🫀Genetic and environmental factors in autoimmunity

Question 1

How do HLA types influence susceptibility to autoimmune disease?

Answer 1

• HLA genes = key Ag-presenting molecules
• Certain HLA alleles → present self-Ags more effectively
• ↑ activation of self-reactive T cells → ↑ AI risk
• e.g., HLA-DR3/DR4 → strong link to T1D

Question 2

What role do non-HLA genes (e.g. PTPN22) play in autoimmunity?

Answer 2

• Affect T/B cell signaling, tolerance, cytokine reg
• ⬇ PTPN22: ⬇ TCR signaling → defective neg selection
• ⬇ CTLA-4: ⬇ co-stim inhibition → failed T cell control
• ⬇ CD25: affects Treg dev/function → poor suppression of IR

Question 3

How does sex (gender) influence autoimmune disease risk?

Answer 3

Inc prevalence of AI in females

Question 4

How can infections break tolerance?

Answer 4

Infections → tissue changes:
- Inflammation:
- Activates bystander T cells
- Impairs Treg function
- Tissue Injury:
- Alters or exposes Ags (cryptic epitopes)
- Molecular Mimicry:
- Microbial Ags resemble self-Ags → cross-reactivity
- Drugs/Toxins:
- Modify self-Ags → recognized as foreign

Question 5

What is bystander activation?

Answer 5

• Inflamm → ck release → non-specific T cell activation
• ⬆ IR incl. self-reactive T cells → AI risk
• Bystander T cells = not specific to trigger Agk

Question 6

How can smoking or environmental toxins increase autoimmune risk?

Answer 6

Drugs/toxins → modify self-ags → recog as foreign → trigger autoreactive IR

Question 7

What role does the gut microbiota play in autoimmune regulation?

Answer 7

Microbiome affects balance b/w regulatory vs effector T cells

Question 8

How do epigenetic changes influence self-tolerance?

Answer 8

• Modify gene expression w/o DNA sequence changes
• Affect immune system regulation (e.g., Tregs, tolerance-related genes)
• Can lead to loss of self-tolerance, triggering autoimmunity
• Factors: DNA methylation, histone modification, non-coding RNAs