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36 Cards in this Set

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What are the 3 phases of autoimmune disease pathogenesis?
1. Induction phase - innate immune system activated. Cells recruited.

2. Inflammatory phase - antigen-specific immune response.

3. Destructive phase - tissue injury occurs. clinical manifestation of disease.
How are auto-reactive T cells eliminated?
If they encounter high affinity self-antigen in the thymus, they are killed
How many signals are needed to activate mature T cells?

What are they?
2 signals needed

Signal 1: Stimulation of TCR by antigen (from APC)

Signal 2: Co-stimulation from B7/CD28 on B cell/APC
What happens if T cells get Signal 1 without 2 or vice a versa?
ANERGY
What is the role of CTLA4 in T cells?
Inhibition (prevents Signal 2 - binding of B7 to CD28)
What are the 3 steps that need to be broken to get autoimmunity?
1. Auto reactive T cells need to escape thymus

2. Receive stimulation from activated APCs

3. Avoid regulatory T cells that would suppress
What type of receptor is key to innate immunity?
Toll-Like Receptors (TLR)
What specific structures on AB's make them specific to an antigen?
Hypervariable regions
How many antibody hypervariable loops does it take to bind an antigen?
ONLY ONE!
What is cross-reactivity?
When an antibody binds more than 1 antigen

This is possible bc hay 6 hypervariable regions but only 1 is needed to bind an antigen
What is it when an external antigen "looks like" an autoantigen?
Molecular Mimicry
How does molecular mimicry cause autoimmunity?
External antigen stimulates B cell AB production of AB that will also attack endogenous cells

Ex: Rheumatic fever after Strep (attacks cardiac myosin)
What are the 4 main ways that AutoAbs can cause disease?
1. Attack self cells - cause direct damage

2. Produce abnormal cell activation (ie Graves disease)

3. Block normal ligand (ACh in myasthenia gravis)

4. Form soluble immune complexes which deposit
What is it called when immunization with a foreign protein elicits an immune complex mediated disease?
Serum Sickness
What are 2 ways that certain HLA (MHC) types could be correlated with autoimmune disease?
1. Certain HLA alleles bind autoantigens and present to T cells

2. Certain HLA allels bind cross reactive viral/bacterial antigens
MCH I and II often bind different peptides, how do they select which ones to bind?
1. Bind the peptide backbone (predominate in MCH II)

2. Bind specificity pockets (predominate in MHC I)
What do MHC II molecules present?

Present to what cells?
- Exogenous antigens

- Presented by APC's

- Presents to CD4+ T cells
What do MHC I molecules present?
- Endogenous peptides

- Present on ALL cells

- Presents to CD8+ T cells
What type of pathogen would be associated with MHC I mediated autoimmunity?

MHC II?
MHC I: intracellular pathogen

MHC II: extracellular pathogen
Which is specific in what they present, MHC or TCR?
TCR, MHC present EVERYTHING
What are the 2 ways that an antigen could act as a molecular mimic?
1. Structural similarity

2. Sequence similarity
What are the roles of the following T cell types?

TH1
TH2
TH17
Treg
TH1: DTH and cytotoxicity (cell mediated)

TH2: Humoral and allergic responses (Humoral)

TH17: Bacteria, cancer, autoimmunity

Treg: immunosuppression
What T cell type is often important in autoimmunity?

What cytokine does it produce?
TH17

IL-17
What is seen (with regard to T cell type) in SLE?
Decreased Treg and increased TH17
How many Antigens can an APC present?
MULTIPLE
What is epitope spreading?
When antigens that are associated together are taken up and ALL are presented by an APC
What are the 2 steps of T cell epitope spreading?
1. APC's take up immune complexes and present multiple epitopes to T cells

2. Multiple T cells are stimulated with multiple epitopes contained within the immune complex
What is the key concept of B cell epitope spreading?
A single epitope specific T cell will stimulate any B cell that presents that epitope
What is the major cytokine in Rheumatoid Arthritis (RA)?
Tumor Necrosis Factor (TNF)
Does 1 gene necessarily mean you only get one autoimmune disease?
No, overlapping therefore families can have multiple diseases
What are the major pathogenic steps in Systemic Lupus Erythematosus (SLE)?
1. Defects in thymic deletion/Treg cells lead to autoreactive T cells

2. T cells produce autoreactive B cells and Ab's

3. Auto Ab's form complexes and activate complement

4. Inflammation cascade initiated
What can immune complex deposition cause?
1. Glomerulonephritis

2. Vasculitis

3. Dermatitis
What HLA molecule is linked to RA?

Why?
- HLA-DR

- Perhas because specific peptide from type II collage (seen Win cartilage) binds HLA-DR
What finding suggested cross-reactivity at T cell level in RA?
Dual TCR expression on T cells present in joint of RA patient
How might environmental triggers play a role in RA?
Oxidative stress (coffee, smoking, etc) causes vimentin mutation and this altered self antigen can trigger auto-immune response
How could apoptotic blebs trigger autoimmunity?
An APC that binds an antigen on an apoptotic bleb will process and present all of the antigens contained within the bleb