Ellen K. Silbergeld, PhD Johns Hopkins University Bloomberg School of Public Health ENVIRONMENTAL...
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Transcript of Ellen K. Silbergeld, PhD Johns Hopkins University Bloomberg School of Public Health ENVIRONMENTAL...
Ellen K. Silbergeld, PhDJohns Hopkins UniversityBloomberg School of Public Health
ENVIRONMENTAL EXPOSURES AS “CO-CONSPIRATORS” IN AUTOIMMUNE DISEASE
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 0:1Systemic lupus erythematosus 10:1 Sjogren's syndrome 9:1 Antiphospholipid syndrome 9:1 Primary biliary cirrhosis 9:1 Mixed connective tissue disease 8:1Chronic active hepatitis 8:1Graves' disease/hyperthyroiditis 7:1Rheumatoid arthritis 4:1Scleroderma 3:1Myasthenia gravis 2:1Multiple sclerosis 2:1Chronic idiopathic thrombocytopenic purpura 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