ToleranceImmunogen (non-self)Immune response (cells, antibodies)Tolerogen (self)No Immune response (tolerance)

Non-self molecules: will induce immune-response or tolerance

DeterminantImmune responseTolerancePhysical form of AgLarge, aggregated, complexSoluble, small, less complexRoute of Ag administrationIntramuscularOralDoseOptimalVery large or very smallAge of responding animalOlder and immunological matureNew born, immunological immature

Immunological features of toleranceTolerance is different from immuno-suppression and immunodeficiencyIt is an immunological process in response to an active antigenSpecific like immune responseCan exist in T cell, B cell or bothTolerance at T cell: longer lasting, can be induced with low amount of tolerogenRequirement for maintenance of tolerance: Tolerance induction to single or multiple epitopes in a tolerogen

Mechanisms for induction of tolerance to self-antigensClonal deletionClonal anergyClonal ignorance

Failure of toleranceNatural failure in autoimmune diseases: Breakdown of bodys tolerance to self antigens Immune response against self-antigensArtificial failure Drugs, X-rays

Termination of experimentally induced toleranceBy prolonged absence of tolerogenBy treatments (X-rays) leading to damaged immune system

Auto-immunity (damage to the self)Classification of autoimmune diseases:Organ specific Non-organ specific

Organ Specific Non-organ specificSelf-antigens induce antibodies specific to an organEffects due to Ab mediated cell lysisSpecific organ damaged

Myasthenia Gravis, Pernicious anemia, Hashimotos thyroiditis

Self-antigens induce non- specific antibodies Due to deposition of Ag-Ab complexesConnective tissue related damage

Rheumatoid ArthritisClassification of Auto-immune diseases

B cells (Antibodies) and Effector T cells (and their products) are involved in damage in autoimmune disease T dependent autoimmune diseasesPrevention of autoimmune diseases by regulation of auto-reactive T helper cells

AutoantigenT helper T cytotoxic autoimmune disease B cell autoantibody

Genetic factors and auto-immune diseasesOccur in clusters in certain familiesAssociation with HLA specificitiesAddisons disease: HLA from DR3Rheumatoid arthritis: HLA from DR4HLA: B8, B27, DR2, DR5, etc. have also been linked to other auto-immune disease

Hormonal factors and auto-immune diseasesSLE (Systemic lupus erythematosus) more in woman during their reproductive phase

Mechanisms of tissue damage/injury in auto-immune diseases

1. Release of inflammatory mediators and cell lysis Cell lysis: Complement pathway or ADCC by K cells

2. Formation of immune complexes Deposition of immune complexes in tissues, joints, blood vessels Fix complement and cause inflammationAuto-antibodies + antigens = immune complexes

3. Cell mediated auto-immune responseAuto-reactive T cells Secrete lymphokinesKill the self-cells directly Amplify inflammatory responses

Etiology of auto-immune diseases1. Exposure of sequestered antigensTissue damage/injuryAntigens are exposedEmergence of auto-antibodiesExamples: Antibodies againstLens protein after the eye injurySperm after vasectomyHeart muscle antigens after heart surgery

2. Modification of self-antigenSelf-antigen: Host is tolerantAltered self-antigen: Host is not tolerantEmergence of auto-immune diseases

Alteration by bacterial viral infectionImmune response against blood group antigens in Mycoplasma pneumoniae infection

Alteration by drugsAuto-immune haemolytic anaemia due to -Methyl dopamodifies RBC; B cell react and lyse

3. Molecular mimicryDue to availability of cross-reacting antigens from exogenous microbial systemsExample: Envelope proteins on Yersinia enterolytica share epitopes with extracellular domain of human thyroid-stimulating hormone (TSH)

4. Defective regulation by TH cells In immune response to non-selfT helper cells B cells to produce AbIn tolerance to self-antigensT helper cells remain inactive and do not activate B cells to produce AbPossible reason for generation of auto-immune response:T helper cells initially tolerant to a specific antigen turn activated and stimulate B cells to produce auto-antibodies

Defective T suppressor cellsT suppressor cells inhibit B cells from producing AbIn tolerance to self-antigensT suppressor cells remain active and inhibit B cells to produce auto-antibodyPossible reason for generation of auto-immune response:T suppressor cells initially active with respect to a self antigen turn inactivated and can not inhibit B cells from producing auto-antibodies

5. Polyclonal B cell activationAdjuvant properties in microorganisms (e.g. bacterial lipopolysaccharides, mycobacterial cell wall antigens)Stimulate several clones of B cells in a non-selective and non-specific manner

6. Abnormal expression of MHC II during viral infectionTH cells are deleted for self-antigens: clonal deletion

Self-neural and endocrine antigens, TH cells are not deleted escape into the peripheral tissuesWill react with self antigens in combination with MHC IINormally prevented because of limited distribution of MHC IIIncreases MHC II in viral infection auto-immune diseases

Myasthenia Gravis (Grave muscle weakness) An auto-immune disease causing muscle weakness and fatigue abilityCaused by a defect in the transmission of nerve signals to muscles at neuro-muscular junctions

Normal immune system: ACH as neurotransmitter

SymptomsMuscle weakness Involves muscles that control eye and eyelid movement, facial expression, chewing, talking, breathing, and swallowing. The thymus gland is abnormal in most MG cases. Some people carry thymomas (benign tumors of the thymus gland)Being an autoimmune disease, it may occur in combination with other autoimmune conditions such as rheumatoid arthritis, pernicious anemia, autoimmune thyroiditis, etc.

Acetylcholine (ACH)receptors (ACH-r) on (released from nerve the muscleendings)Muscle contractions

In Mys-Gravis auto-antibodies are generated:against Acetylcholine receptors (Ach-r)against MuSk No transmission of neuromuscular signal

Neonatal myasthenia Congenital myasthenia Ocular myastheniaMyasthenic crisis

TreatmentDrugs to enhance nerve-muscle communication (e.g. pyridostigmine). Immunosuppressive drugs to suppress immune system, and hence the production of auto-antibodies. Thymectomy: surgical removal of the thymus gland in patients with or without tumors. Plasmapheresis: Blood is taken from the patient, filtered to remove the abnormal antibodies. Purified blood is re-transfused.

Asthma: an example of local anaphylaxisIgE antibodies bind to basophils/mast cellsAllergen binds to IgE Granules undergo exocytosis

Asthma: The bronchi constricted; Difficulty in breathing Symptoms: wheezing and coughAllergenlungsmast cells in the lung undergo exocytosis releasing histamine and leukotrienessmooth muscle cells of the bronchi contract and narrow the lumen of the bronchi: Early phase of the disease

Onset of late phase of the diseaseAccumulation of inflammatory cells (e.g eosinophils) and production of mucus (that blocks airways). With repeated attacks, the lining of the bronchi becomes damaged

Presence of T helper cells of asthma patients are largely of the Th2 type not Th1 typeTh2 helper cells: help B cells make IgE antibodies by synthesizing IL-4 and IL-13, which promote class switchingrelease IL-5 which attracts eosinophils and other inflammatory cells to the site, producing the late phase of the response

Treatment1. Corticosteroids: To reduce the inflammation of the late phase 2. Cromolyn sodium: to inhibit exocytosis of mast cells thus blocking the release of histamine and leukotrienes3. Use of leukotriene inhibitors

Possible future treatments

Anti-IgE antibodies: interfere with the binding of IgE to mast cells, e.g., Omalizumab (Xolair)Drugs that bind to IL-4 and IL-13 to prevent IgE synthesis. Treatments that stimulate the production of Th1 cells. Th1 cells secrete interferon-gamma, a powerful inhibitor of Th2 cells.

Non-organ specific auto-immune diseasecan lead to long-term joint damage, results in chronic pain, loss of function and disability Rheumatoid arthritis

Progresses in 3 stagesSwelling of the synovium, redness, stiffness, pain around the joints

Caused by the inflammation of the lining, or synovium, of the joints

Rapid growth of cells, causes synovium to thicken (Pannus)Release of enzymes: digest bones and cartilege; loss of size, shape and function

Being a systemic disease, it can affect other organs in the body (skin, heart, lung, muscle, etc.) Role of gender? The disease affects women 3 times more than men

Signs and symptoms Morning stiffness Polyarthritis Symmetric arthritis Rheumatoid nodules: Nodules are firm, pea-sized masses made up of inflammatory by-products; not painful and can occur anywhere in the body

Immunological basis1. Rheumatoid factor: An antibody produced during the inflammationMainly IgM but also IgG and IgA produced by the B cells and plasma cells in the synovial membrane2. A number of cytokines are produced in the diseasePro-inflammatory: IL1, IL6, TNF, GM-CSF, IL15 etc

DiagnosisLatex test: Measurement of Rheumatoid factorSedimentation rate test of blood: for testing the status of inflammation

TreatmentDisease modifying antirheumatic drugs (DMARDs) Anti-inflammatory drugs Analgesics Antibodies for blocking TNF, IL1

Weight loss, surgery (knee/joint replacement)