Tolerance Flashcards
What factors pre-dispose to auto-immunity?
- Genes – discovered through use of “twin studies” and GWAS – e.g. 40 loci key in SLE
- Sex – females more susceptible – e.g. SLE.
- Infections – provide an inflammatory environment – e.g. EBV
- Diet – obesity, effects on microbiome
- Stress – can release stress-related hormones – e.g. cortisol
- Microbiome – the microbiome helps shape immunity
What are the mechanisms of autoimmunity?
breaks T-cell tolerance
Effector mechanisms resemble those of hypersensitivity reactions – specifically T2, 3, 4
- self-tissue always present -> auto-immunity is chronic
What is the impact of AI disease?
- > 100 chronic diseases linked to AI causes
- ~8% of people affected by AI diseases – remember T1DM is AI
- 80% of those affected are women
- Incidence of AI diseases (and hypersensitivity) is increasing – the “hygiene hypothesis”
What are important clinical examples of autoimmunity?
- rheumatoid arthritis
- T1DM
- multiple sclerosis
- SLE
- autoimmune thyroid disease
How is autoimmunity classified?
- Organ affected – as seen on the first page with Grave’s disease being very specific and SLE being very systemic
- Involvement of specific autoantigens – i.e. as in autoimmune haemolytic anaemia (AIHA)
- Types of immune response
Which AI diseases fall in the Type 2 hypersensitivity category (antibody response)?
Goodpasture’s syndrome:
- Autoantigen – non-collagenous domain of BM collagen T4
- Consequence – glomerulonephritis, pulmonary haemorrhage
Grave’s disease:
- Autoantigen – TSH receptor
- Consequence – stimulation of TSHR by autoantibody so lots of T4 production
Which AI diseases fall in the Type 3 hypersensitivity category (immune complex)?
SLE – immune complex deposition in glomerulus
- Autoantigen – DNA, histones, ribosomes, snRNP, scRNP
- Consequence – glomerulonephritis, vasculitis, arthritis
Which AI diseases fall in the Type 4 hypersensitivity category (T-cell mediated)?
- mediated (delayed type hypersensitivity) – CD8+(cytotoxic) and CD4+ (T-cell) responses may become involved AS WELL AS B-cell responses
Diabetes mellitus:
- Autoantigen – pancreatic beta cell antigen
- Consequence – beta-cell destruction
Rheumatoid arthritis:
- Autoantigen – synovial joint antigen
- Consequence – join inflammation & destruction
Multiple sclerosis:
- Autoantigen – myelin basic protein, proteolipid protein
- Consequence – brain degeneration (demyelination), weakness/paralysis
Which MHC classes present to each type of t-cell?
MHC II (DP, DQ, DR) -> CD4+ TCR
MHC I (A, B, C) -> CD8+ TCR
What model shows the importance of timing of tolerance?
mouse models
- If the donor supplied spleen and BM cells to a NEONATAL mouse, then the same adult mouse can accept a skin graft
- If the donor supplied to an adult mouse, that same adult could not then accept a skin graft – cells had to be received in neonatal phase
How do mouse models show the specificity of tolerance?
If donor supplies cells to neonate then the same adult couldn’t accept a graft from a random other mouse
What is immunological tolerance?
the acquired inability to response to an antigenic stimulus
Defined by “The 3 As”:
- Acquired – involves cells of acquired immune system and is learned
- Antigen specific
- Active process in neonates – effects of which are maintained throughout life
What are the mechanisms of immunological tolerance?
- Central tolerance
- Peripheral tolerance – anergy, active suppression (T-reg cells), immune privilege (ignorance of antigen) - Failure in one or more of these systems may result in AI disease
How do T cells mature?
T-cells mature in the thymus
- T-cells recognise peptides presented on MHC in the thymus – Thymic epithelial cells (TEC) or DC:
> MHC II (DP, DQ, DR) -> CD4+ TCR.
> MHC I (A, B, C) -> CD8+ TCR
- Thymus selection – end results:
- Useless – can’t see MHC – apoptosis
- Useful – see MHC weakly - +ve selection
- Dangerous – see MHC strongly - -ve selection and signal to apoptose
- Only 5% of thymocytes survive the process
How do B cells mature?
B-cells mature in the bone marrow:
B-cell selection:
- No self-reaction -> migration to periphery -> mature b-cell.
- Multi-valent self-molecule -> clonal deletion or receptor editing -> apoptosis or mature b-cell
- Soluble self-antigen -> migrate to periphery -> anergic b-cell
- Low-affinity, non-crosslinking self-molecule -> migrates -> mature b-cell that is clonally ignorant
* This last one has potential to become autoreactive
B-cell selection occurs by x-linking of surface IG by polyvalent antigens expressed on BM stromal cells to facilitate deletion
