samples were obtained from sensitized SLK candidates with documented DSA. Intra-operative samples were obtained from a sub-group of SLK recipients. Pretransplant anti-HLA antibody profiles were created and flow cytometry and anti-human globulin complement-dependent cytotoxic crossmatches were performed. Significant reductions in anti-HLA class I and II DSA were seen intra-operatively shortly after reperfusion of the liver allograft. This effect was most pronounced for anti-HLA class I DSA (mean change, -85%, p  < 0.05); changes to anti-HLA class II DSA were less robust (mean change, -47%, p  = 0.15). Importantly, non-DSA anti-HLA antibodies remained unchanged throughout the perioperative period, suggesting the mechanism(s) by which the liver lowers DSA levels are specific to the DSA. These data demonstrate the immunologic benefit of performing SLK is lasting and occurs very shortly after liver reperfusion., (© 2020 Published by Elsevier Inc.)

There is growing evidence supporting the genetic variability outside of HLA system that is contributing to the variation in transplant outcomes. Determining novel predictors could help to identify patients at risk and tailor their immunosuppressive regimens. This article discusses the various single nucleotide polymorphisms in costimulatory molecules and cytokines that have been evaluated for their effect on transplantation. An overview of how gene polymorphism studies are conducted and factors to consider in the experimental design to ensure meaningful data can be concluded are discussed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

HLA epitope matching provides a better approach to stratify patients at risk of developing antibody-mediated rejection compared with counting HLA mismatches. However, several immunologic parameters are not incorporated into these algorithms used to assess HLA epitopes, raising questions about the predictive value of these programs. Therefore, it is imperative to obtain more 3D structural data of antibody-antigen binding to "train" these computer algorithms. Also, mechanistic studies should be performed to prove these theoretic "epitopes." Most important, more information is needed to ensure these predictive computer algorithms are equitable and safe to use in clinical diagnostics before wide-scale implementation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is a metabolically demanding disease involving immune-mediated destruction of myelin in the central nervous system. We previously demonstrated a significant alteration in disease course in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS due to diet. Based on the established crosstalk between metabolism and gut microbiota, we took an unbiased sampling of microbiota, in the stool, and metabolites, in the serum and stool, from mice (Mus musculus) on the two different diets, the Teklad global soy protein-free extruded rodent diet (irradiated diet) and the Teklad sterilisable rodent diet (autoclaved diet). Within the microbiota, the genus Lactobacillus was found to be inversely correlated with EAE severity. Therapeutic treatment with Lactobacillus paracasei resulted in a significant reduction in the incidence of disease, clinical scores and the amount of weight loss in EAE mice. Within the metabolites, we identified shifts in glycolysis and the tricarboxylic acid cycle that may explain the differences in disease severity between the different diets in EAE. This work begins to elucidate the relationship between diet, microbiota and metabolism in the EAE preclinical model of MS and identifies targets for further study with the goal to more specifically probe the complex metabolic interaction at play in EAE that may have translational relevance to MS patients.

Seizure disorders are often associated with infectious etiologies. Infection, via the intracerebral (i.c.) route, of C57BL/6J mice with the Daniels (DA) strain of Theiler's murine encephalomyelitis virus (TMEV) results in approximately 50% of the mice developing acute behavioral seizures. TMEV-DA is the wild-type strain of the virus that replicates within the parenchyma of the brain. A variant of TMEV-DA, TMEV-H101, does not replicate within the parenchyma of the brain. However, infection with TMEV-H101 via the i.c. route still results in approximately 40% of the mice developing acute behavioral seizures. Infiltrating macrophages producing interleukin-6 (IL-6) have been implicated in the induction of acute seizures following TMEV-DA infection. We examined macrophage infiltration and microglial activation within the brain and cytokine levels in the periphery in mice infected with TMEV-DA or TMEV-H101 and assessed the effects of the addition of recombinant IL-6 to the periphery in wild-type and IL-6 knockout mice infected with TMEV-DA. We found that pathologic levels of IL-6 in the periphery may play a role in the development of seizures when viral replication within the brain is limited. Examination of the role played by the peripheral immune system in the development of seizures/epilepsy in the TMEV-induced seizure model, the first viral infection driven model for epilepsy, could lead to the elucidation of novel therapeutics.

The individual innate immune components, interleukin-6 and complement component C3, play a role in the development of acute seizures in the Theiler's murine encephalomyelitis virus-induced seizure model. We examined the mRNA expression of various other complement components, cytokines, chemokines, and major histocompatibility complex antigens both within brain and in isolated ramified microglial and infiltrating macrophage/activated microglial cell populations over a time course covering the first 3 days postinfection. We found that complement component C3 showed the greatest increase in expression in brain of all of the complement components assayed and its level of expression was higher in infiltrating macrophages/activated microglia than in ramified microglial cells.

Objective: Many things can impact the reproducibility of results from laboratory to laboratory. For example, food from various sources can vary markedly in composition. We examined the effects of two different food sources, the Teklad Global Soy Protein-Free Extruded Rodent Diet (irradiated diet) and the Teklad Sterilizable Rodent Diet (autoclaved diet), on central nervous system disease., Methods: Three preclinical models for human disease: Two different experimental autoimmune encephalomyelitis models (multiple sclerosis) and the Theiler's murine encephalomyelitis virus-induced seizure model (epilepsy), were examined for the effects of two different food sources on disease., Results: We found that mice fed the irradiated diet had more severe clinical disease and enhanced seizures compared with animals provided the autoclaved diet in both experimental autoimmune encephalomyelitis models examined and in the Theiler's murine encephalomyelitis virus-induced seizure model, respectively., Conclusions: Therefore, just altering the source of food (lab chow) can have marked effects on disease severity and outcome., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The presence of donor-specific HLA antibodies before or after transplantation may have different implications based on the antibody strength. Yet, current approaches do not provide information regarding the true antibody strength as defined by antigen-antibody dissociation rate. To assess currently available methods, we compared between neat mean fluorescence intensity (MFI) values, C1q MFI values, ethylenediaminetetraacetic acid (EDTA)-treated samples, as well as titration studies and peak MFI values of over 7000 Luminex-based single-antigen HLA antibody data points. Our results indicate that neat MFI values do not always accurately depict antibody strength. We further showed that EDTA treatment (6%) does not always remove all inhibitory factors compared with C1q or titration studies. In this study of patients presenting with multiple antibody specificities, a prozone effect was observed in 71% of the cohort (usually not affecting all antibody specificities within a single serum sample, though). Similar to titration studies, the C1q assay was able to address the issue of potential inhibition; however, its limitation is its low sensitivity and inability to detect the presence of weak antibodies. Titration studies are the only method among the approaches used in this study to provide information suggesting antigen-antibody dissociation rates and are, therefore, likely to provide better indication of true antibody strength., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The new national Kidney Allocation System of the Organ Procurement and Transplantation Network (OPTN), effective as of December 4, 2014, was designed to improve the chances of transplanting the most highly sensitized patients on the waitlist, those with calculated panel reactive antibody values of 98%, 99% and 100%. Recently, it was suggested that these highly sensitized patients will experience inequitable access, given the reported high prevalence of antibodies to HLA-DP, and the fact that only about 1/3 of deceased donors are typed for HLA-DP antigens. Here we report that 320/2948 flow cytometric crossmatches performed for the Northwestern transplant program over the past 28 months were positive solely due to HLA-DP donor-specific antibodies (11%; 16.5% of patients with HLA antibodies-sensitized patients). We further show that 58/207 (12%) HLA-DR serologically matched donor-recipient pairs had a positive B cell flow crossmatch due to donor-specific HLA class II antibodies, and 2/34 (6%) serologic zero-HLA-A-B-DR mismatch had a positive flow crossmatch due to HLA-DSA. We therefore provide information regarding the necessity and importance of complete donor HLA typing including both chains of the HLA-DP antigen (encoded by HLA-DPA1 and HLA-DPB1) at the time of organ offer., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Acthar gel is indicated for the treatment of acute exacerbations of multiple sclerosis (MS) in adults. Its effects on immune cells during a relapse are unknown. This study investigated the effects of Acthar in an animal model of relapsing-remitting MS, using SJL/J mice sensitized with myelin peptide. All animal studies were reviewed and approved by the University of Utah Institutional Animal Care and Use Committee and conducted in accordance with the guidelines prepared by the Committee on Care and Use of Laboratory Animals, Institute of Laboratory Animals Resources, National Research Council. Mice injected with Acthar to treat the second attack had a significantly lower mean clinical score during relapse and a significantly reduced cumulative disease burden compared to Placebo gel-treated mice. Furthermore, Acthar treatment ameliorated inflammation/demyelination in the spinal cord and markedly suppressed ex vivo myelin peptide-induced CD4(+) T cell proliferation.

The field of histocompatibility testing has seen significant changes and advancements in the past quarter of a century. The introduction of polymerase chain reaction amplification into routine human leukocyte antigen (HLA) typing has informed us on the magnitude of polymorphism among HLA alleles. Solid phase testing for antibodies has provided unparalleled insight into antibody specificity and the role of antibody mediated rejection in transplant outcomes. Herein, we provide a brief overview of advancements in the field that are currently in progress. We also provide our own personal opinion on what is on the horizon and the direction in which we think the field should progress., (Copyright© 2016 by the Terasaki Foundation Laboratory.)

Viruses use various mechanisms to evade clearance by the host. Investigating how a few changes in the genome of a non-lethal virus can lead to altered disease, from survivable to immunosuppression/death, would provide valuable information into viral pathogenesis. The Daniels strain of Theiler's murine encephalomyelitis virus causes an asymptomatic infection or acute encephalitis followed by viral clearance. A mutant, H101, carries several alterations in the viral genome. H101 infection causes profound immunosuppression and death. Thus, a virus that is normally cleared by its natural host can become lethal due to just a few changes in the viral genome., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The mouse MHC class Ib gene H2-T11 is 95% identical at the DNA level to H2-T23, which encodes Qa-1, one of the most studied MHC class Ib molecules. H2-T11 mRNA was observed to be expressed widely in tissues of C57BL/6 mice, with the highest levels in thymus. To circumvent the availability of a specific mAb, cells were transduced with cDNA encoding T11 with a substituted α3 domain. Hybrid T11D3 protein was expressed at high levels similar to control T23D3 molecules on the surface of both TAP(+) and TAP(-) cells. Soluble T11D3 was generated by folding in vitro with Qa-1 determinant modifier, the dominant peptide presented by Qa-1. The circular dichroism spectrum of this protein was similar to that of other MHC class I molecules, and it was observed to bind labeled Qa-1 determinant modifier peptide with rapid kinetics. By contrast to the Qa-1 control, T11 tetramers did not react with cells expressing CD94/NKG2A, supporting the conclusion that T11 cannot replace Qa-1 as a ligand for NK cell inhibitory receptors. T11 also failed to substitute for Qa-1 in the presentation of insulin to a Qa-1-restricted T cell hybridoma. Despite divergent function, T11 was observed to share peptide-loading specificity with Qa-1. Direct analysis by tandem mass spectrometry of peptides eluted from T11D3 and T23D3 isolated from Hela cells demonstrated a diversity of peptides with a clear motif that was shared between the two molecules. Thus, T11 is a paralog of T23 encoding an MHC class Ib molecule that shares peptide-binding specificity with Qa-1 but differs in function., (Copyright © 2014 by The American Association of Immunologists, Inc.)

Clinicopathological paradox has hampered significantly the effective assessment of the efficacy of therapeutic intervention for multiple sclerosis. Neuroimaging biomarkers of tissue injury could guide more effective treatment by accurately reflecting the underlying subclinical pathologies. Diffusion tensor imaging-derived directional diffusivity and anisotropy indices have been applied to characterize white matter disorders. However, these biomarkers are sometimes confounded by the complex pathologies seen in multiple sclerosis and its animal models. Recently, a novel technique of diffusion basis spectrum imaging has been developed to quantitatively assess axonal injury, demyelination and inflammation in a mouse model of inflammatory demyelination. Lenaldekar, which inhibits T-cell expansion in a non-cytolytic manner, has been shown to suppress relapses and preserve white matter integrity in mice with experimental autoimmune encephalomyelitis. In this study, relapsing-remitting experimental autoimmune encephalomyelitis was induced through active immunization of SJL/J mice with a myelin proteolipid protein peptide. The therapeutic efficacy of Lenaldekar treatment was evaluated via daily clinical score, cross-sectional ex vivo diffusion basis spectrum imaging examination and histological analysis. Lenaldekar greatly reduced relapse severity and protected white matter integrity in these experimental autoimmune encephalomyelitis mice. Diffusion basis spectrum imaging-derived axial diffusivity, radial diffusivity and restricted diffusion tensor fraction accurately reflected axonal injury, myelin integrity and inflammation-associated cellularity change, respectively. These results support the potential use of diffusion basis spectrum imaging as an effective outcome measure for preclinical drug evaluation., (Copyright © 2014 John Wiley & Sons, Ltd.)

Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervous system (CNS). Although the etiology of MS is unknown, genetic and environmental factors play a role. Infectious pathogens are the likely environmental factors involved in the development of MS. Pathogens associated with the development or exacerbation of MS include bacteria, such as Mycoplasma pneumoniae and Chlamydia pneumoniae, the Staphylococcus aureus-produced enterotoxins that function as superantigens, viruses of the herpes virus (Epstein-Barr virus and human herpesvirus 6) and human endogenous retrovirus (HERV) families and the protozoa Acanthamoeba castellanii. Evidence, from studies with humans and animal models, supporting the association of these various pathogens with the development and/or exacerbation of MS will be discussed along with the potential mechanisms including molecular mimicry, epitope spreading and bystander activation. In contrast, infection with certain parasites such as helminthes (Schistosoma mansoni, Fasciola hepatica, Hymenolepis nana, Trichuris trichiura, Ascaris lumbricoides, Strongyloides stercolaris, Enterobius vermicularis) appears to protect against the development or exacerbation of MS. Evidence supporting the ability of parasitic infections to protect against disease will be discussed along with a brief summary of a recent Phase I clinical trial testing the ability of Trichuris suis ova treatment to improve the clinical course of MS. A complex interaction between the CNS (including the blood-brain barrier), multiple infections with various infectious agents (occurring in the periphery or within the CNS), and the immune response to those various infections may have to be deciphered before the etiology of MS can be fully understood.

Viruses, such as HIV, hepatitis A, poliovirus, coxsackievirus B3 and foot-and-mouth disease virus, use a variety of mechanisms to suppress the human immune system in order to evade clearance by the host. Therefore, investigating how a few changes in the viral genome of a nonlethal virus can lead to an alteration in disease, from survivable to immunosuppression and death, would provide valuable information into viral pathogenesis. In addition, we propose that gaining a better insight into how these viruses suppress an antiviral immune response could lead to viral-based therapeutics to combat specifc autoimmune diseases such as multiple sclerosis and Type 1 diabetes.

In patients with multiple sclerosis (MS) and in mice with experimental autoimmune encephalomyelitis (EAE), proliferating autoreactive T cells play an important role in the pathogenesis of the disease. Due to the importance of these myelin-specific T cells, these cells have been therapeutic targets in a variety of treatments. Previously we found that Lenaldekar (LDK), a novel small molecule, could inhibit exacerbations in a preclinical model of MS when given at the start of an EAE exacerbation. In those studies, we found that LDK could inhibit human T cell recall responses and murine myelin responses in vitro. In these new studies, we found that LDK could inhibit myelin specific T cell responses through the insulin-like growth factor-1 receptor (IGF-1R) pathway. Alteration of this pathway led to marked reduction in T cell proliferation and expansion. Blocking this pathway could account for the observed decreases in clinical signs and inflammatory demyelinating disease, which was accompanied by axonal preservation. Our data indicate that IGF-1R could be a potential target for new therapies for the treatment of autoimmune diseases where autoreactive T cell expansion is a requisite for disease.

Aim: To determine whether modulation of T-cell responses by naturally occurring viral variants caused an increase in numbers of Tregs in HCV-infected patients., Patients Materials & Methods: Human peripheral blood mononuclear cells, having proliferative responses to a wild-type HCV-specific CD4 + T-cell epitope, were used to quantify, via proliferative assays, flow cytometry and class II tetramers, the effects of naturally occurring viral variants arising in the immunodominant epitope., Results: In combination, the wild-type and variant peptides led to enhanced suppression of an anti-HCV T-cell response. The variant had a lower avidity for the wild-type-specific CD4 + T cell. Variant-stimulated CD4 + T cells had increased Foxp3, compared with wild-type-stimulated cells., Conclusion: A stable viral variant from a chronic HCV subject was able to induce Tregs in multiple individuals that responded to the wild-type HCV-specific CD4 + T-cell epitope.

Purpose of Review: This review will explore two new aspects of the involvement of viruses in multiple sclerosis pathogenesis. The first aspect is the complex interactions between viruses. The second aspect is the proposal of a mechanism by which autoreactive T cells are able to escape thymic selection and potentially recognize self and a pathogen., Recent Findings: With regard to viruses, recent work has demonstrated that one virus may enhance the replication of another virus, potentially leading to an increase in inflammation and disease progression. Also, interactions between human endogenous retroviruses, which likely do not replicate, and certain herpes viruses, may also play a role in disease pathogenesis. Mechanistically, T cells expressing dual T-cell receptors would be able to recognize self and a foreign antigen specifically. Therefore, human endogenous retroviruses potentially play a role in multiple sclerosis pathogenesis, and both interactions between multiple viruses and autoreactive CD8(+) T cells with dual T-cell receptors may play a role in the pathogenesis of the disease., Summary: The complex interactions between multiple viral infections, either within the central nervous system or in the periphery, and the host immune response to viral infection may be such that a variety of viral specificities result in the activation of T cells that recognize self and induce multiple sclerosis. Therefore, it is unlikely that any one microbe will be determined to be the causative agent of multiple sclerosis as reflected by the number of potential triggering mechanisms of the disease.

Viral infections of the central nervous system (CNS) can trigger an antiviral immune response, which initiates an inflammatory cascade to control viral replication and dissemination. The extent of the proinflammatory response in the CNS and the timing of the release of proinflammatory cytokines can lead to neuronal excitability. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), two proinflammatory cytokines, have been linked to the development of acute seizures in Theiler's murine encephalomyelitis virus-induced encephalitis. It is unclear the extent to which the infiltrating macrophages versus resident CNS cells, such as microglia, contribute to acute seizures, as both cell types produce TNF-α and IL-6. In this study, we show that following infection a significantly higher number of microglia produced TNF-α than did infiltrating macrophages. In contrast, infiltrating macrophages produced significantly more IL-6. Mice treated with minocycline or wogonin, both of which limit infiltration of immune cells into the CNS and their activation, had significantly fewer macrophages infiltrating the brain, and significantly fewer mice had seizures. Therefore, our studies implicate infiltrating macrophages as an important source of IL-6 that contributes to the development of acute seizures.

AIMS: To determine if in vitro production of IL-22 and IL-17 correlated with resolution of HCV infection. MATERIALS #ENTITYSTARTX00026; METHODS: Human peripheral blood cells isolated from a well-defined cohort of resolved and chronic HCV-infected subjects were used to measure HCV-, influenza- and mitogen-activated T-cell proliferation. In addition, IL-22 and IL-17 production was measured via ELISAs and flow cytometry. RESULTS: Resolved HCV subjects had a significantly higher T-cell proliferative response to recombinant NS3 protein compared with chronic HCV subjects. Resolved subjects had a dose-dependent IL-22 response to recombinant NS3 compared with chronic HCV subjects. CONCLUSION: IL-22 production is associated with antigen-specific induction of CD4 (+) T cells in individuals that resolved HCV infection, suggesting a potential role for IL-22 in HCV clearance.

Immune-mediated diseases [multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE)] are driven by proliferating, highly activated autoreactive T-cells that are unresponsive to in vivo immunoregulatory mechanisms. The compound Lenaldekar (LDK) was identified in a zebrafish screen by inhibiting T-cell expansion. By monitoring mitogen- and antigen-driven proliferation, we found that LDK inhibited human and murine T-cell expansion in a non-cytolytic manner. This suppressive activity directly correlated with the degree of activation/proliferation of the T-cells. In testing LDK in an EAE model of MS, exacerbations were suppressed in treated animals. Therefore, LDK represents a novel therapeutic approach to T-cell-mediated autoimmune diseases., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Major histocompatibility complex class I-restricted CD8(+) cytotoxic T lymphocytes are involved in the pathogenesis of multiple sclerosis (MS) and both autoimmune, experimental autoimmune encephalomyelitis, and viral, Theiler's murine encephalomyelitis virus (TMEV) infection, animal models of MS. Following TMEV infection, certain T cell hybridomas, generated from cloned TMEV-induced CD8(+) T cells, were able to produce clinical signs of disease (flaccid hind limb paralysis) upon adoptive transfer into naive mice. Dual T cell receptors (TCR) are present on the surface of these cells as both Vβ3 and Vβ6 were detected by polymerase chain reaction (PCR) screening and flow cytometry and multiple Vα mRNAs were detected by PCR screening. This is the first demonstration of antiviral CD8(+) T cells having more than one TCR initiating an autoimmune disease in the natural host of the virus. We hypothesize that this is a potential mechanism for virus-induced autoimmune disease initiated by CD8(+) T cells.

A variety of mechanisms have been suggested as the means by which infections can initiate and/or exacerbate autoimmune diseases. One mechanism is molecular mimicry, where a foreign antigen shares sequence or structural similarities with self-antigens. Molecular mimicry has typically been characterized on an antibody or T cell level. However, structural relatedness between pathogen and self does not account for T cell activation in a number of autoimmune diseases. A proposed mechanism that could have been misinterpreted for molecular mimicry is the expression of dual T cell receptors (TCR) on a single T cell. These T cells have dual reactivity to both foreign and self-antigens leaving the host vulnerable to foreign insults capable of triggering an autoimmune response. In this review, we briefly discuss what is known about molecular mimicry followed by a discussion of the current understanding of dual TCRs. Finally, we discuss three mechanisms, including molecular mimicry, dual TCRs, and chimeric TCRs, by which dual reactivity of the T cell may play a role in autoimmune diseases.

Hepatitis C virus (HCV) has a high rate of replication and lacks RNA-proofreading capabilities, thereby leading to variant or mutant viruses circulating within the host as a quasispecies. Previous work in our laboratory identified viral variants that emerged in a class-II immunodominant epitope NS3(358-375) of the non-structural-3 (NS3) protein region of HCV, the sequence of which is based on genotype 1A, the most prevalent genotype in the United States. Further work suggested that positive immune selection pressure was driving viral variation. Paradoxically, viral variants account for only a small percentage of the circulating virus in human beings and in chimpanzees, suggesting that passive evasion is not the only means of escape by HCV. This observation suggests a unique pathogenesis for HCV as it persists in the host. In the current study, we hypothesize that viral variants are acting as altered peptide ligands (APLs). To test this hypothesis, we used cloned T cells specific for NS3(358-375) peptide, which demonstrated attenuated T-cell and interferon-γ (IFN-γ) responses to individual variant peptides, when compared with the NS3(358-375) stimulated T-cell clones. Furthermore, such variants could act as APLs, based on their ability to antagonize the IFN-γ proliferative responses of clones specific for NS3(358-375). In addition, major histocompatibility complex (MHC) class II tetramer staining demonstrated that variant peptide-MHC complexes were able to specifically bind to NS3(358-375) T-cell clones and that both the variant and NS3(358-375) tetramers were able to bind to the same CD4(+) T cells. Taken together, the results suggest that viral variants may act as APL to effectively blunt the T-cell response to an important HCV epitope., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Regulatory T cell markers are increased in chronically infected individuals with the hepatitis C virus (HCV), but to date, the induction and maintenance of Tregs in HCV infection has not been clearly defined. In this paper, we demonstrate that naturally occurring viral variants suppress T cell responses to cognate NS3(358-375) in an antigen-specific manner. Of four archetypal variants, S370P induced regulatory T cell markers in comparison to NS3(358-375)-stimulated CD4 T cells. Further, the addition of variant-specific CD4 T cells back into a polyclonal culture in a dose-dependent manner inhibited the T cell response. These results suggest that HCV is able to induce antigen-specific regulatory T cells to suppress the antiviral T cell response in an antigen-specific manner, thus contributing to a niche within the host that could be conducive to HCV persistence.

To address the question of whether human T cells are capable of recognizing novel isolates of influenza virus, in vitro responses to recombinant Ags and synthetic peptides derived from the sequences of H1, H3, and H5 were examined in a cohort of 64 individuals selected from a healthy blood donor population. Humans respond in vitro to H1 and H3 following exposure through natural infection and vaccination. Responses to H5 were well correlated with those to H1 or H3, and thus, a significant repertoire of H5-responsive T cells is present in many individuals; clear nonresponders to H1, H3, and H5, however, do exist. Differences were observed in the cytokine responses to H1, H3, and H5, whereas both IL-2 and IFN-gamma production characteristic of memory responses were observed for H1 and H3, and H5-specific responses elicited primarily IL-2 and little or no IFN-gamma, consistent with a naive T cell phenotype. Responses to all influenza HA were restricted by HLA-DR molecules. To address the structural basis for T cell recognition of H1 and H5, overlapping synthetic peptides were used to identify epitopes and to determine whether recognition of H5 was limited to homologous sequences in H1, the most closely related HA phylogenetically. Although responses were generally correlated, no complete structural overlap was observed. These results suggest that helper T cell cross reactivity between different influenza strains may impart cross-protection to H5N1 strain of influenza.