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
What are the causes and effects of APECED?
Central tolerance failure -> Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy
Caused by a mutation in transcription factor AIRE – Autoimmune Regulator.
- important for expression of “tissue-specific” genes in the thymus and is therefore involved in negative selection of self-reaction T-cells
Affects – kidneys, thyroid, gonadal failure, DM, pernicious anaemia, chronic mucocutaneous candidiasis
What causes SLE?
40-50 genes implicated in genetic susceptibility involved in…
- Induction of tolerance – failure of tolerance
> CD22, SHP-1
- Apoptosis – failure of cell-death
> Fas, Fas-L mutations
- Clearance of antigen – abundance of autoantigen
> C1q, C1r, C1s complement proteins
How is tolerance maintained in the periphery?
Some antigens may not be expressed in the thymus or BM and may only be expressed after maturity of the immune system -> mechanisms required to prevent the auto-immunity here
- Anergy
- Suppression by T-reg cells
- Ignorance of antigen
What is anergy?
Naïve T-cells require co-stimulation for activation:
- Co-stimulatory molecules – CD80, 86, 40 (absent on most cells of the body)
- Without co-stimulation, cell proliferation wouldn’t proceed
- Subsequent stimulation then leads to a refractory state termed – anergy
When does ignorance occur?
- when antigen concentration is too low
- when relevant APC is absent – most cells in periphery are MHC II –ve
- at immunologically privileged sites – immune cells cannot penetrate as an immune reaction could do more harm than good – i.e. the brain
What is an example of failure of ignorance?
Sympathetic Ophthalmia:
- Trauma to an eye leads to release of intraocular proteins which trigger immune system
What happens in suppression/regulation?
Autoreactive T-cells may be present but DO NOT respond to auto-antigen
Controlled by T-reg cells:
- CD4+, CD25+, CTLA-4+, FOXP3+
> CD25 – IL-2 receptor
> CTLA-4 – binds to B7 and sends a –ve signal
> FOXP3 – TF required for T-reg cell development
What is IPEX?
when there is a mutation in FOXP3 -> fatal recessive disorder presenting early in childhood and leads to an accumulation of autoreactive T-cells causing:
- Early onset DM, enteropathy, eczema, infections and AI symptoms
How can infection lead to a break in tolerance?
- Molecular mimicry of self-molecules – i.e. Grave’s disease
- Induce changes in expression and recognition of self-proteins
- Induction of co-stimulatory molecules or inappropriate MHC II expression
- Failure of regulation – effects in T-reg cells
- Immune deviation – shift in type of immune response – e.g. Th1 -> Th2
- Tissue damage at immunologically privileged sites such as the eye
