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1 The biochemistry and genetics of autoimmune disease
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Immunology at a glance Immune responses distinguish “self” from “non-self” Beneficial immunity Innate and adaptive responses to pathogens Cellular damage/wound healing Diseases associated with abnormal immune function Inadequate responses (immunodeficiencies) Excessive responses (hypersensitivities and autoimmunities) Effective immune responses to transplanted grafts
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The immune system as a complex phenotype Multiple cell types arising in a variety of tissues, passing though a variety of developmental stages and circulating throughout the body
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Cytokine mediated regulation Th1 and Th2 cross-regulate (proinflammatory) (anti-inflammatory)
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Why is the immune response sensitive to stressors? The immune system is a sensitive system with multiple targets for toxicants Immune cells circulate throughout the body sampling a multitude of tissue environments and are readily obtained from the blood Intentional manipulations of the immune system with drugs or biologics can influence the progression of diseases that affect a large percentage of the human population Autoimmune disease, allergy, immunodeficiencies, hypersensitivities, infectious disease, cardiac disease, cancer Undesirable immune effects of investigational new drugs with non-immune targets can result in dropping a compound from further study Less stringent oversight is applied to the thousands of industrial chemicals brought into the environment each year: effects on the immune system can be problematic
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A few examples of stressors that alter immune functions… Metals Cadmium is immunosuppressive Mercury can elicit autoimmunity Nickel can stimulate hypersensitivity/contact dermatitis Organics 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) associated with immunosuppression, thymic involution, decreased antibody production and cytotoxic T-lymphocyte development, and increased susceptibility to a variety of infectious diseases Polycyclic aromatic hydrocarbons (e.g.benzo(a)pyrene) can be immunosuppressive, and can cause contact hypersensitivity Psychological stress, physical stress (e.g. x-rays, heat and cold) and biological stressors Toxins Superantigens from viral, bacterial, and mycoplasm sources a as polyclonal T cell activators that produce massive cytokine release events Lipopolysaccharide (LPS) as a polyclonal activator of B cells and macrophages Mycobacterial products as adjuvant components Pathogens, symbionts and the microbiome
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One person’s toxicant is another person’s therapeutic… Glucocorticoids as immunosuppressors Inflammatory skin diseases and asthma Drugs that alter signaling cascades Cyclosporin A isolated from a fungus (Tolypocladium inflatum) and inhibits calcineurin used in transplant rejection, psoriasis, ulcerative colitis, and other undesirable immune responses TNF-a antagonists monoclonal antibodies Infliximab (Remicade), adalimumab (Humera) and TNF Receptor fusion protein etanercept (Enbrel). Treatments for Rheumatoid arthritis, Crohn’s disease
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Manipulating the immune response can be dangerous TGN1412 Phase I clinical trial of a biologic (a humanized mouse anti-CD28 Mab) in 2006 by TeGenero Immuno Therapeutics Biologic is a strong agonist of CD28 (co-receptor of TcR on T cells) pre-clinical safety testing in macaque monkeys failed to indicate safety issues due to lack of CD28 expression on CD4+ effector memory T-cells in the macaques (no observed adverse effect level was 50mg/kg Mab Target ‪Image: www.eurofinspanlabs.co ‪J.A. Mulligan, R. Shively, and C.L. O'Day MDS Pharma Services – Bothell, WA, USA‬
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In six human volunteers, a “cytokine storm” was initiated by 0.1mg/kg of TGN1412, and produced angioedema (swelling of skin and mucous membranes similar to severe allergic reaction). Most WBC had vanished from circulation a few hours after antibody administration. Effects of the treatment kept five of the six in hospital for more than a month and there is speculation that the effects of the TGN1412 treatment will be life-long for all six patients. Mediators of the cytokine storm and the associated phenotypes. Microbiol Mol Biol Rev. 2012 Mar;76(1):16-32
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One person’s toxicant is another’s research tool MAP kinase inhibitors PD98059 has been shown to act in vivo as a highly selective inhibitor of MEK1 activation and the MAP kinase cascade protein tyrosine phosphatase inhibitors Orthovanadate,Na3VO4; Phenylarsine Oxide, C6H5)AsO PLC A2 inhibitors LY311727, AACOCF3 GPCR inhibitors Cholera toxin, pertussis toxin Cell function inhibitors Macrophage deletion with chlodronate-loaded liposomes
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Immunotoxicological assessments of investigational new drugs (INDs) Five adverse event categories Immunosuppression: Effects on the immune system that result in decreased immune function Immunogenicity: Immune reactions elicited by a drug and/or its metabolites Hypersensitivity: Immunological sensitization due to a drug and/or its metabolites Autoimmunity: Immune reactions to self-antigens Adverse Immunostimulation: Activation of immune system effector mechanisms Immunotoxicology Evaluation of Investigational New Drugs; U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)
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Methods for measuring immunotoxicological effects In vitro assays; some examples: Proliferation Cell viability (apoptosis and necrosis) Functional assays (Ig synthesis, cytokine production) Developmental analysis (surface markers, gene activity assays) In vivo assays; some examples: Antibody production and cytokine production after antigen challenge Local lymph node assay for inflammation Hypersensitivity assays (drug allergy) Drug immunogenicity There are so many targets, appropriate assays are a matter of considerable debate….
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Conclusions, part I The immune system offers a window into toxin, toxicant, biologic and drug actions The effects of these agents can be stimulatory or inhibitory of immune cell activities with either beneficial or deleterious effects An understanding of the mechanisms of the agents action may suggest new applications for the agent, and may provide a useful tool for exploration of basic cellular mechanisms NEXT: Autoimmune disease
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Autoimmunity: self recognition by the immune response Dual recognition (self-MHC plus antigenic peptide) Jerne network hypothesis “don’t eat me” signaling (CD47 on erythrocytes) Autoimmune disease: self recognition with damaging consequences to tissue function Tissue specific (e.g. T1D) Systemic (SLE) Autoimmunity vs Autoimmune disease
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4 main hypersensitivities (I-IV) Type I Anaphalaxis; Immediate; IgE mediated mast cell degranulation Allergies, atopy Type II Cytotoxic (IgM and IgG mediated) Erythroblastosis fetalis, autoimmune hemolytic anemia, pemphigus vulgaris Type III Immune complex Serum sickness, RA, Type IV DTH/contact sensitivity Contact dermatitis, T1D, RA, Multiple sclerosis Hypersensitivities
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Figure 10-2
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Figure 10-1
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Discrimination of self vs non-self Central tolerance develops in thymus and bone marrow (negative selection to eliminate cells reactive with antigens Present soon after cell expresses antigen receptor Present at high concentration over long periods of time Peripheral tolerance/anergy When cells encounter antigen in the absence of co-stimulatory signals that are usually provided by inflammation Antigen segregation Physical barriers to restrict immune cell access Thyroid, pancreas, intracellular Regulatory cells that suppress responses Clonal deletion post activation Tolerance
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Organ specific T1D Multiple sclerosis Grave’s disease Autoimmune hemolytic anemia Myasthenia gravis Systemic RA Scleroderma SLE Differentiation of autoimmune diseases; organ specific vs systemic
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Examples of autoimmune disease that can be transferred across the placenta
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Components of immunity that are part of autoimmune disease
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Pathogens Cross-reactive antigens/molecular mimicry Lyme arthritis Rheumatic fever Chronic inflammation, immune dysregulation Disruption of cell/tissue barriers Sympathetic ophthalmia (granulomatous uveitis) Toxicants and other stressors Genetic predisposition Combinations of the above Routes to Autoimmune Disease
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http://pubs.acs.org/doi/pdf/10.1021/tx9003787 (see class website for link)
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Figure 10-28 part 1 of 2
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Figure 10-28 part 2 of 2
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Single gene models Fas, FasL; ALPS (defects in apoptosis, lymphoaccumulation, angergy and SLE-like autoimmune disease) Mev; viable motheaten, Hcph-1; SHP1 (chronic inflammation) IPEX immune dysregulation X linked recessive mutation in transcription factor FoxP3; severe allergic inflammation, hemolytic anemia, thrombocytopenia, etc. Deficiency in CD25 (IL2R); impaired peripheral tolerance CTLA4 mutation; Graves disease, T1D, etc. C1q mutation SLE MHC associations with autoimmune disease (e.g. HLA-B27) Genes involved in autoimmune disease
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Mutations at the Motheaten Locus are Within the Hcph Gene
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Negative regulator of signal transduction growth factor receptors: c-kit, EPO activation signaling: BCR, TCR, NK activating receptor SHP-1 inactivates anti-apoptotic signaling molecules in neutrophil proliferation induces apoptosis in sympathetic neurons Function of SHP-1
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Clinical disease in viable motheaten mice Anemia Immunodeficiency Autoimmunity Death from acidophilic macrophage pneumonia
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Macrophage pneumonia in mev/mev mice mev/mev +/?
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GWAS genome wide associational studies Family studies to identify SNP that track with autoimmune disease Animal models with mutations in candidate genes Meta-analysis of data to enlarge patient populations studied for autoimmune disease Approaches to identifying genes involved in autoimmune disease
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Biochemical events that potentiate autoimmunity events that cause damage to membrane, etc Reactive oxygen, chronic inflammation Biochemistry of damaging events associated with autoimmune disease Reactive oxygen, chronic inflammation Biochemistry of autoimmune disease
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Oxidative Stress SIGMA-ALDRICH
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Figure 1. Pathogenesis of diabetic microvascular complications. This schematic proposes that the development of microvascularcomplications begins early in the course of diabetes, well before clinical diabetes is detected. Certain genetic characteristicsor polymorphisms (Apo E4, Aldose reductase, ACE) may increase individual predisposition for development of microvascularcomplications of diabetes [30,31], whereas other genetic factors, such as the toll receptor, are protective and decreasepredisposition. The various inflammatory mediators listed under the heading of inflammation cause direct cellular injury andinitiate the cycle of functional and progressive pathologic changes, which ultimately manifest as microvascular complications[13,15–18,21]. As the disease progresses, lipotoxicity [28], glucotoxicity [42,43], and epigenetic factors further contribute to thefunctional and pathologic changes. Intervention with insulin or insulin sensitizers, particularly in the early stages of pathogenesis,can counteract inflammatory changes, control glycemia, prevent formation of advanced glycation end products, and ameliorateoxidative-stress-induced overactivation of poly adenosine diphosphate ribose polymerase (PARP), with the potential to changethe natural history of microvascular complications [29,37]. ApoE4 = Apolipoprotein E4; ACE = Angiotensin-converting enzyme;PKCβ = Protein kinase C beta; IL-6 = Interleukin-6; TNFα = Tumor necrosis factor alpha; NFκ B = Nuclear factor kappa B. Adaptedwith permission from Vinik A, Mehrbyan A. Diabetic neuropathies. Med Clin North Am 2004; 88: 947–999 http://onlinelibrary.wiley.com/doi/10.1002/dmrr.530/pdf Diabetes Metab Res Rev 2005; 21: 85–90.
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http://nihroadmap.nih.gov/epigenomics/epigeneticmechanisms.asp
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Histone modifications http://www.nature.com/nsmb/journal/v14/n11/images/nsmb1337-F1.gif
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http://www.cellsignal.com/reference/pathway/Histone_Methylation.html
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H3K4me3 demethylases : link between histone modifications and XLMR. X-linked mental retardation (XLMR) gene SMCX (JARID1C), which encodes a JmjC-domain protein, reversed H3K4me3 to di- and mono- but not unmethylated products//Cell 2007 The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3//Nature (2006) 442: 307-11. Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. //J Hepatol. 2009, 50: 323-33 Perturbation of epigenetic status by toxicants// Toxicology LettersVolume 149, Issues 1-3, 1 April 2004, Pages 51-58 Diabetes is not the only context in which histone methylation is potentially important. For example:
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http://www.cdc.gov/diabetes/consumer/learn.htm Type 1 diabetes, which was previously called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes, may account for 5% to 10% of all diagnosed cases of diabetes. Type 2 diabetes, which was previously called non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes, may account for about 90% to 95% of all diagnosed cases of diabetes. Gestational diabetes is a type of diabetes that only pregnant women get. If not treated, it can cause problems for mothers and babies. Gestational diabetes develops in 2% to 5% of all pregnancies but usually disappears when a pregnancy is over. Other specific types of diabetes resulting from specific genetic syndromes, surgery, drugs, malnutrition, infections, and other illnesses may account for 1% to 2% of all diagnosed cases of diabetes.
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Stop here 40
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Rate of new cases of type 1 and type 2 diabetes among youth aged <20 years, by race/ethnicity, 2002–2003 CDC. National Diabetes Fact Sheet, 2007. Source: SEARCH for Diabetes in Youth Study NHW=Non-Hispanic whites; AA=African Americans; H=Hispanics; API=Asians/Pacific Islanders; AI=American Indians <10 years 10–19 years
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Humanized mouse models Humanized mouse models to study human diseases Brehm et al.
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NOD/SCID/Akita mouse
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Metal mediated autoimmune disease Mercury-Induced Autoimmunity in Mice Jesper Bo Nielsen and Per Hultman Environmental Health Perspectives • VOLUME 110 | SUPPLEMENT 5 | OCTOBER 2002 44
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Mercury induced autoimmunity in mice 45
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50 -Genetically determined susceptibility is linked to the murine H-2 haplotype, and a susceptible haplotype is a prerequisite for an autoimmune response expressed as antifibrillarin antibodies. Because haplotypes H-2t4 and H-2s confer susceptibility to mercury-induced autoimmune response to a comparable extent, whereas H-2t1 causes resistance, our data suggest that susceptibility may be restricted to the Aα and Aβ loci in H-2. Different quantitative autoimmune responses were observed among susceptible mouse strains with identical H-2 haplotype. We conclude that induction and development of AFA may be modulated by mercury toxicokinetics, but non-H-2 genes may also modulate this response independent of kinetics. AFA and IgE are both important markers for adverse immune reactions after exposure to mercuric chloride, but the responses are probably mechanistically unrelated. Thresholds exist below which no autoimmune response is observed even after prolonged exposure. At low mercury exposures, autoimmune response is not observed within the first weeks but develops gradually. This observation is probably caused by mercury accumulation in whole body and target organs along with increased exposure time. The autoimmune response depends on gender. Female mice have a higher sensitivity (lower threshold for induction of AFA) as well as a higher responsivity (lower WBR to reach 100% autoimmune response) than male mice. The experimental model for induction of autoimmune responses demonstrates good agreement with observations from human autoimmune diseases.
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51 Exposure to inorganic mercury in vivo attenuates extrinsic apoptotic signaling in Staphylococcal aureus enterotoxin B stimulated T-cells Michael D. Laiosa*, Kevin G. Eckles*, Margaret Langdon*, Allen J. Rosenspire†, and Michael J. McCabe Jr.* Toxicol Appl Pharmacol. 2007 December 15; 225(3): 238–250.
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52 http://ghr.nlm.nih.gov/handbook/illustrations/apoptosismacrophage
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53 http://cbm.msoe.edu/scienceOlympiad/module2012/apoptosis.html
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54 How does Hg influence the progression to autoimmune disease?
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55 Previous work: Low concentrations of Hg attenuate CD95 (Fas) dependent apoptosis SEB attenuates Vb8 expansion Hg has little effect on termination phase of response at 72 hrs
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56 SEB is a Superantigen
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57 Hg attenuates Caspase activation
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62 Conclusion: Hg blocks caspace induction that is critical for apoptosis and leads to accumulation of cells that would otherwise be deleted Accumulation of autoreactive cells? Accumulation of cells that then die by necrosis?
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Each presentation is ~1 hour Spend first 20 minutes or so describing the fundamental information: what do we need to know to understand the papers you have assigned? How does this presentation fit into the course main topic? Divide the second 30 minutes into discussions of each of the two contemporary papers that you assigned to the class at the previous class period Your presentations
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Grantsmanship: NIH Steps to the NIH grant application process https://grants.nih.gov/grants/about_grants.htm NIH electronic grant forms https://grants.nih.gov/grants/forms.htm R03 description https://grants.nih.gov/grants/funding/r03.htm NIH reporter https://grants.nih.gov/grants/planning_application.htm#reporter Examples of grants that work https://www.niaid.nih.gov/grants-contracts/sample-applications#r03 Search engine for currently funded grants http://projectreporter.nih.gov/reporter.cfm Tongue-in-cheek": how to fail in grant writing https://www.chronicle.com/article/How-to-Fail-in-Grant-Writing/125620
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What is the fundamental hypothesis that is being tested? What techniques did they use that we have to understand to evaluate the data? What are the most important figures/data sets that we should discuss? Are there alternative interpretations of their data? What conclusions did they reach? What new questions do they open up with their results? Discussion points to include
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Hypothesis and ONE specific aim are due March 5 We will discuss all specific aims on March 4th Grant is due May 1st Grant application
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TEXT: Hypothesis and specific aim (0.5 page) Background and Significance (3-4 pages) What do we know about the system? What makes this hypothesis tenable? How is the approach you propose innovative? Research designs and Experimental approach (4-5 pages) Rationale Experimental design and methods Anticipated outcomes Potential pitfalls and alternative approaches We will talk about NIH forms later in the semester Grant format:
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Student presentation schedule 1. GWAS identification of T1D markers (Jen) (March 11) 2. The Gut microbiome and T1D (Brandon) (March 25) 3. Environmental stressors and T1D (note PFAS controversy) (Jon) (April 1) 4. Macrophages, oxidative stress and T1D (Paige) (April 8) 5. Inflammation of the brain (Insulin signaling and T1D) (Didem) (April 15) 6. Pancreatitis vs Insulitis in T1D (Meghan) (April 22) 7. T1D therapeutic approaches (Kyle) (April 29) 68