Tolerance & AutoImmunity Flashcards
• Factors that predispose you 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
• There is a gradient of AI disease sex tropism though; DM affects more men whilst SLE and thyroid disease affects much more women
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
Mechanisms of Autoimmunity?
(1) T-cell tolerance broken
• HLA associations strongly imply T-cell role in AID initiation
(2) AID are CHRONIC conditions as reaction is to self-tissue, which is always present
(3) Effector mechanisms resemble those of hypersensitivity reactions
• Types II, III & IV
Example of an AI that we have studied in endo?
T1DM!!
How is AI classified in humans?
(1) Organ affected
• e.g. Grave’s is very specific
• e.g. SLE is very systemic
(2) Involvement of specific auto-antigens
• i.e. as in AI haemolytic anaemia
(3) Types of I.R
• either Type II, III or IV hypersensitivity
Explain the Type II I.R to AI and give examples
Type II hypersensitivity:
• Ab-response/mediated (to cellular OR ECM antigen [i.e. insoluble antigen])
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.
Explain the Type III I.R to AI and give examples
Type III hypersensitivity:
• Immune complex mediated (formed by antigens against soluble antigens)
Classic Example = SLE:
• immune complex deposition in glomerulus
• Autoantigen – DNA, histones, ribosomes, snRNP, scRNP.
• Consequence – glomerulonephritis, vasculitis, arthritis
Explain the Type IV I.R to AI and give examples
Type IV hypersensitivity:
• T-cell mediated (delayed type hypersensitivity)
• CD8+ (cytotoxic) & CD4+ (T-cell) responses may also be involved AS WELL AS B-cell responses
Diabetes mellitus (DM):
• Autoantigen – pancreatic beta cell antigen.
• Consequence – beta-cell destruction.
Rheumatoid arthritis (RA):
• Autoantigen – synovial joint antigen.
• Consequence – join inflammation & destruction.
Multiple sclerosis (MS):
• Autoantigen – myelin basic protein, proteolipid protein.
• Consequence – brain degeneration (demyelination), weakness/paralysis.
Normal T-cell Response and suggest which MHC is dominant in AID
Antigen is presented to T-cells by MHC:
o MHC II (DP, DQ, DR) –> CD4+ TCR.
o MHC I (A, B, C) –> CD8+ TCR
Therefore:
MHC II is the dominant genetic factor affecting susceptibility to autoimmune disease – T-cells may initiate AI disease…
Evidence for Self-Tolerance?
Freemartin cattle:
Share a placenta in utero and they exchange cells and antigens
o The cattle CAN have different blood groups – that don’t react with each other so tolerance must be present
o The cattle can accept skin grafts from each other and tolerate blood transfusions from a non-identical twin.
Evidence showing how the TIMING of tolerance is important
Mouse Models:
o If the donor supplied spleen and BM cells to a NEONATAL mouse, then the same adult mouse can accept a skin graft.
o 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.
Evidence showing how the SPECIFICITY of tolerance is important
Mouse Models:
o If donor supplies cells to neonate then the same adult couldn’t accept a graft from a random other mouse.
Define Tolerance
The ACQUIRED INABILITY to respond to an antigenic stimulus
What are the “3 A’s” of Tolerance
Acquired
• involves cells of acquired I.R and is learned
Antigen specific
Active process
• active in neonates
• effects which are maintained throughout life
2 broad types of Tolerance Mechanisms
CENTRAL tolerance:
(a) Mature T-cells
(b) Ab-secreting B cells
vs.
PERIPHERAL tolerance:
(a) Anergy
(b) Active suppression by Tregs
(c) Immune privlege (ignorance of antigens)
• Failure in ONE OR MORE of these = AI disease
Explain CENTRAL TOLERANCE: (a) Mature T-cells
T-cells mature in the thymus:
T-cells recognise peptides presented on MHC in the thymus
• via. Thymic epithelial cells (TEC) or DC:
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
o Only 5% of thymocytes survive the process.
Explain CENTRAL TOLERANCE: (b) Ab-secreting B-cells
B-cells mature in the bone marrow
B-cell selection based on its reaction w. the antigens in the bone marrow:
No self-reaction –> migration to periphery –> mature b-cell
MULTI-VALENT self-molecule –> clonal deletion or receptor editing –> apoptosis or mature b-cell
Recognise soluble auto-antigens –> migrate to periphery –> anergic b-cell, migrates to periphery
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.
Explain how Central Tolerance fails in AI disease and what it affects
APECED
• Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy
Affects:
• kidneys, thyroid, gonadal failure
• DM, pernicious anaemia, chronic mucocutaneous candidiasis
Arises:
• results from a FAILURE TO DELETE T-CELLS in thymus
• caused by mutation in TF AIRE (AI Regulator)
• AIRE is essential for expression of “tissue-sepcific” genes in the thymus
• AIRE is therefore involved in the -VE selection of self-reaction T-cells
Most AI diseases are associated with multiple defects in genetic traits - which ones in particular?
e.g. SLE - 40-50 genes implicated in genetic susceptibility involved in:
Induction of tolerance – failure of tolerance.
• B-cell activation = autoAb production - e.g. CD22, SHP-1.
Apoptosis – failure of cell-death.
• Fas, Fas-L mutations
Clearance of antigen – abundance of autoantigen.
• C1q, C1r, C1s complement proteins.
Explain the Induction & Maintenance of PERIPHERAL TOLERANCE
Some antigens may NOT be expressed in the thymus or BM:
• may only be expressed after maturity of the immune system
• SO mechanisms required to prevent the auto-immunity here:
o Anergy.
o Suppression by T-reg cells.
o Ignorance of antigen.
Explain PERIPHERAL TOLERANCE: (a) Anergy
ABSENCE of co-stimulation by molecule on APC
Naïve T-cells require co-stimulation for activation:
• Co-stimulatory molecules – CD80, 86, 40.
• These are ABSENT on most cells of the body
Without co-stimulation, cell proliferation wouldn’t proceed:
• Subsequent stimulation (even in the presence of costimulators now) then leads to a refractory state termed – anergy.
Explain PERIPHERAL TOLERANCE: (b) Suppression by T-reg cells
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.
• IPEX is when there is a mutation in FOXP3 –> fatal recessive disorder presenting early in childhood and leads to an accumulation of autoreactive T-cells causing:
o Early onset DM, enteropathy, eczema, infections and AI symptoms.
Explain PERIPHERAL TOLERANCE: (c) Ignorance of Antigen
Ignorance occurs when:
Occurs when [antigen] is too low
Occurs when relevant APC is absent
– most cells in periphery are MHC II – -VE
Occurs at immunologically privileged sites
– immune cells cannot penetrate as an immune reaction could do more harm than good – i.e. the eye, CNS, PNS, testes
In immunological ignorance, T-cells NEVER see their antigens
• i.e. T-cells have NEVER BEEN TOLERISED against auto-antigens SO could react
Give an example when (c) Ignorance to antigen can lead to a failure
Example of failure of ignorance:
– Sympathetic Ophthalmia:
o Trauma to an eye leads to release of intraocular proteins which trigger immune system.
Explain how Infections can break Peripheral Tolerance
Infection can lead to a break in tolerance and then lead to AI disease – i.e. EBV & measles and Multiple Sclerosis.
This can be done via:
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.
• may occur in pregnancy
Tissue damage at immunologically privileged sites such as the eye.
