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Molecular Mechanisms ofMolecular Mechanisms of Autoimmunity
By: Nadia Chanzu, PhD Student, UNITID
Infectious Minds Presentation
November 17, 2011
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IntroductionIntroduction
3�m
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Pick an organ, any organ . . .g , y gAutoimmunity can affect ANY organ/organ system in the human body
Multiple SclerosisAutoimmune Uveitis
PemphigusSjogren’s Syndrome
Goodpasture’s SyndromeRheumatic Fever
Autoimmune Hepatitis
Goodpasture s Syndrome
Diabetes
Addi ’ Di
Ulcerative Colitis
Addison’s Disease
Autoimmune Oophoritis
Autoimmune hemolytic AnemiaRheumatoid Arthritis
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Molecular Mechanisms of Autoimmunityy
How is autoimmunityHow is autoimmunity induced?
What could go wrong here?
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Major factors in initiation and regulation of AI disease
1. MHC Control
2. Antigen Mimicry2. Antigen Mimicry
3. Altered Proteins
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Major Histocompatibility ComplexMajor Histocompatibility Complex
• Human – A set of linked genes located onHuman A set of linked genes, located on chromosome 6
• Molecules encoded by the MHC:– Cell surface receptors
– Bind unique antigen fragments
– Display them for recognition by immune effectors; most importantly T – Cells
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AntigenAntigen Presentation
APC to T-cell
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• The MHC accomplishes its major role in immune recognition by satisfying two distinct molecular functions:– Binding of peptides (or in some cases non‐peptidic molecules)
– Interaction with T cells, usually via the αβ T‐cell receptor (TCR).
MHC TCR
PEPTIDE
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MHC CLASS I MHC CLASS II
Three MHC Class I alpha chain genes:
Three MHC Class II alpha chain genes:chain genes:
HLA – A, B and Cchain genes:HLA – DR, DP and DQ
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MHC & AutoimmunityMHC & Autoimmunity
• Regardless of the underlying cause ofRegardless of the underlying cause of autoimmunity, predisposition to a given autoimmune response is associated withautoimmune response is associated with certain HLA allele(s)
• Involvement of the requisite HLA allele is at h l l f i i b h APCthe level of antigen presentation by the APCs for T Cell recognition
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MHC Control gone wrong? DR3, DR4g g ,
Normal Pancreas
Diabetes
Pancreas with Insulitis
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Major factors in initiation and regulation of AI disease
1. MHC Control
2. Antigen Mimicry2. Antigen Mimicry
3. Altered Proteins
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Molecular MimicryMolecular Mimicry
(Oldstone, 1998)
14
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Molecular MimicryMolecular Mimicry• Microbe and Host Cell:
Share of a linear amino acid– Share of a linear amino acid sequence
– Share of conformation fit
• Host immune response against the microbe reacts if the host sequence comprises a biologically important domain
• Autoimmunity may occur(Oldstone, 1998)
15
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Rheumatic fever is a classic example of molecular mimicry
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Major factors in initiation and regulation of AI disease
1. MHC Control
2. Antigen Mimicry2. Antigen Mimicry
3. Altered Proteins
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Figure 7-2 part 1 of 2The development of T cells:
Figure 7 2 part 1 of 2
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Figure 7-2 part 2 of 2Figure 7 2 part 2 of 2
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Protein Mutation & Altered ExpressionProtein Mutation & Altered Expression
Expression of Autoimmune Regulator Gene (AIRE) in the thymus shape the immune repertoire:
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Exceptions to the Rule – SimpleExceptions to the Rule Simple Genetic Autoimmune Illnesses
Di G M h iDisease Gene Mechanism
APS 1 AIRE Decreased expression ofAPS-1(Autoimmune polyglandularsyndrome type 1)
AIRE Decreased expression of self-antigens in the thymus, resulting is a defect in negative selection
IPEX(Immunodysregulation,
FOXP3 Decreased generation of Tregs
( y gpolyendocrinopathy, enteropathy,X-linked)
ALPS FAS, FASL Failure of apoptotic death of self reactive T or B cellsALPS
(autoimmune lymphoproliferative syndrome )
FAS, FASL self reactive T or B cells
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Major factors in initiation and regulation of AI disease
1. MHC Control
2. Antigen Mimicry2. Antigen Mimicry
3. Altered Proteins
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Posttranslational ModificationPosttranslational Modification• Translation: Process of synthesizing the peptide chain of amino acids specified by the nucleotidespecified by the nucleotide sequence on the mRNA
• Post‐translational modification: The chemical modification of a protein after its translation
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T CELL MEDIATED DISEASET-CELL MEDIATED DISEASE
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Autoimmunity to Sequestered Proteins
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• Sequestered proteins are normally sheltered q p yfrom immune recognition
• However, they can become immunogenic once exposed to recognition by immune cells andexposed to recognition by immune cells and induce efficient immune responses
• A good example: Antibodies in blood can g pattack Myelin Basic Protein if Blood‐Brain barrier is breached
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Multiple Sclerosisp
MS patients can have autoantibodies and/or self reactive T cells which are responsible for the demyelination
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Additional Factors!!Additional Factors!!
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PregnancyPregnancy
• Antibody‐mediated autoimmune diseases can appear in the infants of affected mothers as a consequence of trans‐placental antibody transfer
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HormonesHormones
• Some autoimmune diseases show a significantSome autoimmune diseases show a significant bias in gender suggesting that sex hormones are involved in pathogenesisare involved in pathogenesis
• Females are much more likely to develop• Females are much more likely to develop autoimmune illness
Hypothesis: estrogen response elements (EREs) in several genesg
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Estrogens and Autoimmunity
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StressStress
STRESS:STRESS:
• Normal Stress (Exams!)
• Chronic Stress = DiseaseChronic Stress = Disease
Stress induces change forStress induces change for adaptation:
• Behavioral (e g Moods)Behavioral (e.g. Moods)
• Physiological (e.g. HBP)
• Immunological (e g AI)• Immunological (e.g. AI)
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IF YOUR WORKLOAD GETS TOO MUCHIF YOUR WORKLOAD GETS TOO MUCH...
THINK OF HOW TO BALANCE YOUR LIFE!
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FutureFuture
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What is an Artificial Pancreas?What is an Artificial Pancreas?
Continuous Glucose Sensor
Control -Algorithm
Insulin Pump
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Questions
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ReferencesReferences
• Atassi MZ and Casali P. (2008). Molecular mechanisms of autoimmunity. Autoimmunity, 41 (2), p.123‐132.
• Wiegers GJ, Kaufmann M, Tischner D and Villunger A. (2011). Shaping the T‐cell repertoire: a matter of life and death. Immunology and Cell Biology, 89, p.33‐39.
• Waterfield M and Anderson MS. (2010). Clues to immune tolerance: the monogenic autoimmune sydromes. Annals of The New York Academy of Sciences Issue: The Year in Human and Medical Genetics, 1214 (2010), p.138 – 155
• Janeway CA, Travers P, Walport M and Shlomchik M. Immunobiology, Sixth Edition, Garland Science.