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Examining Autoimmune Sequelae During Cancer Immunotherapy In A Combined Autoimmune Thyroiditis And Tumor Mouse Model, Suresh Kari

Wayne State University Dissertations

Some clinical trials of immunotherapeutic agents against cancers have resulted in the development of autoimmune sequelae, including autoimmune thyroiditis. It has been suggested that the immunotherapy resulted in an alteration in the immunoregulatory mechanism(s). Using experimental autoimmune thyroiditis (EAT), a mouse model of Hashimoto's thyroiditis (HT), the importance of regulatory T cells (Tregs) has been well established; inhibition of Tregs leads to enhanced thyroiditis with repeated doses of mouse thyroglobulin (mTg) without adjuvant. To simulate cancer patients, we developed a combined EAT and tumor model in our EAT-susceptible mice (CBA/J). In first establishing the tumor model, we found Treg depletion …

Membrane-Bound Immunomodulators As Adjuvants In A Cell Culture-Based Avian Influenza Vaccine, David Daniel Fischer

Wayne State University Dissertations

Inactivated viral vaccines often generate suboptimal immune responses. Adjuvants are incorporated into vaccines to increase their immunogenicity, however currently available adjuvants have shortcomings which have limited their use in human and veterinary medicine. This necessitates the development of new adjuvants and delivery systems. Cytokines have been extensively tested as adjuvants in vaccines but challenges such as diffusion from antigen, short half-lives and production costs have been encountered. To address this, we developed a technology that efficiently produces inactivated, whole-virus influenza vaccine bearing membrane-bound cytokines. Tethering the cytokine to the antigen of interest keeps the immunomodulator in close contact with the …

Substance P And The Host Immune Response, Megan Elizabeth Foldenauer

Wayne State University Dissertations

This body of work examined the mechanism by which SP regulates host immunity, specifically, its control of growth factors and TLR expression in the P. aeruginosa-infected cornea. The role of mTOR and VIP in corneal infection and inflammation also was tested.

SP has a dual role in bacterial infection, unexpectedly upregulating growth factor production. This was accompanied by macrophage-specific upregulation of pro-inflammatory cytokines, downregulation of anti-inflammatory cytokines, and upregulation of anti-apoptotic genes, as well as a decrease in arginase-producing macrophages (M2 cells), important in stromal healing in these mice. All of these lead to worsened disease, despite the stimulatory effects …

Positive Emotions And Immune Respose To Influenza In Medically Stable Older Adults, Maryann J. Gierloff

Dissertations

Influenza results in substantial human suffering and health care costs. Evidence from psychoneuroimmunology suggests that emotions influence the immune system and may alter susceptibility to infectious diseases, like influenza. The purpose of this investigation was to evaluate the influence of psychological factors, health behaviors, circulating levels of proinflammatory cytokines and the development of influenza-like illness in older adults. Medically stable participants, 55 years of age and over, were enrolled from the general community and an elderly community. Psychological factors (emotions and perceived stress), health behaviors (sleep and physical activity) and plasma cytokine levels (IL-6 and IL-1B) were evaluated with respect …

Establishment Of A Quiescent Infection Of Hsv-1 In L929 Fibroblasts Using A Mitotic Inhibitor And Ifn-Γ, Neelam V. Shinde

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The goal for this study was to determine if a quiescent infection of HSV-1 could be induced in murine fibroblasts L929 by treating them with the anti-mitotic agent 5-fluoro 2'deoxy uridine (FUDR) alone and with interferon-γ. Since neurons are post-mitotic and exhibit a lower metabolic rate than other cells, fibroblasts were treated with FUDR to induce a post-mitotic state. The cell cycle arrest of fibroblasts would decrease the thymidylate metabolism and impair HSV-1 replication. An evaluation of cytopathic effects of FUDR was used to determine the optimal concentration which arrests cell growth and inhibits viral replication. Image J program developed …

Q-Ve-Oph, A Control Caspase Inhibitor For Analyzing Neuronal Death, Rebecca L. Bricker

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Sarin is a neurotoxin that has been used in terrorist attacks in Japan and is a potential bioterrorist weapon. It induces seizures by affecting the regulation of neurotransmitters in the brain. Seizures are directly correlated to neuronal damage. Two types of neuronal damage that can occur are apoptosis and necrosis. One of the main regions of the brain where neuronal death occurs is the hippocampus, which is involved in memory. Victims showed chronic decline of memory loss 3 and 7 years after the Tokyo's terrorist attack incident. There are treatments available that can break down sarin or can block the …

The Effects Of Enteropathogenic And Commensal Escherichia Coli On Tight Junction Permeability, Hilary Kaye Allen

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The intestinal mucosa maintains a barrier between materials from the external environment and the internal environment of the host. Disruption of the gut wall integrity is involved in the development of various intestinal diseases, such as Irritable Bowel Syndrome (IBS) and Crohn's disease. The intestinal mucosa is lined with epithelial cells that are connected by tight junctions, the intercellular junctions that form a selectively permeable barrier between paracellular pathways. Enteric pathogens, such as enteropathogenic Escherichia coli (EPEC), can disrupt the tight junctions of epithelial cells by altering the cellular cytoskeleton or by directly affecting tight junction proteins. Commensal Escherichia coli …

Mhc Class I Expression In Murine Fibroblast And Keratinocyte Cell Lines During The First Twenty-Four Hours Of Infection With Herpes Simplex Virus-1 (Hsv-1), Prasanthi Kumchala

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The hypothesis of this study is: HSV-1 infection of murine fibroblasts and keratinocytes inhibits expression of MHC class I molecules during first 24 hours of infection. IFN-γ pretreatment of fibroblasts protected the cells from virus-induced inhibition of MHC class I expression, but did not protect keratinocytes. Herpesviruses are known for their ability to establish persistent infections. Herpesviruses exert many different ways to suppress host defense mechanisms. One such way is by down regulating expression of the major histocompatibility complex I (MHC I) molecules in infected cells. Epidermal cells such as keratinocytes are the major sites for herpes simplex virus type …

The Effects Of Hsv-1 Challenge On Polarized Murine Macrophages: An In Vitro Model Using The J774a.1 Murine Macrophage Cell Line, Adam Craig Reichard

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In our current study we examined the effects of HSV-1 challenge on J774A.1 macrophages polarized to either a proinflammatory (M1) or anti-inflammatory (M2) phenotype. Polarized J774A.1 macrophages were characterized using CD14-CD86 and SOCS1-SOCS3 expression levels. SOCS proteins are a family of proteins that are capable of inhibiting cytokine-signaling pathways. HSV-1 up regulates expression of SOCS1 protein levels in infected cells, inhibiting the ability of infected cells to produce proinflammatory products (Nowoslawski Akhtar and Benveniste, 2011). This study shows that signals within the microenvironment play a greater role in macrophage polarization, and SOCS1-SOCS3 expression levels, than does HSV-1 challenge. M1 macrophages …

Suppressor Of Cytokine Signaling (Socs) 1 & 3 Expression In Hsv-1- Infected And Interferon-Γ-Treated Neuro-2a Cells, Melinda Jones

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This study examined the effects of HSV-1 infection and IFN-γ treatment on Neuro-2A cells. HSV-1 induces expression of SOCS1 and SOCS3 in infected cells, inhibiting the ability of these cells to produce the pro inflammatory, antiviral cytokine IFN-γ (Nowoslawski and Benveniste, 2011). SOCS1 and SOCS3 levels were determined in IFN-γ-treated cells, virus-infected cells, and cells that were both IFN-γ-treated and virus-infected. Results were compared with untreated, uninfected control cells. Flow cytometry data analysis showed a slight decrease in SOCS1 and SOCS3 protein levels in cells treated with IFN-γ for 6 hours compared to control cells. A significant decrease in SOCS1 …

The Construction Of A Plasmid For Detecting The Pathway Of Arginine Metabolism In Human Macrophages: A Real-Time Assessment Of Macrophage Polarity, Benjamin A. Holmes

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Macrophages are "first responders", innate immune system cells which quickly arrive to a site of infection and injury, consuming cell debris and foreign matter and recruiting other immune system cells to the area. While historically they have been thought to react uniformly to all challenges, the discovery of toll-like receptors has shown that macrophages actually work closely with the adaptive immune system in fine-tuning the immune response. Furthermore, it has recently been discovered that macrophages can become polarized to one of two subtypes-M1 or M2.

M1 macrophages are efficient producers of reactive oxygen species, nitrogen intermediates, and inflammatory cytokines. They …

Rhodotorula Minuta Fungemia In A Ewe Lamb, C G. Chitko-Mckown, K A. Leymaster, M. P. Heaton, D D. Griffin, J K. Veatch, S A. Jones, M. L. Clawson

School of Veterinary and Biomedical Sciences: Faculty Publications

An 8-month-old crossbred ewe, normal upon physical examination, was humanely euthanized for tissue collection. After approximately 3 weeks in tissue culture, fungi began budding out of cells obtained from the choroid plexus. After an additional 3 weeks, budding was observed in kidney cell cultures and eventually in monocyte cultures as well. Serum from the lamb was submitted to the Veterinary Diagnostic Laboratory at Colorado State University for fungal diagnosis and was found negative for Aspergillus, Blastomyces, Coccidioidomycosis and Histoplasmosis. DNA was isolated from fungi collected from tissue culture supernatants and used in a set of pan-fungal PCR assays with DNA …

Posttranslational Modification Of Vesicular Stomatitis Virus Glycoprotein, But Not Jnk Inhibition, Is The Antiviral Mechanism Of Sp600125, Sabrina Marozin, Jennifer Altomonte, Sibylle Apfel, Phat X. Dinh, Enrico De Toni, Antonia Rizzani, Andreas Nüssler, Nobuyuki Kato, Roland M. Schmid, Asit K. Pattnaik, Oliver Eberta

School of Veterinary and Biomedical Sciences: Faculty Publications

Vesicular stomatitis virus (VSV), a negative-sense single-stranded-RNA rhabdovirus, is an extremely promising oncolytic agent for cancer treatment. Since oncolytic virotherapy is moving closer to clinical application, potentially synergistic combinations of oncolytic viruses and molecularly targeted antitumor agents are becoming a meaningful strategy for cancer treatment. Mitogenactivated protein kinase (MAPK) inhibitors have been shown to impair liver cell proliferation and tumor development, suggesting their potential use as therapeutic agents for hepatocellular carcinoma (HCC). In this work, we show that the impairment of MAPK in vitro did not interfere with the oncolytic properties of VSV in HCC cell lines. Moreover, the administration …

Identification Of Amino Acid Residues Important For Anti-Ifn Activity Of Porcine Reproductive And Respiratory Syndrome Virus Non-Structural Protein 1, Lalit Beura, Sakthivel Subramaniam, Hiep Vu, Byungjoon Kwon, Asit K. Pattnaik, Fernando A. Osorio

School of Veterinary and Biomedical Sciences: Faculty Publications

The non-structural protein 1 (nsp1) of porcine reproductive and respiratory syndrome virus is partly responsible for inhibition of type I interferon (IFN) response by the infected host. By performing alanine-scanning mutagenesis, we have identified amino acid residues in nsp1α and nsp1β~ (the proteolytic products of nsp1) that when substituted with alanine(s) exhibited significant relief of IFNsuppression. A mutant virus (16-SA, in which residues 16-20 of nsp1β were substituted with alanines) encoding mutant nsp1β recovered from infectious cDNA clone was shown to be attenuated for growth in vitro and induced significantly higher amount of type I IFN transcripts in infected macrophages. …

A Single Amino Acid Change Resulting In Loss Of Fluorescence Of Egfp In A Viral Fusion Protein Confers Fitness And Growth Advantage To The Recombinant Vesicular Stomatitis Virus, Phat X. Dinh, Debasis Panda, Phani B. Das, Subash C. Das, Anshuman Das, Asit K. Pattnaik

School of Veterinary and Biomedical Sciences: Faculty Publications

Using a recombinant vesicular stomatitis virus encoding eGFP fused in-frame with an essential viral replication protein, the phosphoprotein P, we show that during passage in culture, the virus mutates the nucleotide C289 within eGFP of the fusion protein PeGFP to A or T, resulting in R97S/C amino acid substitution and loss of fluorescence. The resultant non-fluorescent virus exhibits increased fitness and growth advantage over its fluorescent counterpart. The growth advantage of the non-fluorescent virus appears to be due to increased transcription and replication activities of the PeGFP protein carrying the R97S/C substitution. Further, our results show that the R97S/C mutation …

Amino Acid Residues In The Non-Structural Protein 1 Of Porcine Reproductive And Respiratory Syndrome Virus Involved In Down-Regulation Of Tnf-Cx Expression In Vitro And Attenuation In Vivo, Sakthivel Subramaniam, Lalit Beura, Byungjoon Kwon, Asit K. Pattnaik, Fernando A. Osorio

School of Veterinary and Biomedical Sciences: Faculty Publications

Porcine reproductive and respiratory syndrome virus (PRRSV) suppresses tumor necrosis factor-alpha (TNF-α) production at both transcriptional and post-transcriptional levels by its non-structural proteins 1α and 1β (Nsp1α and Nsp1β). To identifY the amino acid residues responsible for this activity, we generated several alanine substitution mutants of Nsp1α and Nsp1β. Examination of the mutant proteins revealed that Nsp1α residues Gly90, Asn91 , Arg97, Argl 00 and Arg124 were necessary for TNF-α promoter suppression, whereas several amino acids spanning the entire Nsp1β ~ were found to be required for this activity. Two mutant viruses, with mutations at Nsp1α Gly90 or Nsp1β residues …

Staphylococcal Response To Oxidative Stress, Rosmarie Gaupp, Nagender Ledala, Greg A. Somerville

School of Veterinary and Biomedical Sciences: Faculty Publications

Staphylococci are a versatile genus of bacteria that are capable of causing acute and chronic infections in diverse host species. The success of staphylococci as pathogens is due in part to their ability to mitigate endogenous and exogenous oxidative and nitrosative stress. Endogenous oxidative stress is a consequence of life in an aerobic environment; whereas, exogenous osidative and nitrosative stress are often due to the bacteria's interaction with host immune systems. To overcome the deleterious effects of oxidative and nitrosative stress, staphylococci have evolved protection, detoxification, and repair mechanisms that are controlled by a network of regulators. In this review, …

A New Species Of Molinema (Nematoda: Onchocercidae) In Bolivian Rodents And Emended Description Of Litomosoides Esslingeri Bain, Petit, And Diagne, 1989, Juliana Notarnicola, F. Agustin Jimenez Ruiz, Scott Lyell Gardner

Harold W. Manter Laboratory of Parasitology: Faculty Publications

We report the distribution of 2 species of filarioid nematodes occurring in different hosts in the central region of South America. Molinema boliviensis n. sp. was recorded as a parasite of sigmodontine and echymyid rodents in Bolivia, and Litomosoides esslingeri was recorded in sigmodontine and ctenomyid rodents from Bolivia and Argentina. Molinema boliviensis n. sp. shares several similarities with other species reported in spiny rats; however, it can be easily differentiated by the presence of a flat anterior end, gradually tapering lappets and a tubercle present in posterior end, a short, uniform buccal capsule, an oval-shaped vagina vera, and a …

A New Genus And Species Of Lungworm (Nemata: Metastrongyloidea) From Akodon Mollis Thomas, 1894 (Rodentia: Cricetidae) In Peru, Maria Elizabeth Morales, Scott Lyell Gardner, John E. Ubelaker

Harold W. Manter Laboratory of Parasitology: Faculty Publications

Akodonema luzsarmientae n.g., n.sp. (Nemata: Metastrongyloidea) is described from the pulmonary arteries and heart from several individuals of "soft grass mouse," Akodon mollis (Rodentia: Cricetidae), collected in the region of Ancash, Peru. The new genus and species is distinguished by a reduction of the dorsal ray to two small widely separated papillae.

New Species Of Arostrilepis (Eucestoda: Hymenolepididae) In Members Of Cricetidae And Geomyidae (Rodentia) From The Western Nearctic, Arseny A. Makarikov, Scott Lyell Gardner, Eric P. Hoberg

Harold W. Manter Laboratory of Parasitology: Faculty Publications

Specimens originally identified as Arostrilepis horrida from the Nearctic are revised, contributing to the recognition of a complex of cryptic species distributed across the Holarctic region. Previously unrecognized species are described based on specimens in cricetid (Neotominae) and geomyid rodents. Arostrilepis mariettavogeae n. sp. in Peromyscus californicus from Monterey County, California, and Arostrilepis schilleri n. sp. in Thomomys bulbivorus from Corvallis, Oregon, are characterized. Consistent with recent studies defining diversity in the genus, form, size, and spination (pattern, shape, and size) of the cirrus are diagnostic; species are further distinguished by the relative position and length of the cirrus sac …

Zoonotic And Human Parasites Of Inhabitants Of Cueva De Los Muertos Chiquitos, Rio Zape Valley, Durango, Mexico, F. Agustín Jiménez-Ruiz, Scott Lyell Gardner, Adauto Araújo, Martín Horacio Fugassa, Richard H. Brooks, Elizabeth Racz, Karl J. Reinhard

Harold W. Manter Laboratory of Parasitology: Faculty Publications

We present the first reconstruction of the parasitoses among the people of the Loma San Gabriel culture, as represented by 36 coprolites excavated from the Cueva de los Muertos Chiquitos in Durango, Mexico. The coprolites date to approximately 1,400-yr ago. Species identified based on eggs recovered include the trematode Echinostoma sp., the tapeworms Hymenolepis sp. and Dipylidium caninum, and the nematodes Ancylostoma duodenale, Enterobius vermicularis, and Trichuris trichiura. After rehydration and screening, 2 methods were used to recover eggs from these samples including spontaneous sedimentation and flotation. Samples were analyzed by 3 different laboratories for independent …

Discovery And Description Of The "Davtiani" Morphotype For Teladorsagia Boreoarcticus (Trichostrongyloidea: Ostertagiinae) Abomasal Parasites In Muskoxen, Ovibos Moschatus, And Caribou, Rangifer Tarandus, From The North American Arctic: Implications For Parasite Faunal Diversity, Eric P. Hoberg, Arthur Abrams, Patricia A. Pilitt, Susan J. Kutz

Harold W. Manter Laboratory of Parasitology: Faculty Publications

Collections to explore helminth diversity among free-ranging ungulates in the North American Arctic revealed the occurrence of a third male, or "davtiani," morphotype for Teladorsagia boreoarcticus. Designated as T. boreoarcticus forma (f.) minor B, the males occurred with T. boreoarcticus f. major and T. borearcticus f. minor A in endemic populations of muskoxen (Ovibos moschatus wardi) and barrenground caribou (Rangifer tarandus groenlandicus) on Victoria Island, Nunavut, Canada, and in muskoxen and Peary caribou (Rangifer tarandus pearyi) on Banks Island, Northwest Territories, Canada. These specimens differ from conspecific morphotypes in the structure …

Synthesizing Parasitology With Archaeology In Paleopathology, Karl Reinhard, Adauto Araujo

Karl Reinhard Publications

Parasitology is the study of organisms that are symbiotic with other organisms. In this form of symbiosis, the parasite species by definition benefits from the interaction while the host is harmed to some degree. In actuality, some parasites benefit their hosts. The animals traditionally studied by parasitologists range from protozoa to arthropods, and include all types of internal and external worms. Ticks, fleas, lice, and a variety of insects that transmit parasites are also studied by parasitologists. Recently, a more holistic view of parasitism appeared, including bacteria and viruses. In essence, parasitology is the study of a certain kind of …

Emerging Microbial And Viral Infections Of The Central Nervous System, Brian J. Balin, Christine J. Hammond

PCOM Scholarly Works

This review focuses on emerging viral and bacterial infections in the human central nervous system (CNS) that are responsible for significant global morbidity and mortality. These infections include those responsible for acute neurological disease such as meningitis and encephalitis as well those associated with chronic neurodegenerative conditions. Recent changes in climate conditions and pollution have been precipitating factors leading to the emergence of many of these pathogenic organisms. In addition, increased urbanization, global travel, life span, and exposure to new vectors have promoted the organisms’ spread across the globe. Categorization of many of these organisms includes identification of new species, …

Efficacies Of Fenbendazole And Albendazole In The Treatment Of Commercial Turkeys Artificially Infected With Ascaridia Dissimilis, Jessica Perkins, Tom Yazwinski, Chris Tucker

Discovery, The Student Journal of Dale Bumpers College of Agricultural, Food and Life Sciences

The goal of this research was to determine the extent of resistance that turkey roundworms, Ascaridia dissimilis, have developed to anti-parasitic chemicals used in commercial poultry operations. Roundworm infections in turkeys have resulted in monetary losses for the poultry industry for years, generally due to poor feed conversion. The infection itself is subclinical and many turkeys have a light to moderate worm burden. Since parasitisms are light, this leads to the infections being noticed only during processing. Ascaridia dissimilis infections consist of adult worms and developing larvae with the latter comprising most of the worm burden and causing the most …

Protein Based Biomimetic Approachs To Surface Hemocompatibility And Biocompatibility Enhancement, Matthew Thomas Dickerson

Theses and Dissertations--Chemical and Materials Engineering

T. pallidum can survive a primary immune response and continue growing in the host for an extended period of time. T. pallidum is thought to bind serum fibronectin (FN) through Tp0483 on the surface to obscure antigens. A Tp0483 fragment (rTp0483) was adsorbed onto functionalized self-assembled monolayers (SAMs) with FN. FN capture by adsorbed rTp0483 depended greatly on surface chemistry with COO- groups being best for FN binding. Hemocompatibility was determined by analysis of plasma protein adsorption, intrinsic pathway activation, and platelet activation. rTp0483+FN bound an equal or lesser amount of fibrinogen (Fg), human serum albumin (HSA), and factor XII …

Promoting Thymopoiesis With Age: Potential Role Of The Transcription Factor Foxn1, Erin Christine Zook

Dissertations

It is known that the elderly are more susceptible to illnesses and infections and respond poorly to immunization. A contributing factor to a decrease in the immune response in the elderly is the decline in the production of naïve T cell by the thymus. In the thymus, the notch receptor expressed on early T cell progenitors (ETP) binds to its ligand expressed on thymic epithelial cells (TEC), signaling ETP to develop through a series of developmental stages before maturing into naive T cells. Because ETP are non-self renewing, the thymus relies on the bone marrow (BM) for a continuous supply …

Cloning Of The Gene, Purification As Recombinant Protein And Functional Characterization Of Leishmania Mexicana Cytochrome B5 Reductase, Ala Azhari

USF Tampa Graduate Theses and Dissertations

Leishmania are protozoan parasites that are transmitted by a sand fly vector. These parasites affect not only humans but also wild animals including domestic dogs and rodents, which form an additional challenge and public health problem to control the disease. Leishmaniasis is an important disease with worldwide distribution, including Saudi Arabia, the Middle East, and other tropical and subtropical areas around the world. Due to the expansion of irrigation and agricultural activities, more exposure to sand fly occurs, which leads to the expansion of leishmaniasis infections as newly emerging disease.

Emerging drug resistance in leishmaniasis is an additional problem, contributed …

Bacterial Host Interactions In Cystic Fibrosis, Máire Callaghan, Siobhan Mcclean

Articles

Chronic infection is a hallmark of cystic fibrosis (CF) and the main contributor to morbidity. Microbial infection in CF is complex, due to the number of different species that colonise the CF lung. Their colonisation is facilitated by a host response that is impaired or compromised by highly viscous mucous, zones of hypoxia and the lack of the cystic fibrosis transmembrane regulator (CFTR). Successful dominant CF pathogens combine an effective arsenal to establish infection and counter-attack the host response, together with an ability to adapt readily to an unfavourable environment. Hypermutability is common among CF pathogens facilitating adaptation and as …

Coxsackievirus B3 Infection Leads To The Generation Of Cardiac Myosin Heavy Chain-Α-Reactive Cd4 T Cells In A/J Mice, Arunakumar Gangaplara, Chandirasegaran Massilamany, Deborah M. Brown, Gustavo A. Delhon, Asit K. Pattnaik, Nora Chapman, Noel Rose, David J. Steffen, Jay Reddy

Jay Reddy Publications

Enteroviruses like coxsackievirus B3 (CVB3) are common suspects in myocarditis/dilated cardiomyopathy patients. Autoimmunity has been proposed as an underlying mechanism, but direct evidence of its role is lacking. To delineate autoimmune response in CVB3 myocarditis, we used IA^k dextramers for cardiac myosin heavy chain (Myhc)-α 334–352. We have demonstrated that myocarditis-susceptible A/J mice infected with CVB3 generate Myhc-α-reactive CD4 T cells and such a repertoire was absent in naïve mice as measured by proliferative response to Myhc-α 334–352 and IA^k dextramer staining. We also detected Myhc-α 334–352 dextramer⁺ cells in the hearts of CVB3-infected mice. The autoreactive …