Immunology and Cancer Biology

Immunology and Cancer Biology

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Tung K.S.K.,University of Virginia | Harakal J.,Immunology and Cancer Biology | Harakal J.,University of Virginia | Qiao H.,University of Virginia | And 15 more authors.
Journal of Clinical Investigation | Year: 2017

Autoimmune responses to meiotic germ cell antigens (MGCA) that are expressed on sperm and testis occur in human infertility and after vasectomy. Many MGCA are also expressed as cancer/testis antigens (CTA) in human cancers, but the tolerance status of MGCA has not been investigated. MGCA are considered to be uniformly immunogenic and nontolerogenic, and the prevailing view posits that MGCA are sequestered behind the Sertoli cell barrier in seminiferous tubules. Here, we have shown that only some murine MGCA are sequestered. Nonsequestered MCGA (NS-MGCA) egressed from normal tubules, as evidenced by their ability to interact with systemically injected antibodies and form localized immune complexes outside the Sertoli cell barrier. NS-MGCA derived from cell fragments that were discarded by spermatids during spermiation. They egressed as cargo in residual bodies and maintained Treg-dependent physiological tolerance. In contrast, sequestered MGCA (S-MGCA) were undetectable in residual bodies and were nontolerogenic. Unlike postvasectomy autoantibodies, which have been shown to mainly target S-MGCA, autoantibodies produced by normal mice with transient Treg depletion that developed autoimmune orchitis exclusively targeted NS-MGCA. We conclude that spermiation, a physiological checkpoint in spermatogenesis, determines the egress and tolerogenicity of MGCA. Our findings will affect target antigen selection in testis and sperm autoimmunity and the immune responses to CTA in male cancer patients.

News Article | February 22, 2017

Two drugs used to treat asthma and allergies may offer a way to prevent a form of pneumonia that can kill up to 40 percent of people who contract it, researchers at the University of Virginia School of Medicine have found. Influenza pneumonia results when a flu infection spreads to alveolar air sacs deep within the lungs. Normally, a flu infection does not progress that far into the lower respiratory tract, but when it does, the results can be deadly. "If infection is severe enough, and the immune response is potent enough, you get injury to these cells and are no longer able to get sufficient oxygen exchange," explained UVA researcher Thomas J. Braciale, MD, PhD. "As a result of the infection of the cells, you can develop lethal pneumonia and die." But early administration of the two asthma drugs, Accolate and Singulair, could prevent the infection of the alveolar cells deep in the lower respiratory tract, Braciale's research suggests. "The excitement of this is the possibility of someone coming to see the physician with influenza that looks a little more severe than usual and treating them with the drugs Singulair or Accolate and preventing them from getting severe pneumonia," he said. "The fatality rate from influenza pneumonia can be pretty high, even with all modern techniques to support these patients. Up to 40 percent. So it's a very serious problem when it occurs." Unlike bacterial pneumonia, influenza pneumonia is caused by a virus. That makes it very difficult to treat - and makes the possibility of prevention all the more tantalizing. "When we look at pandemic strains of influenza that have high mortality rates, one of the best adaptations of those pandemic viruses is their ability to infect these alveolar epithelial cells," explained researcher Amber Cardani, PhD. "It's one of the hallmarks for certain strains that cause the lethality in these pandemics." Once influenza spreads deep into the lungs, the body's own immune response can prove harmful, resulting in severe damage to the alveolar air sacs. "It's an important observation the field is coming to," Cardani said. "We really need to limit the infection of these lower respiratory airways." The researchers determined that the alveolar epithelial cells are typically protected from influenza infection by immune cells called alveolar macrophages. In some instances, however, the flu virus can prevent the macrophages from carrying out their protective function, allowing the epithelial cells to become vulnerable to infection. "It's not as though they lack alveolar macrophages, it's just that their alveolar macrophages don't work right when they get exposed to the flu," Braciale said. "And those are the types of patients, who potentially would eventually go to the intensive care unit, that we think could be treated early in infection with Accolate or Singulair to prevent infection of these epithelial cells and prevent lethal infection." For their next steps, the researchers are consulting with colleagues to determine if patients being treated with Accolate and Singulair are less likely to develop influenza pneumonia during flu outbreaks. "This was a totally unexpected observation," Braciale said. "When I told multiple colleagues who are infectious disease or pulmonary physicians, they were absolutely flabbergasted." The findings have been published by the scientific journal PLOS Pathogens. It was written by Cardani, Adam Boulton, Taeg S. Kim and Braciale. Braciale and Cardani are both part of UVA's Department of Microbiology, Immunology and Cancer Biology and UVA's Beirne B. Carter Center for Immunology Research. Braciale's primary appointment is with the Department of Pathology. The work was supported by the National Institutes of Health, grant R01AI015608-35, and the NIH's National Institute of General Medical Sciences, grants T32 GM007055 and T32 GM007055.

Ta H.Q.,Immunology and Cancer Biology | Gioeli D.,Immunology and Cancer Biology | Gioeli D.,University of Virginia
Endocrine-Related Cancer | Year: 2014

It is increasingly clear that castration-resistant prostate cancer (PCa) is dependent on the androgen receptor (AR). This has led to the use of anti-androgen therapies that reduce endogenous steroid hormone production as well as the use of AR antagonists. However, the AR does not act in isolation and integrates with a milieu of cell-signaling proteins to affect cell biology. It is well established that cancer is a genetic disease resulting from the accumulation of mutations and chromosomal translocations that enables cancer cells to survive, proliferate, and disseminate. To maintain genomic integrity, there exists conserved checkpoint signaling pathways to facilitate cell cycle delay, DNA repair, and/or apoptosis in response to DNA damage. The AR interacts with, affects, and is affected by these DNA damage-response proteins. This review will focus on the connections between checkpoint signaling and the AR in PCa. We will describe what is known about how components of checkpoint signaling regulate AR activity and what questions still face the field. © 2014 Society for Endocrinology

Johnson J.M.,Immunology and Cancer Biology | Li M.,Immunology and Cancer Biology | Smith J.S.,Immunology and Cancer Biology | French S.L.,University of Virginia | And 3 more authors.
Molecular and Cellular Biology | Year: 2013

Ribosomal DNA (rDNA) genes in eukaryotes are organized into multicopy tandem arrays and transcribed by RNA polymerase I. During cell proliferation, ~50% of these genes are active and have a relatively open chromatin structure characterized by elevatedaccessibility to psoralen cross-linking. In Saccharomyces cerevisiae, transcription of rDNA genes becomes repressed and chromatin structure closes when cells enter the diauxic shift and growth dramatically slows. In this study, we found that nucleosomes are massively depleted from the active rDNA genes during log phase and reassembled during the diauxic shift, largely accounting for the differences in psoralen accessibility between active and inactive genes. The Rpd3L histone deacetylase complex was required for diauxic shift-induced H4 and H2B deposition onto rDNA genes, suggesting involvement in assembly or stabilization of the entire nucleosome. The Spt16 subunit of FACT, however, was specifically required for H2B deposition, suggesting specificity for the H2A/H2B dimer. Miller chromatin spreads were used for electron microscopic visualization of rDNA genes in an spt16 mutant, which was found to be deficient in the assembly of normal nucleosomes on inactive genes and the disruption of nucleosomes on active genes, consistent with an inability to fully reactivate polymerase I (Pol I) transcription when cells exit stationary phase. © 2013, American Society for Microbiology. All Rights Reserved.

Koryakina Y.,Immunology and Cancer Biology | Ta H.Q.,Immunology and Cancer Biology | Gioeli D.,Immunology and Cancer Biology | Gioeli D.,University of Virginia
Endocrine-Related Cancer | Year: 2014

The androgen receptor (AR) is a ligand-regulated transcription factor that belongs to the family of nuclear receptors. In addition to regulation by steroid, the AR is also regulated by post-translational modifications generated by signal transduction pathways. Thus, the AR functions not only as a transcription factor but also as a node that integrates multiple extracellular signals. The AR plays an important role in many diseases, including complete androgen insensitivity syndrome, spinal bulbar muscular atrophy, prostate and breast cancer, etc. In the case of prostate cancer, dependence on AR signaling has been exploited for therapeutic intervention for decades. However, the effectiveness of these therapies is limited in advanced disease due to restoration of AR signaling. Greater understanding of the molecular mechanisms involved in AR action will enable the development of improved therapeutics to treat the wide range of AR-dependent diseases. The AR is subject to regulation by a number of kinases through post-translational modifications on serine, threonine, and tyrosine residues. In this paper, we review the AR phosphorylation sites, the kinases responsible for these phosphorylations, as well as the biological context and the functional consequences of these phosphorylations. Finally, what is known about the state of AR phosphorylation in clinical samples is discussed. © 2014 Society for Endocrinology. Published by Bioscientifica Ltd.

Moreau G.B.,Immunology and Cancer Biology | Mann B.J.,Immunology and Cancer Biology
Virulence | Year: 2013

Francisella tularensis is a highly virulent bacterial pathogen that is easily aerosolized and has a low infectious dose. As an intracellular pathogen, entry of Francisella into host cells is critical for its survival and virulence. However, the initial steps of attachment and internalization of Francisella into host cells are not well characterized, and little is known about bacterial factors that promote these processes. This review highlights our current understanding of Francisella attachment and internalization into host cells. In particular, we emphasize the host cell types Francisella has been shown to interact with, as well as specific receptors and signaling processes involved in the internalization process. This review will shed light on gaps in our current understanding and future areas of investigation.

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