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1.
Self Nonself ; 2(1): 43-48, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21776334

ABSTRACT

Half a century after the major histocompatibility complex (MHC) was discovered, its functional roles in health and disease remain poorly understood. Many hallmarks of the MHC, including its unusual evolution, structurefunction properties of its gene products and allele-specific associations with dozens of diseases and health traits cannot be convincingly explained by the tenets of existing paradigms. It is therefore becoming increasingly apparent that in order to better understand MHC-health/disease association-a phenomenon that impacts the health of millions-heterodox ideas are critically needed. Here we propose a testable, novel theory concerning the functional role of MHC molecules in health and disease. At the focus of this theory is an evolutionarily-conserved, tri-dimensional cusp-like prominence ('kink'), found in the midst of one of the two α helices that form the perimeter of the groove of all MHC molecules. Based on structural, functional and evolutionary considerations, as well as our recent experimental data, it is proposed here that the MHC cusp region is enriched in allele-specific signal transduction ligands that interact with non-MHC cell surface receptors and trigger signaling events. Aberrations in these pathways could lead to disease development, or affect the severity of such diseases.

2.
Vet Ophthalmol ; 14(3): 174-9, 2011 May.
Article in English | MEDLINE | ID: mdl-21521441

ABSTRACT

The aims of the study were (1) to quantify the influence of selected imaging parameters on the image quality (slice thickness, mAs, and beam orientation) defining optimal conditions for scan protocols and (2) to evaluate the benefits of the 3D reconstruction techniques for visualization of NDS structures in dogs. CT-DCG was performed bilaterally in 32 heads of dogs. CT transverse images were obtained using a combination of two slice thickness values (0.8 mm and 2 mm) and two mAs values (50 mAs and 300 mAs). Two beam projection orientations were also tested: transverse plane (perpendicular to the hard palate) and oblique to the hard palate. Three-dimensional images were obtained using Volume Rendering (VR). Transverse beam projection proved to be superior for the assessment of the inferior and superior lacrimal canaliculi and lacrimal sac. In this study, there was no statistical difference regarding mAs values (50 mAs and 300 mAs) and slice thickness values (0.8 mm and 2 mm). Three-dimensional images were helpful for the assessment of topographic relationship between nasolacrimal structures and cranial landmarks.


Subject(s)
Image Processing, Computer-Assisted , Nasolacrimal Duct/anatomy & histology , Tomography, X-Ray Computed/veterinary , Animals , Cadaver , Dogs , Female , Male , Skull/anatomy & histology
3.
FEBS Lett ; 585(23): 3619-26, 2011 Dec 01.
Article in English | MEDLINE | ID: mdl-21420962

ABSTRACT

The shared epitope (SE) - an HLA-DRB1-encoded 5-amino acid sequence motif carried by the vast majority of rheumatoid arthritis (RA) patients - is a risk factor for severe disease. The mechanistic basis of RA-SE association is unknown. This group has previously demonstrated that the SE acts as a signal transduction ligand that activates nitric oxide and reactive oxygen species production. SE-activated signaling depends on cell surface calreticulin, a known innate immunity receptor previously implicated in immune regulation, autoimmunity and angiogenesis. Recent evidence that the SE enhances the polarization of Th17 cells, which is a key mechanism in autoimmunity, is discussed highlighting one of several potential functional effects of the SE in RA.


Subject(s)
Arthritis, Rheumatoid/immunology , Epitopes/immunology , Amino Acid Sequence , Animals , Epitopes/chemistry , Humans , Immunity, Innate/immunology , Models, Immunological , Molecular Sequence Data , Signal Transduction/immunology
4.
Ann N Y Acad Sci ; 1209: 91-8, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20958321

ABSTRACT

Calreticulin (CRT) plays a role in the clearance of dying cells and has been implicated in autoimmunity. Recent evidence indicates that cell surface CRT (csCRT) acts as a signal transducing receptor for the rheumatoid arthritis (RA) shared epitope (SE). The SE binding site on CRT has been mapped to amino acid residues 217-223 in the P-domain. Upon interaction with dendritic cells (DCs), the SE activates potent immune regulatory events. In CD8α(+) DCs, which express higher abundance of csCRT, the SE inhibits the tolerogenic enzyme indoleamine 2,3 dioxygenase with resultant inhibition of regulatory T (Treg) cell differentiation. In CD8α(-) DCs, the SE ligand increases secretion of IL-6 and IL-23 and facilitates generation of Th17 cells, a T cell subset known to play a role in autoimmunity. On the basis of these recent findings, we discuss the possibility that the csCRT may play a pathogenic role in RA by transducing SE-activated Th17-polarizing signals.


Subject(s)
Arthritis, Rheumatoid/physiopathology , Calreticulin/physiology , Animals , Arthritis, Rheumatoid/immunology , CD8 Antigens/immunology , Cell Differentiation , Epitopes/immunology , Humans , Mice , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/immunology
5.
J Immunol ; 185(3): 1927-34, 2010 Aug 01.
Article in English | MEDLINE | ID: mdl-20592276

ABSTRACT

Rheumatoid arthritis (RA) is closely associated with HLA-DRB1 alleles that code a five-amino acid sequence motif in positions 70-74 of the HLA-DRbeta-chain, called the shared epitope (SE). The mechanistic basis of SE-RA association is unknown. We recently found that the SE functions as an allele-specific signal-transducing ligand that activates an NO-mediated pathway in other cells. To better understand the role of the SE in the immune system, we examined its effect on T cell polarization in mice. In CD11c(+)CD8(+) dendritic cells (DCs), the SE inhibited the enzymatic activity of indoleamine 2,3 dioxygenase, a key enzyme in immune tolerance and T cell regulation, whereas in CD11c(+)CD8(-) DCs, the ligand activated robust production of IL-6. When SE-activated DCs were cocultured with CD4(+) T cells, the differentiation of Foxp3(+) T regulatory cells was suppressed, whereas Th17 cells were expanded. The polarizing effects could be seen with SE(+) synthetic peptides, but even more so when the SE was in its natural tridimensional conformation as part of HLA-DR tetrameric proteins. In vivo administration of the SE ligand resulted in a greater abundance of Th17 cells in the draining lymph nodes and increased IL-17 production by splenocytes. Thus, we conclude that the SE acts as a potent immune-stimulatory ligand that can polarize T cell differentiation toward Th17 cells, a T cell subset that was recently implicated in the pathogenesis of autoimmune diseases, including RA.


Subject(s)
Arthritis, Rheumatoid/immunology , Cell Differentiation/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Epitopes/physiology , HLA-DR Antigens/physiology , Amino Acid Sequence , Animals , Arthritis, Rheumatoid/metabolism , Arthritis, Rheumatoid/pathology , Cell Polarity/immunology , Cells, Cultured , Coculture Techniques , Dendritic Cells/pathology , Epitopes/metabolism , Forkhead Transcription Factors/antagonists & inhibitors , Forkhead Transcription Factors/biosynthesis , Growth Inhibitors/physiology , HLA-DRB1 Chains , Humans , Interleukin-17/biosynthesis , Ligands , Lymphocyte Activation/immunology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Transgenic , Molecular Sequence Data , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Helper-Inducer/pathology
6.
Vet Immunol Immunopathol ; 125(3-4): 234-45, 2008 Oct 15.
Article in English | MEDLINE | ID: mdl-18602164

ABSTRACT

Mycobacterium avium subspecies paratuberculosis (MAP) is an intracellular pathogen that survives in the host's intestinal macrophages and causes chronic enteritis in ruminants. The subclinical stage of MAP infection is accompanied by loss of pro-inflammatory T(H)1 response, and a predominant, but ineffective, antibody-mediated T(H)2 response. How MAP interacts with the bovine immune system and suppresses T(H)1 responses is unclear. Studies carried out in our lab and others indicate that when peripheral blood mononuclear cells (PBMCs) from subclinical MAP-infected cattle are stimulated with MAP-antigen, IL-10 is up-regulated and leads to suppression of IFN-gamma expression in MAP-antigen-reactive effector T cells. IL-10 up-regulation and reduction in IFN-gamma would favor MAP survival and proliferation in macrophages. Depletion studies in PBMCs from MAP-infected cattle also revealed that the MAP responsive T-cell population that produces IL-10 is CD4(+) and CD25(+). Therefore, we hypothesize that cattle infected with MAP develop regulatory T (Treg) cells capable of producing IL-10 that in turn limits peripheral and tissue-specific T(H)1 immune responses. The aim of this review is to summarize current thinking regarding Treg cells and provide preliminary evidence that infection of cattle with MAP may lead to development of Treg cells.


Subject(s)
Cattle Diseases/immunology , Cattle Diseases/microbiology , Epitopes, T-Lymphocyte/immunology , Intestinal Diseases/veterinary , Mycobacterium avium subsp. paratuberculosis/immunology , Paratuberculosis/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Cattle , Cattle Diseases/blood , Female , Interferon-gamma/biosynthesis , Interferon-gamma/immunology , Interleukin-10/biosynthesis , Interleukin-10/immunology , Intestinal Diseases/blood , Intestinal Diseases/immunology , Intestinal Diseases/microbiology , Leukocytes, Mononuclear/immunology , Paratuberculosis/blood , Paratuberculosis/microbiology , Th1 Cells/immunology , Th2 Cells/immunology
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