Browsing by Subject "Histocompatibility Antigens Class I"
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Item Functional Characterization of the HIV-1 NEF Acidic Cluster(2005-05-12) Baugh, Laura Louise; Garcia-Martinez, J. VictorThe human immunodeficiency virus (HIV) infects over 39.5 million people worldwide (UNAIDS/WHO 2006 Epidemic Report). Unfortunately, various socioeconomic factors have hastened the epidemic spread of HIV in Africa and in third world countries where many individuals do not have access to appropriate healthcare. Vaccines have, as of yet, been unsuccessful as a preventive measure; however, new measures, including peptide inhibitors and microbicides, are currently being developed and studied for their efficacy. The potential of finding new targets for controlling or preventing infection relies heavily on developments relating to the basic science of the virus as well as the host environment. HIV and simian immunodeficiency virus (SIV) encode an accessory protein Nef proposed to promote pathogenesis based on evidence from HIV-infected longterm nonprogressors and SIV studies in non-human primates. The pathogenic potential of Nef has been studied in relation to some of its in vitro effects including: (1) the downregulation of major histocompatibility complex I (MHC-I), (2) the downregulation of CD4, (3) infectivity enhancement, and (4) Pak2 activation. These in vitro effects, with the exception of CD4 downregulation, rely in part upon Nef's acidic cluster which has been reported to affect Nef's redirection of cell surface MHC-I to the trans-Golgi network by binding to the cytosolic adapter phosphofurin acidic cluster sorting-1 (PACS-1) (19, 147). Because Nef is potentially significant to the course of disease progression, correlations between the amino acid composition of the Nef acidic cluster and Nef activity were characterized. Nef acidic cluster mutants reducing the acidic residues in the cluster from 4 to 2, 1, and 0 were developed. Phenotypes for these mutants indicate at least one or more of the four acidic cluster glutamates are involved not only in MHC-I downregulation, but also Pak2 activation and infectivity enhancement. However, because partial activity is observed with one acidic residue and full activity with only two acidic residues, these data lead to the following conclusion: Although the Nef acidic cluster contributes to a conformational integrity important for Nef-mediated MHC-I downregulation as well as other Nef activities, it is not a prototypical acidic cluster determinant involved in PACS-1-mediated trafficking.Item Targeting the Neonatal Fc Receptor, FcRn, to Treat Autoimmunity and Elucidation of Sites of FcRn Function(2016-10-13) Challa, Dilip Kumar; Eberhart, Robert C.; Ward, E. Sally; Greenberg, Benjamin M.; Satterthwaite, Anne B.; Stüve, OlafThe neonatal Fc receptor, FcRn, is expressed in many different cell types and serves several functions, some of which are cell type-specific. A function common to most cell types that express this receptor is salvage of IgG from cellular degradation which is responsible for the long in vivo half-life of IgG. This property of IgG is responsible for its indispensable role in humoral immunity and also contributes to the successful use of IgGs as therapeutics. In autoimmunity, however, autoantibodies are generated that can contribute to pathology. FcRn-mediated salvage is also responsible for the long half-life of autoreactive IgGs. Therefore, this study employed an engineered antibody (Abdeg, a novel FcRn inhibitor) that lowers endogenous IgG levels by competing for binding to FcRn, to directly assess the effect of decreased antibody levels in an autoantibody-dependent murine model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Essentially, Abdeg delivery reduced the accumulation of autoantibodies in the target organs and ameliorated the disease. Autoreactive CD4+ T cells are also known to play an important role in the pathogenesis of autoimmune diseases. Thus, with the goal of inducing antigen-specific T cell tolerance, the current study employed immunoglobulin Fc engineering to develop a novel platform for the delivery of peptide epitopes as Fc-peptide fusions with different dynamic properties. Using very low doses of these engineered antigens to avoid anaphylactic shock, the study demonstrates that the longevity of the peptide antigen is the primary determinant of tolerance induction in a murine EAE model that is driven by autoreactive CD4+ T cells. Long-lived Fc-antigen fusions are effective tolerogens in both prophylactic and therapeutic treatments, although distinct mechanisms lead to tolerance in these two settings. Further, to identify the FcRn-expressing cell types that mediate the effects of Abdegs and Fc-antigen fusions on autoantibodies and autoreactive T cells, respectively, cre-loxp technology was used to generate multiple cell type-specific FcRn knockout mice. This study indicates that macrophages are the primary sites among hematopoietic cells where IgG homeostasis occurs. Collectively, these studies have led to an improved understanding of FcRn function at both the level of its sites of functional activity and targeting this receptor for therapy.Item Tissue-Specific Transplantation Antigens: Structurally Unique Isoforms of MHC-Related Proteins in Immunologically Tolerant Milieus(2009-01-14) Guidry, Paula Ann; Stroynowski, IwonaThe immune network of the small intestine must maintain tolerance to an immense and diverse community of commensal microorganisms and a broad array of dietary antigens while constantly at the ready for insult from a variety of infectious agents. Situated at the front lines of intestinal immune defense are intraepithelial lymphocytes, the largest population of T cells in the body whose functions are only recently beginning to be revealed. Key to unlocking the roles of these unique immune effectors in health and disease is a better understanding of the receptor/ligand interactions that instruct their education, maintenance and reactivity. Many lines of evidence investigating the identity and function of IEL ligands point to molecules of the nonclassical class I major histocompatibility complex. We describe here five nonclassical, or class Ib, MHC - H2-Bl, Tw5, Q1, Q2 and T3 - that are transcriptionally restricted to cells of the intestinal epithelium, in close association with IEL. Canonical and alternatively spliced transcripts of these class Ib MHC encode protein products that can be expressed at the cell surface and nonamer peptides capable of associating with the CD94/NKG2A inhibitory receptor ligand Qa-1. We and others have demonstrated that, in addition to alpha beta and gamma delta TCR, IEL are capable of expressing natural killer cell activating and inhibitory receptors including CD94/NKG2A, NKG2D, Ly49E and Ly49F. Thus, multiple products of gut-restricted class Ib MHC are positioned to associate with class I MHC-engaging T cell and NK cell receptors expressed by IEL. Since the intestine is not the only organ that must balance immune reactivity and tolerance, we wondered if tissue-specific class Ib MHC expressed in other tolerance-associated or immune privileged tissues have similar properties to gut-specific class Ib MHC. We found that liver-restricted Q10 and brain-expressed Q5, like gut-restricted class Ib MHC and human placental HLA-G, are also extensively alternatively spliced and encode nonamer peptides capable of engaging Qa-1. We postulate that these properties of tissue-specific class Ib MHC are critical to MHC-mediated tolerance induction and/or maintenance in tolerance-associated tissues.