Week 6 - Autoimmunity Flashcards
What is Tolerance? What is the underpinning function?
= failure of the adaptive immune system to respond to self antigen
underpinning function:
- ability to distinguish self from non-self
How is diversity in antigen receptors created?
created by somatic recombination
- germline receptor genes are comprised of multiple V and J gene segments
- during development -> these randomly recombine to form many unique antigen receptors
What is good and bad about the diversity of antigens?
- It is essential to have such diversity to protect us from all possible pathogens
- However, it is inevitable some may be auto-reactive
What do central tolerance mechanisms do?
ensure that self-reactive lymphocytes are deleted during development
-> occurs in thymus for T cells
-> occurs in bone marrow for B cells
What is clonal selection
Pretty much, lymphocytes that do not react to self-antigens are selected to be proliferated so many clones of them can be made during an adaptive immune response
Summary of the mechanisms of tolerance
What factors affect the development of autoimmune diseases?
environmental factors and genetic components
What are some common HLA alleles associated with autoimmune diseases?
B27, DR2, DR3, DR4, DR5
What are some environmental factors that can lead to autoimmunity?
- Events that lead to breaching immunologically privileged sites
- Stress can induce post-translational modifications
- Infection and molecular mimicry
Whats an example of an event that leads to breaching immunologically privileged sites leading to autoimmunity?
Eg -> Sympathetic Opthalmia
1. Trauma to one eye -> release of sequestrated intraocular protein antigens
2. Released intraocular antigens are carried to lymph ndoes and activates T cells
3. Effector T cells return via bloodstream and encounter antigen in both eyes
Whats an example of how stress can induce post-translational modifications leading to autoimmunity?
PAD (Peptidylarginine deaminase) converts Peptidyl Arginine into Peptidyl Citrulline
- PAD is not expressed in thymus but is expressed in periphery in response to stress and smoking
- By converting one protein to another, PAD is creating neoantigens thus altering self
Whats an example of how infection and molecular mimicry can lead to autoimmunity?
In Rheumatic Fever:
- antibodies specific for streptococcus cross-react with self-antigens in the heart valve bc they have a molecular similarity to antigens in the heart valves -> causes inflammation in the heart
What is Type 1 Diabetes?
Autoimmune disease that attacks the pancreas
What is specifically targeted in Type 1 diabetes?
Beta cells in the Islets of Langerhans in the pancreas are targeted by CD8 T cells and CD4 T cells have a role as well
What are the major auto-antigens associated with Type 1 diabetes?
- Insulin
- Protein tyrosine phosphatase
- IGRP (islet-specific glucose 6-phosphatase catalytic subunit related protein)
What are treatments for T1 Diabetes?
- Insulin replacement
- Islet transplant
What is Rheumatoid Arthritis?
Chronic inflammatory environment of the joints -> immune cells destroying cartilage
What are the target antigens in Rheumatoid arthritis?
Collagen, Proteoglycans, vimentin heat-shock protein
What are the immune mechanisms in Rheumatoid Arthritis?
What is Rheumatoid Factor
= Autoantibodies against IgG
What is Systemic Lupus Erythromatosus (SLE)?
= an autoimmune disease of circulating immune complexes of DNA and aDNA antibodies
Immune complexes lodge in the kidneys, skin and blood vessels -> glomerulonephritis and vasculitis
How does Vasculitis occur in SLE?
Immune complexes lodge in capillary beds -> activate complement pathway -> induces lysis and is pro-inflamm and recruits neutrophils
How do TLR9 and BAFF play a role in the pathogenesis of SLE?
- Unknown trigger leads to release of DNA and histones -> immune response
-> DNA containing immune complexes stimulate the pattern recog receptor TLR9 on a plasmacytoid dendritic cell
-> Plasmacytoid DC secrete Type 1 interferon
-> Type 1 interferon stim monocytes/DC to produce BAFF (a cytokine that promotes B cell survival)
-> Excess B cell survival including autoreactive B cells
What are managements of SLE?
Corticosteroids
Immunosuppressants
Biologics
