🫀Self-tolerance and mechanisms of autoimmunity Flashcards
(13 cards)
What is central tolerance and where does it occur?
Central tolerance: Eliminate/inactivate self-reactive lymphocytes
Occurs:
• Thymus (T cells)
• Bone marrow (B cells)
Process: Immature Ls + self-Ag → deletion/inactivation
How does clonal deletion in the thymus prevent autoimmunity?
- Random TCR rearrangement → some bind self-Ags
- APCs in thymus present self-Ags → deletion via apoptosis
What is negative selection of T cells?
Negative selection = colonal deletion (apop) of self reactive LCs in thymus
Aided by AIRE + APCs
What is the role of AIRE in central tolerance?
transcription factor → presents peripheral Ags in thymus → immature self reactive LCs will bind → deleted via apop before activation → central tolerance :)
What is peripheral tolerance and where does it occur?
Process of suppressing/inactivating/deleting autoreactive LCs outside thymus
Occurs in peripheral tissues + LNs
How do regulatory T cells prevent autoimmunity?
Suppress autoreactive T/B cells
• Cytokine secretion (IL-10, TGF-β)
• CTLA-4 expression → inhibit co-stimulation
What is anergy and how does it contribute to peripheral tolerance?
Anergy
• CD28 + B7 = Signal 2 (co-stim)
• CTLA-4 inhibits CD28 → no activation
No co-stim → T cell presentg but non-responsive
Peripheral Tolerance
• Self-Ags w/o co-stim → T cell inactivation
• Prevents autoimmunity by inactivating self-reactive T cells
What are cryptic epitopes and how do they become targets?
• Self-Ags normally hidden/ inaccessible
• Exposed due to tissue injury, inflammation, or dmg
• exposed → recog by IS → may trigger AI re
What is molecular mimicry and how is it a environmental trigger for autoimmunity?
• Microbial Ags resemble self-Ags
• IS attacks microbial Ags → cross-reactivity with self-Ags
• Environmental trigger for AI (e.g., infection)
How do post-translational modifications of self-proteins lead to autoimmunity?
• drugs/toxins → PTMs (e.g. citrullination, phosphorylation) → alter self-Ags
• Modified self-Ags = “neo-Ags” → not present during tolerance induction
• IS sees as foreign → activates self-reactive Ls
• Can trigger AI diseases (e.g. RA via citrullinated peptides)
What is epitope spreading in autoimmune disease?
• Initial self-Ag target → tissue dmg
• New self-Ags released (cryptic/secondary)
• IR expands → multiple self-Ags targeted
• Drives chronic, progressive autoimmunity
How can tissue injury lead to the exposure of self-antigens?
• Cell dmg → release of hidden (cryptic) Ags
• Ags normally shielded → now seen by immune system
• Triggers new/self-reactive IR → AI risk
How does defective clearance of apoptotic cells contribute to autoimmunity?
• Uncleared apoptotic cells → release nuclear Ags (e.g., DNA, histones)
• Ags persist → picked up by APCs → activate self-reactive T/B cells
• Promotes chronic IR → ↑ AI disease risk (e.g., SLE)
