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
sta in-B
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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