Autoimmune Responses

8/8/2019 Autoimmune Responses

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Amity Institute of Biotechnology

M.Tech. Biotechnology Programme

III Semester-Section ACourse Code: MBT301

Immunology and Immunotherapy

Faculty: Pankaj Sharma, PhD


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Autoimmunity OutlineHistoryDefinition

Disease statesCausesImmunopathologyDiagnosisTreatmentMouse Models of human disease


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Autoimmunity OriginsHorror autotoxicus:

Literally, the horror of self-toxicity.

A term coined by theGerman immunologistPaul Ehrlich (1854-

1915) to describe the body's innate aversionto immunological self-destruction.


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AutoimmunityBasically means immunity to self

A condition that occurs when the immune systemmistakenly attacks and destroys healthy body tissue.


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The Immunology Definition

Failure of immune

tolerance


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Autoimmune Response

Antibody directed against self, termed auto-antibody

Considered abnormal but usually does notresult in disease.May occur in healthy individuals.


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Autoimmune Di sease

Disorder in which tissue injury is caused by animmunologic reaction of the host to its owntissues.Precise mechanisms unknown.Classified as systemic or organ specific,frequently have overlap.


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MECHANISMS OF BREAKING OF

SELF-TOLERANCEDisruption of self or tissue barrier

Infection of antigen presenting cell

Binding of pathogen to self antigen

Molecular mimicry

Superantigen


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Autoimmunity Classification

Can be classified into clusters that are either organ-specific or systemic


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ORGAN-SPECIFIC AND NON ORGAN-

SPECIFIC AUTOIMMUNE DISEASESOrgan-specific

Autoimmune attack vs.self-antigens of givenorganIt results in a damage of organ structure and

functionTreatment is focused onthe replacement of organ function

No n o rgan- specific (systemic)Widespread self-anti-gens are targets for autoimmune attackDamage affects suchstructures as blood

vessels, cell nuclei etc.Treatment is aimed toinhibit excessiveactivation of the immunesystem


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Examples of Organ Specific

Lungs of apatient withGoodpastures

VitiligoHashimotos disease(thyroiditis)


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Examples of Systemic Autoimmunity

SLE


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Examples of Systemic Autoimmunity

Sjogrens Syndrome


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Causes of Autoimmunity


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Genes and AutoimmunityThe concept that a single gene mutation leadsto a single autoimmune disease is theEXCEPTION not the rule.

Because of this autoimmune diseases are

generally classified as complex diseases asthere is not a single pinpoint-able gene


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Exceptions to the Rule Simple

Genetic Autoimmune IllnessesDisease Gene Mechanism

APS-1(Autoimmune polyglandular syndrometype 1)

AI RE Decreased expression of self-antigens in the thymus,resulting is a defect in negativeselection

IPEX(Immunodysregulation,

polyendocrinopathy, enteropathy,X-linked)

FOXP3 Decreased generation of Tregs

ALPS(autoimmune lymphoproliferativesyndrome )

F AS, F ASL Failure of apoptotic death of self reactive T or B cells


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Complex Disease and GeneticsThere have been numerous disease associated genes or disease

susceptibility genes linked to autoimmunity


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EnvironmentPathogens, drugs, hormones, and toxins are

just a few ways that the environment cantrigger autoimmunity


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PATHOGENSExamples of Molecular Mimicry between Self-antigens and Pathogens


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MOLECULAR MIMICRY

D efiniti o n : Determinants of infectious agent mimic a hostantigen and trigger self-reactive T-cell clones toattack host tissues.

Ex amples :S tromal keratitis due to herpes simplex virus type IRheumatic fever due to group A streptococcusSLE due E pstein-Barr virus cross reactive with nuclear S m antigenLyme artrhritis due Borrelia burgdorferi reactive with LF A-1

(lymphocyte function antigen-1)


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EPITOPE SPREADING

D efiniti o n : Initial response to one self determinant (onepeptide) could expand to involve additionaldeterminants on the same molecule as wellas additional self-proteins. It explains how aresponse to one cryptic epitope can matureinto a full-blown autoimmune responseEx amples :

anti- S m to U1RNP anti Ro/ SS -A to anti- La/ SS -B lead to lupus-like

disease


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Drugs and ToxinsDrugs Examples: Procainamide (Pronestyl)

Drug induced lupus

Toxins Examples: Toxic Oil Syndrome

Occurred in Spain in 1981 after people atecontaminated olive oil.

People developed unique illness marked by lungdisease, eosinophilia, and excessive IgE


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HormonesFemales are much more likely to developautoimmune illnessRise in hormones associated with pregnancy mayeven cause abortion of the fetus (RSA)Endometriosis and preeclampsia are both thought to

be autoimmune in nature

Hypothesis: estrogen responseelements (EREs) in several genes


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Sex Differences in Autoimmunity


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Immune RegulationA defect in any arm of the immune system can trigger

autoimmunity

Complement

T cells B cells


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Complement Deficiencies

CD59 or CD55 Paroxysmal nocturnal

hemoglobinuria autoimmune hemolytic anemia

autoimmune thrombocytopenia lupus lymphopenia

Deficiencies in the classicalcomplement pathway renders pts

more likely to develop immunecomplex diseases SLE RA


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The Complement See-Saw

The complement system is a mediator in both the pathogenesis and prevention of immune complex diseasesIt has a protective effect when functioning in moderationagainst pathogens; at the same time, the inflammation

promoted by complement activation can result in cellular

damage when not kept in check.


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B or T? That is the question?

Autoimmunity is hard to classify as strictly a Bcell or T cell mediated disease as multiplearms of the immune system are involved


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Myasthenia Gravis

Disease marked by progressive weakness andloss of muscle control

Classified as a B cell DiseaseAutoantibodies against nicotinic acetylcholinereceptors


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DIABETES

Disease in whichthe body does not

produce or properly

use insulin T cell DiseaseT cells attack anddestroy pancreatic

beta cells


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Multiple Sclerosis

MS patients can have autoantibodies and/or self reactive T

cells which are responsible for the demyelination


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Cytokine Dysregulation in Autoimmunity


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IL-17: The Autoimmunity Cytokine?IL -17 KO mice less susceptible to autoimmunity especially

MS and RA


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SYMPTOMS

Initial diagnosis may be missed in patients asdiseases present with general symptoms

Fever, muscle ache, fatigue, joint pain

Disease specific manifests

SLE rash Sjogrens dry mouth, dry eyes


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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


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Treatment

The key to treatingautoimmunity is

immunomodulation


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THERAPY OF AUTOIMMUNE DISEASES:I. SELF-ANTIGEN SPECIFIC

1. Antibodies vs. autoreactive TCR2. Vaccine containing autoreactive TCR3. Administration of peptides TCR antagonists

4. Parenteral infusion of autoantigen or cDNA5. Oral administration of autoantigenC o mment :

all above are at the stage of experiment


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Treatment Options

Anti-inflammatory drugsNSAIDS, CorticosteroidsImmunosuppressant drugs

Methotrexate

RadiationPlamapheresisCell Blocking Reagents

E CD20 (Rituxan)E CD3 (Teplizumab)

Cytokine Blocking ReagentsTNF (Humira, Enbrel)


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Mouse Models

Human Disease Mouse ModelRA Collagen Induced Arthritis

(CIA)MS Experimental Autoimmune

Encephalitis (EAE)Ulcerative Colitis (UC) Dextran Sodium Sulfate

induced Colitis (DSS)Diabetes Non Obese Diabetic (NOD)

Lupus MRL lpr (Lpr = lupus prone)

Documents

Autoimmune Responses