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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
– NFB 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