Autoimmunity engl

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)



Cross-ReactivityMolecular Mechanisms of Autoimmunity

Molecular mimicry- model in IDDM



•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



• 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


• 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

Documents

Autoimmunity engl