IMMUNOLOGIC TOLERANCE AND AUTOIMMUNITY

AmithBabu

Syed.Khaja.Aliuddin

O.R.Ganesh

Self-nonself discrimination

Self

No response Strong response

Non-selfor foreign

Tolerance

Tolerance--->specific unresponsiveness triggered by previous exposure to Ag.

Natural Tolerance (self tolerance): Unresponsiveness to self Ags.

Acquired tolerance:

Unresponsiveness to foreign Ags.

Tolerance in non-identical cattle twins:

Tolerance

Tolerance

It is a specific immunologic unresponsiveness i.e. the absence of specific immunoresponses to a particular antigen in a fully immunocomptent person Unresponsiveness to self antigens is known as auto toleranceBoth B-cells and T-cells participate in tolerence But T-cells play the primary role

High zone and low zone tolerance

Theories of Tolerance Induction

We can divide the mechanisms the immune system uses to ensure the absence of selfreactivity

It is divided in two main types:

• Central Tolerance: this occurs during lymphocyte development.

• Peripheral Tolerance: occurs after lymphocytes leave the primary organs

Central Tolerance

Burnet’s Hypothesis:(1949) During neonatal stage of life, or when

immune system is developing, all Ags present are recognized as self.

Immune system becomes tolerant to these Ags.

How is tolerance accomplished? By clonal deletion--cells which come across

self-Ag undergo apoptosis.

Medawar proves Burnet’s Hypothesis:

Burnett & Medawar won Nobel Prize in 1960.

stra in A new born

8 w eeks

10 days

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Peripheral Tolerance

Clonal anergy It has therefore emerged as a possible

alternative mechanism for self tolerance. The term clonal anergy was coined by Gustav

Nossal in the mid - 1970s.

two signal hypothesis for lymphocyte activation

ligand-induced activation or antigen blockade

Factors affecting tolerance:role of antigen

Favor toleranceFavor immune response

Factors which affect response

Very large or very small dose

Optimal doseDose of antigen

Physical form of antigen

Large, aggregated, complex molecules

soluble, aggregate-free, simple small molecules

Antigen processing properly processed improperly processed

Route of injection Subcutaneous or intra-muscular

Oral or, sometimes, intravenous

Factors affecting tolerance:role of antigen

Favor toleranceFavor immune

responseFactors which affect

response

Age of responding animal

Adult, immunologically mature

Newborn (mice)Immunologically immature

Differentiation state of cells

Fully differentiated, Memory

Undifferentiated B cell with only IgM, T cells in the thymic cortex

Factors Influencing The Induction Tolerance

1) Immunologic maturity of the host:

Neonates are immunologically immature and well accept allograft that would be rejected by mature host

2) Structure and dose of antigen:

a- Simple molecules induce tolerance more readily than complex ones

b- Very high and very low doses of antigen may result in tolerance

Factors Influencing The Induction Tolerance

3) T-cells become tolerant more readily and remain tolerant longer than B-cells

4) The continuous presence of antigen helps to maintain tolerance

5) Administration of immunosuppressive drugs enhances tolerance as in transplantation

Clinical Importance of Tolerance

1) Organ transplantation:

Introduction of tolerance may help prevention of rejection

2) Tumor development:

Tolerance to tumor antigen results in growth of the tumor without being detected by the immune mechanisms

3) Autoimmune disorders:

Disturbance of self-tolerance results in autoimmune disease

Autoimmunity When the Good Turns Bad……..

Autoimmunity

Failure of immune tolerance * Autoimmune diseases occur due to breakdown of the mechanisms that maintain auto tolerance

* Auto-antibodies and self reactive T-cells are produced, resulting in tissue damage by several mechanisms

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

Etiology Of Autoimmune Diseases

1) Genetic predisposition:

- Familial incidence of autoimmune diseases

- Most of them appear to be associated with certain MHC genes, specially MHC II genes

e.g. Rheumatoid arthritis is associated with DR4

Thyroditis with DR5

Multiple sclerosis with DR2

SLE with DR2/DR3

Type I diabetes with DR3/DR4

Ankylosing spondylitis with B27

2.Environment

Pathogens, drugs, hormones, and toxins are just a few ways that the environment can trigger autoimmunity

3.Pathogens

4.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

5.Hormones

Females are much more likely to develop autoimmune illnessRise in hormones associated with pregnancy may even cause abortion of the fetus (RSA)Endometriosis and preeclampsia are both thought to be autoimmune in nature

Hypothesis: estrogen response elements (EREs) in several genes

Estrogens and Autoimmunity

Nature Immunology  2, 777 - 780 (2001)

Sex differences in autoimmunity

Autoimmunity ClassificationCan 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

Immune RegulationA defect in any arm of the immune system can

trigger autoimmunity

Complement

T cells B cells

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

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.

B or T? That is the question?

Autoimmunity is hard to classify as strictly a B cell or T cell mediated disease as multiple arms of the immune system are involved

Myasthenia Gravis

Disease marked by progressive weakness and loss of muscle control

Classified as a “B cell” Disease

Autoantibodies against nicotinic acetylcholine receptors

Diabetes

Disease in which the body does not produce or properly use insulin

“ T cell” Disease

T cells attack and destroy pancreatic beta cells

Multiple Sclerosis

MS patients can have autoantibodies and/or self reactive T cells which are responsible for the demyelination

Mechanisms of Tissue Injury in Autoimmune Diseases

Three mechanisms are principally responsible for inflammation and tissue injury in

autoimmune disease

1. Cell lysis and release of inflammatory

mediators triggered by auto antibodies

2. Immune complex disease

3. T-cell mediated damage

Cell lysis by autoantibodies

In Myasthenia Gravis, Antibodies

To The Acetylcholine

Receptor Block Neuromuscular Transmission Needed Form

Muscle Contraction

Immune complex deposition

1.systemic lupus erythematosus

2.Rheumatoid arthritis, the auto antibody called rheumatoid factor, is usually an IgM,

which is directed towards the Fc portion of the patient’s own IgG. Complexes of rheumatoid

factor IgM coupled with IgG, get deposited at various sites leading to the characteristic synovitis and vasculitis of rheumatoid arthritis

T-cell mediated damageThis term implies that the recognition of autoantigen by T cells leads to tissue destruction

without requiring the production of autoantibody. There are a number of ways this can come about:

• Direct T cell cytotoxicity via CD8+ CTL

• Self-destruction of tissue cells induced by cytokines, e.g. TNF α

• Recruitment and activation of macrophages leading to bystander tissue destruction

• Induction of target tissue apoptosis by the T cell membrane protein FasL

DiagnosisHistory

Examination

Immunofluorescence

Antibody assay

Autoantibodies are used to diagnose many autoimmune diseases. The levels of autoantibodies are measured to determine the progress of the disease

Diagnosis

General tests– C Reactive Protein – Autoantibody titers (anti DNA, anti

phospholipids, etc)– Presence of Rheumatoid Factor

Disease specific tests– Neurological exam – MS– Fasting glucose - Diabetes

Laboratory Diagnosis

1- There is elevated serum immunoglobulins

2- Complement levels may be decreased

3- Immune complexe detected in serum or organ biopsy

4- Auto antibodies can be detected in serum

e.g. anti-nuclear, anti-smooth muscles, Rh factor

and anti-mitochondrial Ab

5- Testing for antibodies specific to particular Ag,

involved in organ specific diseases (anti-thyroid Ab)

Treatment

The key to treating autoimmunity is

immunomodulation

Treatment Options

•Anti-inflammatory drugs• NSAIDS, Corticosteroids

•Immunosuppressant drugs• Methotrexate

•Radiation •Plamapheresis•Cell Blocking Reagents

• aCD20 (Rituxan)• aCD3 (Teplizumab)

•Cytokine Blocking Reagents• TNF (Humira, Enbrel)

****** Remember ******

Autoimmunity is a failure of tolerance!

Knowing the tolerance mechanisms the immune system uses, will help you better understand autoimmune diseases!

Questions

Thank you