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ENVIRONMENTAL EXPOSURES AS “CO-CONSPIRATORS” IN AUTOIMMUNE DISEASE Ellen K. Silbergeld, PhD Johns Hopkins University Bloomberg School of Public Health AUTOIMMUNE DISEASES: A WOMEN’S HEALTH ISSUE • DIFFERENTIAL INCIDENCE – 1.5 to 50 times more frequent • INTERACTIONS WITH PREGNANCY, STEROIDS and MENOPAUSE – Cause or exacerbation? • IMPACTS ON HEALTH and QUALITY OF LIFE – Symptomatic treatment, no cures Table I Female:Male Ratios in Autoimmune Diseases Hashimoto's disease/hypothyroiditis Systemic lupus erythematosus Sjogren's syndrome Antiphospholipid syndrome Primary biliary cirrhosis Mixed connective tissue disease Chronic active hepatitis Graves' disease/hyperthyroiditis Rheumatoid arthritis Scleroderma Myasthenia gravis Multiple sclerosis Chronic idiopathic thrombocytopenic purpura 0:1 10:1 9:1 9:1 9:1 8:1 8:1 7:1 4:1 3:1 2:1 2:1 2:1 AUTOIMMUNE DISEASES • SYSTEMIC or TARGET ORGAN SPECIFIC DISEASES • SEXUALLY DIMORPHIC – incidence? Severity? Both? • COMPLEX GENE:ENVIRONMENT INTERACTIONS GENE:ENVIRONMENT INTERACTIONS • GENETICS: FAMILIAL PATTERNS OF DISEASE • SEX – GENES and ENDOCRINOLOGY • ACQUIRED RISK FACTORS – DRUGS – INFECTIONS – ENVIRONMENTAL CHEMICALS? ENVIRONMENTAL EXPOSURES AS CAUSES • INFECTIONS – AUTOIMMUNE MYOCARDITIS • CHEMICALS/METALS – TOXIC OIL SYNDROME – GOLD + IODINE and SELENIUM DEFICIENCY – MERCURY…. MERCURY and the IMMUNE SYSTEM • IMMUNOSUPPRESSION – Decreased resistance to malaria – Impaired immunity to malaria • NEUROIMMUNOTOXICOLOGY – Interrupted cerebellar neural migration • AUTOIMMUNITY – Lupus-like disease in rodents – Increased [auto]antibodies in humans MERCURY AND AUTOIMMUNE DISEASE • CAN MERCURY CAUSE AI DISEASE? – HUMAN DATA? • NEPHROTOXICITY MAY INVOLVE AUTOIMMUNE MECHANISMS • FRANK AI DISEASE NOT DEMONSTRATED BUT EPI DATA ARE LIMITED • NEUROTOXICITY MORE SENSITIVE OUTCOME – EXPERIMENTAL DATA – YES • INBRED RODENT STRAINS ARE SUSCEPTIBLE • RESPONSE CAN INCLUDE AUTOANTIBODIES, VASCULITIS, NEPHROPATHY • DOSES ARE RELATIVELY HIGH COMPARED TO HUMAN EXPOSURES CAN MERCURY ACCELERATE AI DISEASE? • HUMAN DATA – HgU higher in patients with more severe scleroderma + antifibrillarin Ab • EXPERIMENTAL DATA – Hg accelerates pathology in lupus-prone strains of mice - NZB, Palmerston North, etc ANIMAL MODELS OF AI DISEASE • SPONTANEOUS – INBRED STRAINS – NZB, PN • ACQUIRED – GRAFT versus HOST DISEASE ADVANTAGES OF ACQUIRED DISEASE MODEL • TIME COURSE OF DISEASE CAN BE PREDICTED • MECHANISTIC INFORMATION IS AVAILABLE • SEVERITY OF DISEASE CAN BE MODULATED GRAFT vs HOST DISEASE (GVHD) • C57Bl/6 x DBA/2 F1 – INJECTION OF PARENTAL SPLENOCYTES INTO B6xD2 F1 OFFSPRING • DBA/2 CELLS into F1 produces chronic lupus like disease • Bl/6 CELLS into F1 produces acute lupus like disease EXPERIMENTAL PROTOCOL • Hg exposure: 20 or 200 ug/kg for 3 weeks every other day, donor and host • Transfer cells • Follow development of disease – proteinuria, morbidity, serum antibodies • Postmortem histopathology of kidney and vasculature MERCURY & AUTOIMMUNE MYOCARDITIS • MYOCARDITIS IS A MAJOR CAUSE OF HEART FAILURE AND SUDDEN DEATH IN YOUNG ADULTS • MYOCARDITIS CAN RESULT IN CHRONIC CARDIOMYOPATHY • MANY CASES ARE AUTOIMMUNE DISEASE • INFECTIONS ARE ASSOCIATED WITH AUTOIMMUNE MYOCARDITIS CARDIAC MYOSIN MODEL OF AIM • INFECTION-ASSOCIATED AIM ASSOCIATED WITH POST-EXPOSURE CARDIOTOXICITY • IMMUNE MIMICRY [CHAGAS DISEASE] OR UNCOVERING INTRACELLULAR EPITOPES IN CARDIOMYOCYTES • CARDIAC MYOSIN A MAJOR AUTOANTIGEN EAM in MICE • A/J MICE [male or female] • Immunization with cardiac myosin peptide • Disease course – 21 days – Dilated cardiomyopathy: myocardial infiltration and cardiomyocyte death – Immune complex deposition in heart – CM-specific IgG in sera – Pathophysiologic cardiac function Mercury + EAM • Pretreat A/J mice with 10 or 100 mcg/kg HgCl2 • Immunize with CMP + adjuvant • Follow disease course for 21 days MERCURY – CAUSE OR CO-CONSPIRATOR • MERCURY CAN CAUSE AI DISEASE IN SUSCEPTIBLE RODENTS • MERCURY CAN ACCELERATE LUPUS IN DISEASE-PRONE MICE • MERCURY BY ITSELF CANNOT CAUSE AI DISEASE IN NONSUSCEPTIBLES MECHANISMS OF MERCURY:AI INTERACTIONS • Mercury alters lymphocyte subsets – No evidence for cell loss or altered ratios • Mercury is a “superantigen” – But no effects by itself • Mercury alters cell:cell signalling – Effects observed on Th1 and Th2 cytokines – Decreases in NO-mediated cell death – NFB binding • Mercury alters costimulatory “support” – B7 family may be target RESEARCH QUESTIONS • WHAT IS THE LOWEST EFFECTIVE DOSE OF MERCURY AS A CO-CONSPIRATOR IN AUTOIMMUNITY? • DOES MERCURY INTERACT WITH SEX/ENDOCRINOLOGY? • WHAT ARE THE CONSEQUENCES OF PRENATAL EXPOSURES TO MERCURY ON LATER SUSCEPTIBILITY TO AUTOIMMUNE DISEASE • IS MERCURY TOXICITY AN AUTOIMMUNE DISEASE? BALTIMORE MERCURY RESEARCH GROUP • Dr CHARLES VIA’S LAB (Univ MD Med Sch) – Phuong Nguyen – John Papadimitriou • DR NOEL ROSE’S LAB (JHMI) – Dr Marina Afanasyeva • DR ELLEN SILBERGELD’S LAB (BSPH) – Dr Jennifer Nyland – Ines Silva – Dr Dennis Hoover RESEARCH SUPPORT • CURE AUTISM NOW FOUNDATION • ARTHRITIS FOUNDATION • NATIONAL INSTITUTES OF HEALTH • HEINZ FAMILY FOUNDATION