Download - 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)