Immune recognition and injury ofself tissues (autoimmunity) results
from a loss of self tolerance.
Definition
Causes of Autoimmunity
• Disruption of self or tissue barrier (Antibodies in blood can attack Myelin Basic Protein if Blood-Brain barrier is breached.)
• Infection of antigen presenting cell
• Binding of pathogen to self antigen
• Molecular mimicry
• Superantigen Superantigen
• Inappropriate MHC expression (Type I Diabetes: Pancreatic β cells express abnormally high levels of MHC I and MHC II (?); MHC II – APC only! This may hypersensitize TH cells to β cell peptides.)
Molecular Mechanisms of Autoimmunity
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)
Molecular Mechanisms of Autoimmunity
Molecular Mechanisms of Autoimmunity
Cross-ReactivityMolecular Mechanisms of Autoimmunity
Molecular mimicry- model in IDDM
Molecular Mechanisms of Autoimmunity
Molecular Mechanisms of Autoimmunity
•Superantigen
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
Molecular Mechanisms of Autoimmunity
Molecular Mechanisms of Autoimmunity
• Inappropriate MHC expression
Type I Diabetes: Pancreatic β cells express abnormally high levels of MHC I and MHC II (?)
MHC II – APC only! This may hypersensitize TH cells to β cell peptides.
Inappropriate MHC Expression
Normal Pancreas Pancreas with Insulitis
Fig. 20-3
Molecular Mechanisms of Autoimmunity
• Polyclonal B Cell Activation by Viruses and Bacteria
If B cells reactive to self-peptides are activated, autoimmunity can occur.
Example: Epstein-Barr Virus, which is the cause of infectious mononucleosis.
Immune dysregulation
A defect in any arm of the immune system can trigger autoimmunity
Complement
T cells B cells
The Complement See-Saw
• The complement system is a mediator in both the pathogenesis and prevention of immune complex diseases
• It has a protective effect when functioning in moderation against pathogens; at the same time, the inflammation promoted by complement activation can result in cellular damage when not
kept in check.
Complement Deficiencies
• CD59 or CD55 – – Paroxysmal nocturnal
hemoglobinuria – autoimmune hemolytic anemia– autoimmune thrombocytopenia– lupus lymphopenia
• Deficiencies in the classical complement pathway renders pts more likely to develop immune complex diseases– SLE – RA
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
Th1/Th2 immune response
Cytokine Dysregulation in Autoimmunity
CD = Crohn’s Disease
Genes and Autoimmunity
• The concept that a single gene mutation leads to a single autoimmune disease is the EXCEPTION not the rule.
• Because of this autoimmune diseases are generally classified as complex diseases as there is not a single “pinpoint-able” gene
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)
HLA testing in diseasesDisease HLA AS
HLA B27
Birdshot retinopathy HLA-A29 Narcolepsy HLA- DR2,
DQВ1*0602
IDDM
HLA-DQ2, DQ3 HLA-DR3, DR4
Recurent abortions/ infertility
anti- HLA class I antibodies
RA
HLA- DRB1 typing
Familial haemohromatosis Familial testing of HLA-А, В, HFE genotype
Congenital adrenal hyperplasy (CAH)-prenatal diagnostic
HLA- А, В, DR pnenotype
HLA алел OR (сила на асоциация)
IDDM Предразполагащи алели
DRB1*0301 6.93 DRB1*04 6.33 DQB1*02 3.23 DQB1*0302 8.14 DQA1*0301 4.76 DQA1*0302 25.62 Протективни алели
DRB1*11 0.24 DQB1*0301 0.25 DQA1*0101 0.28
HLA association with IDDM in Bulgarian population
MS Predisposing alleles
DRB1*1001 7,9 DRB1*1303 15,9 DRB1*1501 2,7 DQB1*0602 3,0 DQA1*0104 21,6 Protective alleles DRB1*1101 0.1 DRB1*1301 0,2 DQB1*0301 0,4 JCA Predisposing allels DQB1*0503 3,9 DQA1*0101 2,5
HLA association with MS and JCA in Bulgarian population
- верига
- верига
57-58
3-ти HVR: 70-74
Вероятен молекулен модел за автоимунна болестВероятен молекулен модел за автоимунна болест
Exceptions to the Rule – Simple Genetic Autoimmune Illnesses
Disease Gene Mechanism
APS-1(Autoimmune polyglandular syndrome type 1)
AIRE Decreased expression of self-antigens in the thymus, resulting is a defect in negative selection
IPEX(Immunodysregulation, polyendocrinopathy, enteropathy,
X-linked)
FOXP3 Decreased generation of Tregs
ALPS(autoimmune lymphoproliferative syndrome )
FAS, FASL Failure of apoptotic death of self reactive T or B cells
Environment in autoimmunity
• Pathogens, drugs, hormones, and toxins are just a few ways that the environment can trigger autoimmunity
Drugs and Toxins
• Drugs– Examples: Procainamide (Pronestyl) – Drug induced lupus
• Toxins– Examples: Toxic Oil Syndrome– Occurred in Spain in 1981 after people ate
contaminated olive oil.– People developed unique illness marked by lung
disease, eosinophilia, and excessive IgE
Sex-based Differences in Autoimmunity
• Differences can be traced to sex hormones- hormones circulate throughout the body and
alter immune response by influencing gene expression
- (in general) estrogen can trigger autoimmunity and testosterone can protect against it
• Difference in immune response- ♀ produce a higher titer of antibodies and mount more vigorous immune responses than ♂- ♀ have a slightly higher cortisol secretion than ♂- ♀ have higher levels or CD4+ T-cells and serum IgM
Sex-based Differences
• Estrogen
- causes autoimmunity (generally)
- stimulates prolactin secretion (helps regulate immune response)
- stimulates the gene for CRH (corticotropin- releasing hormone) that promotes cortisol
secretion
- causes more TH1-dominated immune responses
(promotes inflammation)• Testosterone
- can cause autoimmunity or protect against it
Sex-based Differences• Pregnancy
- during this, ♀ mount more of a TH2-like response
- the change in hormones creates an anti- inflammatory environment (high cortisol levels)
- diseases enhanced by TH2-like responses are exaggerated and diseases that involve inflammatory responses are suppressed
- fetal cells can persist in the mother’s blood or the mother’s cells may appear in the fetus
(microchimerism)
- can result in autoimmunity if the fetal cells mount an immune response in the
mother’s body (or vice versa)
Estrogens and Autoimmunity
Nature Immunology 2, 777 - 780 (2001)
Sex differences in autoimmunity
Pathogenetic mechanisms of Autoimmune diseases
Autoimmune diseases
The immune response turns against the host
- Antibodies direct against cell-surface or extracellular-matrix molecules (Type II)
- Antibodies bound to molecules circulating in the plasma than deposit as immune complexes (Type III)
- T cells that are reactive with self antigens (Type IV)
Pathogenesis of SLE
Pick an organ, any organ . . .Autoimmunity can affect ANY organ/organ system in the human body
Pemphigus
Multiple Sclerosis
Sjogren’s Syndrome
Rheumatic Fever
Autoimmune Hepatitis
Ulcerative Colitis
Goodpasture’s Syndrome
Diabetes
Autoimmune Uveitis
Autoimmune hemolytic Anemia
Addison’s Disease
Rheumatoid Arthritis
Autoimmune Oophoritis
Autoimmunity Classification
Can be classified into clusters that are either organ-specific or systemic
Examples of Organ Specific
Lungs of a patient with Goodpasture’s
VitiligoHashimoto’s disease (thyroiditis)
Examples of Systemic Autoimmunity
SLE
Examples of Systemic Autoimmunity
Sjogren’s Syndrome
Putting it all together…
• Autoimmunity can be caused by immunological, genetic, viral, drug-induced, and hormonal factors.
• There are 4 immunological mechanisms of autoimmunity.
• All mechanisms cause abnormal B or T cell activation.• Centrality of the Ternary Complex• Most instances of autoimmune diseases occur with
multiple mechanisms, which makes treatment difficult.
I. Current Therapies
• Immunosuppressive drugs- corticosteroids, azathioprine- slows the proliferation of lymphocytes
• Cyclosporin A
- blocks signal transduction mediated by the TCR (inhibits only antigen-activated T cells while
sparing non-activated ones)• Thymectomy
- removal of thymus from patients with myasthenia gravis
• Plasmapheresis- removes antigen-antibody complexes for a short- term reduction in symptoms
II. Experimental Therapeutic Approaches
• T-cell Vaccination
- autoimmune T-cell clones elicit regulator T-cells that are specific for the TCR on the autoimmune
T- cells
- results in suppression of the autoimmune cells• Peptide Blockade of MHC molecules
- a synthetic peptide is used to bind in place of the regular peptide on the MHC
- induces a state of clonal anergy in the autoimmune T-cells
(Experimental Therapies continued)
• Monoclonal-Antibody Treatment
- monoclonal antibody against the IL-2 receptor blocks activated TH-cells
- blockage of preferred TCRs with monoclonal antibodies
- monoclonal antibody against an MHC molecule that is associated with autoimmunity while
sparing the others• Oral antigens
- tend to induce tolerance
- still in early clinical trials
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