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The biochemistry and genetics of autoimmune disease Mcb5255 2015 1 Autoimmunity vs Autoimmune disease 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) Hypersensitivities 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 Figure 10-2 Figure 10-1 Tolerance ◦ 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 costimulatory 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 Differentiation of autoimmune diseases; organ specific vs systemic Organ specific ◦ ◦ ◦ ◦ ◦ T1D Multiple sclerosis Grave’s disease Autoimmune hemolytic anemia Myasthenia gravis Systemic ◦ RA ◦ Scleroderma ◦ SLE Examples of autoimmune disease that can be transferred across the placenta disease autoantibody Symptom Myesthenia gravis Anti-acetylcholine receptor Muscle weakness Graves disease Anti-thyroid stimulating hormone receptor Hyperthyroidism Thrombocytopenic propura Anti-platelet antibodies Bruises and hemorrhaging Pemphigus vulgaris Anti-desmoglein Blistering rash Components of immunity that are part of autoimmune disease Disease T cells B cells Antibody SLE Pathogenic help for antibody Present antigen to T cells Pathogenic T1D Pathogenic Present antigens to T cells Present but unclear role Myesthenia gravis Help for antibody Antibody secretion Pathogenic Multiple sclerosis Pathogenic Present antigen to T cells Present but unclear role Routes to Autoimmune Disease 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 http://pubs.acs.org/doi/pdf/10.1021/tx9003787 (see class website for link) Figure 10-28 part 1 of 2 Figure 10-28 part 2 of 2 Genes involved in autoimmune disease 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. HLAB27) Mutations at the Motheaten Locus are Within the Hcph Gene Function of SHP-1 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 Clinical disease in viable motheaten mice • Anemia • Immunodeficiency • Autoimmunity • Death from acidophilic macrophage pneumonia Macrophage pneumonia in mev/mev mice +/? mev/mev Approaches to identifying genes involved in autoimmune disease 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 Biochemistry of autoimmune disease 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 Oxidative Stress SIGMA-ALDRICH Figure 1. Pathogenesis of diabetic microvascular complications. This schematic proposes that the development of microvascular complications begins early in the course of diabetes, well before clinical diabetes is detected. Certain genetic characteristics or polymorphisms (Apo E4, Aldose reductase, ACE) may increase individual predisposition for development of microvascular complications of diabetes [30,31], whereas other genetic factors, such as the toll receptor, are protective and decrease predisposition. The various inflammatory mediators listed under the heading of inflammation cause direct cellular injury and initiate 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 the functional 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 ameliorate oxidative-stress-induced overactivation of poly adenosine diphosphate ribose polymerase (PARP), with the potential to change the 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. Adapted with 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. http://nihroadmap.nih.gov/epigenomics/epigeneticmechanisms.asp Histone modifications http://www.nature.com/nsmb/journal/v14/n11/images/nsmb1337-F1.gif http://www.cellsignal.com/reference/pathway/Histone_Methylation.html Diabetes is not the only context in which histone methylation is potentially important. For example: •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 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. http://www.cdc.gov/diabetes/consumer/learn.htm Rate of new cases of type 1 and type 2 diabetes among youth aged <20 years, by race/ethnicity, 2002–2003 <10 years 10–19 years 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=A Indians Humanized mouse models Humanized mouse models to study human diseases Brehm et al. NOD/SCID/Akita mouse Metal mediated autoimmune disease Mercury-Induced Autoimmunity in Mice Jesper Bo Nielsen and Per Hultman Environmental Health Perspectives • VOLUME 110 | SUPPLEMENT 5 | OCTOBER 2002 31 Mercury induced autoimmunity in mice 32 33 34 35 36 -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. 37 The experimental model for induction of autoimmune responses demonstrates good agreement with observations from human autoimmune diseases. 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. 38 http://ghr.nlm.nih.gov/handbook/illustrations/apoptosismacrophage 39 http://cbm.msoe.edu/scienceOlympiad/module2012/apoptosis.html 40 How does Hg influence the progression to autoimmune disease? 41 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 42 SEB is a Superantigen 43 Hg attenuates Caspase activation 44 45 46 47 48 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? 49 Your presentations 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 Grantsmanship: NIH Steps to the NIH grant application process http://funding.niaid.nih.gov/researchfunding/grant/pages/apply ing.aspx NIH electronic grant forms http://grants.nih.gov/grants/funding/424/index.htm Examples of outstanding titles and abstacts http://funding.niaid.nih.gov/researchfunding/grant/pages/titleabs.aspx Search engine for currently funded grants http://projectreporter.nih.gov/reporter.cfm Tongue-in-cheek": how to fail in grant writing http://chronicle.com/article/How-to-Fail-in-Grant-Writing/125620/ Discussion points to include 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? Grant application Hypothesis and ONE specific aim are due March 5 We will discuss all specific aims on march 4th Grant is due May 4th Grant format: 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 Student presentation schedule 1. Mechanisms of danger-signal mediated immune modulation (Bevan) (March 11) 2. MT and type I diabetes (Dawei) (March 11) 3. Bacterial stress response proteins and their influence on the immune response (Amy) (April 1) 4. Chemical toxicants and their roles in chronic inflammation (Kristen) (April8) 5. Inflammation of the brain (Frances) (April8) 6. The chemistry of stress: the role of reactive oxygen and nitrogen species in inflammation and stress, and the management of ROS and RNS in stress (Matthew) (April 15) 7. Molecular indicators of stress as indicators of immune status (Amanda) (April 22) 8. Stress response proteins and their roles as vaccine adjuvants (Brandon) (April 22) 9. The interplay of infection, stress and the immune response (Abraham) (April 29) 55