MECHANISMS OF AUTOIMMUNITY

Lecture 11

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 harm-

less 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 ORGAN- SPECIFIC AUTOIMMUNE DISEASES

Organ-specific

• Autoimmune attack vs. self-antigens of given organ

• It results in a damage of organ structure and function

• Treatment is focused on the replacement of organ function

Non organ- specific (systemic)

• Widespread self-anti-gens are targets for autoimmune attack

• Damage affects such structures as blood vessels, cell nuclei etc.

• Treatment is aimed to inhibit excessive activation of the immune 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

• 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. eliminationb. maintenance of immunologic ignorancec. functional inactivation (anergy)d. 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. Disturbances of apoptosis

3. Adjuvant effect of microorganisms

4. Pre-existing defects in the target organ

5. Direct stimulation of autoreactive cells by foreign antigen

PATHOGENICITY OF HUMAN AUTOANTIBODIES

• 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

• 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 cytokines6. Administration of anti-inflammatory cytokines

THANK YOU

&

GOOD LUCK !