Transcript Document

Lecture 11
MECHANISMS OF
AUTOIMMUNITY
2007/2008
Jan Żeromski
POINTS TO BE DISCUSSED
• Autoimmunity versus autoimmune disease
• Features of autoimmune disease (AD)
• Organ-specific and non organ-specific AD
• Experimental animal models
• Genetic background of AD
• Effects of environment on the induction of AD
• Cellular mechanisms and treatment of AD
AUTOIMMUNITY VS.
AUTOIMMUNE DISEASE
Autoimmunity
• Existence of harmless self-reactive
lymphocytes and
antibodies
• Potentially reversible
• Incidence higher in
older age
• Significance unclear,
possibly physiological
Autoimmune disease
• Dependent on
genetic viral and
hormonal factors
• Features of severe
tissue damage
• Clinical symptoms
• Protracted course
but usually fatal
• Familiar clustering
AUTOIMMUNE DISEASE –
KEY CONCEPTS
• Recognition of autoantigens by
lymphocytes is critical
• Tissue destruction not just autoimmune
cells must be present
• AD involve self-reactive T cells
• AD induction almost always depends on
triggering of autoreactive CD4+ T cells
MECHANISMS OF BREAKING OF
SELF-TOLERANCE
• Disruption of self or tissue barrier
• Infection of antigen presenting cell
• Binding of pathogen to self antigen
• Molecular mimicry
• superantigen
EXAMPLES 0F ORGAN-SPECIFIC AND NON
ORGAN-SPECIFIC (SYSTEMIC)
AUTOIMMUNE DISEASES
Organ-specific
• Hashimoto
thyroiditis
• Thyrotoxicosis
• Addison’s disease
• Atrophic gastritis
• Juvenile diabetes
mellitus
• Multiple sclerosis
Non organ-specific
• Systemic lupus (SLE)
• Rheumatoid arthritis
(RA)
• Scleroderma
• Dermatomyositis
• Mixed connective
tissue disease
(MCTD)
• Sjögren’s syndrome
ORGAN-SPECIFIC AND NON ORGANSPECIFIC AUTOIMMUNE DISEASES
Organ-specific
Non organ- specific
(systemic)
• Widespread self-anti• Autoimmune attack vs.
gens are targets for
self-antigens of given
autoimmune attack
organ
• It results in a damage of • Damage affects such
structures as blood
organ structure and
vessels, cell nuclei etc.
function
• Treatment is focused on • Treatment is aimed to
inhibit excessive
the replacement of
activation of the immune
organ function
system
EXPERIMENTAL ANIMAL MODELS
OF AUTOIMMUNE DISEASES
Three categories:
1. Spontaneously occurring AD (systemic lupus
in New Zealand mice ([NZBxNZW]F1)
2. Diseases induced by exogenous action such
as immunization (experimental allergic
encephalomyelitis – EAE, CIA, EAU)
3. Diseases due to genetic manipulation such
as in knockout (IL-2, Fas) or transgenic
(bcl-2, HLA-B27) animals (SLE, RA, IBD)
AUTOREACTIVE T CELLS ARE PRESENT IN
LYMPHOID TISSUES AND BLOOD
•
•
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Central tolerance does not delete T cells
autoreactive to organ-sequestered antigens
and cryptic epitopes
Subset of these T cells are potentially
pathogenic
These T cells must be kept tolerant by:
a.
b.
c.
d.
elimination
maintenance of immunologic ignorance
functional inactivation (anergy)
suppression
AD ARE COMPLEX GENETIC TRAITS
• Multiple genes determine susceptibility to AD
• No particular gene is necessary or sufficient
for disease expression (relatively low gene
penetrance)
• MHC and multiple non-MHC genes are
involved
• Epistasis (interaction of susceptibility genes)
• Genetic alleles increasing susceptibility are
relatively frequent in the general population
EXAMPLES OF GENE DEFECTS IN
AUTOIMMUNITY
• Multiple sclerosis – particular alleles of
HLA-DR (DRB1*1501, DRB5*0101)
• Systemic lupus – lack of C1q and C4
• Genetically determined low expression of
given self-antigen in the thymus
• Mutation (usually deletion) of autoimmune
regulator-1 gene (AIRE-1)
IMPACT OF ENVIRONMENTAL
TRIGGERS ON INDUCTION OF AD
• Virus clustering (RA, Sjögren’s s., SLE, MS)
• Infectious microorganisms (molecular
mimicry – see later)
• Geographic clustering
• Sun exposure (SLE)
• Exogenous estrogens, sex hormones in
general
MOLECULAR MIMICRY
Definition:
Determinants of infectious agent mimic a
host antigen and trigger self-reactive T-cell
clones to attack host tissues.
Examples:
Stromal keratitis due to herpes simplex virus type I
Rheumatic fever due to group A streptococcus
SLE due Epstein-Barr virus cross reactive with nuclear
Sm antigen
Lyme artrhritis due Borrelia burgdorferi reactive with
LFA-1 (lymphocyte function antigen-1)
EPITOPE SPREADING
• Definition:
Initial response to one self determinant (one
peptide) could expand to involve additional
determinants on the same molecule as well
as additional self-proteins. It explains how a
response to one cryptic epitope can mature
into a full-blown autoimmune response
• Examples:
– anti-Sm to U1RNP
– anti Ro/SS-A to anti-La/SS-B – lead to lupus-like
disease
HLA CLASS II EXPRESSION ON TISSUE
CELLS IN AUTOIMMUNE DISEASES
• Hashimoto thyroiditis – follicular cells of
the thyroid
• Type I diabetetes – beta cells of Langerhans
islets
• Primary biliary cirrhosis – cells of billiary
ducts
• Autoimmune hepatitis – hepatocytes
HLA CLASS II EXPRESSION ON TISSUE
CELLS IN AUTOIMMUNE DISEASES - 2
• Rheumatoid arthritis – synovial cells
• Sjogren’ syndrome –epithelium of salivary
ducts
• Multiple sclerosis – glial cells
• Chronic iridoscleritis – pigment epithelium
of retina
• Crohn’s disease – epithelium of small
intestine
OTHER FACTORS FAVORING
AUTOIMMUNITY
1. Overproduction and/or dysregulation of
cytokines
2.
3.
4.
5.
Disturbances of apoptosis
Adjuvant effect of microorganisms
Pre-existing defects in the target organ
Direct stimulation of autoreactive cells by
foreign antigen
PATHOGENICITY OF HUMAN
AUTOANTIBODIES
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Autoimmune blood dyscrasias
Antiphospholipid syndrome
Myasthenia gravis
Thyrotoxicosis (Graves disease)
Male infertility
Anti-receptor mediated diabetes mellitus
Goodpasture’s syndrome
Immune complexes (SLE, RA)
DIAGNOSTIC STEPS IN SYSTEMIC
LUPUS
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Immunoglobulin level (↑ >90%)
Complement components level (↓60%)
Anti-nuclear antibodies(ANA)(1:80< 95%)
Anti-ds DNA Ab (90-95%)
Rheumatoid factor (30%)
Immune complex deposits in the skin(60%)
„
„
„ in kidney (90%)
THERAPY OF AUTOIMMUNE DISEASES:
I. SELF-ANTIGEN SPECIFIC
1. Antibodies vs. autoreactive TCR
2. Vaccine containing autoreactive TCR
3. Administration of peptides – TCR
antagonists
4. Parenteral infusion of autoantigen or cDNA
5. Oral administration of autoantigen
Comment:
all above are at the stage of experiment
THERAPY OF AUTOIMMUNE DISEASES:
II. ANTIGEN NON-SPECIFIC
1. Monoclonal antibodies vs.T cells -CD2, CD3,
CD4
2. Antibodies vs. CD28, CD40L (modulation of
T cell – APC interaction)
3. Antibodies vs. cell adhesion molecules
(VLA-4, ICAM-1) and chemokines
4. Intravenous infusion of immunoglobulin
(IVIG)
5. Neutralization of proinflammatory cytokines
6. Administration of anti-inflammatory cytokines
THANK YOU
&
GOOD LUCK !