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The biochemistry and genetics of autoimmune disease

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)

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The biochemistry and genetics of autoimmune disease

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  1. The biochemistry and genetics of autoimmune disease • Mcb5255 2015 1

  2. 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)

  3. 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

  4. Figure 10-2

  5. Figure 10-1

  6. 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 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

  7. 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

  8. Examples of autoimmune disease that can be transferred across the placenta

  9. Components of immunity that are part of autoimmune disease

  10. 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

  11. http://pubs.acs.org/doi/pdf/10.1021/tx9003787 (see class website for link)

  12. Figure 10-28 part 1 of 2

  13. Figure 10-28 part 2 of 2

  14. 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. HLA-B27)

  15. Mutations at the Motheaten Locus are Within the Hcph Gene

  16. 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

  17. Clinical disease in viable motheaten mice • Anemia • Immunodeficiency • Autoimmunity • Death from acidophilic   macrophage pneumonia

  18. Macrophage pneumonia in mev/mev mice +/? mev/mev

  19. 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

  20. 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

  21. Oxidative Stress SIGMA-ALDRICH

  22. 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.

  23. http://nihroadmap.nih.gov/epigenomics/epigeneticmechanisms.asphttp://nihroadmap.nih.gov/epigenomics/epigeneticmechanisms.asp

  24. Histone modifications http://www.nature.com/nsmb/journal/v14/n11/images/nsmb1337-F1.gif

  25. http://www.cellsignal.com/reference/pathway/Histone_Methylation.htmlhttp://www.cellsignal.com/reference/pathway/Histone_Methylation.html

  26. 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

  27. 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

  28. 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=American Indians

  29. Humanized mouse models Humanized mouse models to study human diseases Brehm et al.

  30. NOD/SCID/Akita mouse

  31. Metal mediated autoimmune disease • Mercury-Induced Autoimmunity in Mice • Jesper Bo Nielsen and Per Hultman • Environmental Health Perspectives • VOLUME 110 | SUPPLEMENT 5 | OCTOBER 2002

  32. Mercury induced autoimmunity in mice

  33. -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.

  34. 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.

  35. http://ghr.nlm.nih.gov/handbook/illustrations/apoptosismacrophagehttp://ghr.nlm.nih.gov/handbook/illustrations/apoptosismacrophage

  36. http://cbm.msoe.edu/scienceOlympiad/module2012/apoptosis.htmlhttp://cbm.msoe.edu/scienceOlympiad/module2012/apoptosis.html

  37. How does Hg influence the progression to autoimmune disease?

  38. 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

  39. SEB is a Superantigen

  40. Hg attenuates Caspase activation

  41. 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?

  42. 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

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