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MCD Immunology > Tolerance and Autoimmunity > Flashcards

Tolerance and Autoimmunity Flashcards

1
Q

what are the factors that predispose to AI disease?

A

These genetic and environmental factors combine to break down self tolerance:
o Genes
o Sex
– females more susceptible – e.g. SLE.
(There is a gradient of AI disease sex tropism however DM affects more men whilst SLE and thyroid disease affects much more women- SLE 9:1)

o Infections
– provide an inflammatory environment – e.g. EBV.

o Diet
– obesity, high fat, effects on microbiome.

o Stress
– can release stress-related hormones – e.g. cortisol.

o Microbiome
– the microbiome helps shape immunity. Dysbiosis

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2
Q

what are the 3 mechanisms that characterise autoimmune disease?

A
  • breakdown of T cell tolerance
  • chronic disease:
    AI disease is chronic due to tissue always being present
  • hypersensitivity reaction:
    the effector mechanisms resemble hypersensitivity reactions 2,3 and 4
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3
Q

describe the epidemiology of AI disease

A

o >100 chronic diseases linked to AI causes.

o ~8% of people affected by AI diseases
– remember T1DM is AI.
of those, 80% of those affected are women

o Incidence of AI diseases (and hypersensitivity) is increasing
– the “hygiene hypothesis” reduces exposure to antigens

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4
Q

Give some clinical examples of AI disease and their prominence

A 
 Rheumatoid Arthritis 
– 1 in 100.
 T1DM
 – 1 in 800.
 Multiple sclerosis 
– 1 in 700.
 SLE 
– 240,000 cases.
 Autoimmune thyroid disease 
– 5 in 1000 women, 0.8 in 1000 men.
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5
Q

what antibody mediates autoimmune disease? what is significant about this antibody?

A

IgG
it can cross the placenta during foetal development therefore AI disease in the mother can present in the newborn for a short period of time after birth until the ABs are removed from the body

e.g. neonatal Grave’s Disease

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6
Q

how would you define autoimmunity (autoimmune response)?

A

involves the adaptive lymphocytes response to self antigens

this response is similar to that in reaction to pathogens

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7
Q

how do symptoms of AI disease progress during pregnancy?

A

sometimes symptoms can improve or deteriorate during pregnancy, dependent on the AI disease

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8
Q

how can AI disease and autoimmunity be classified?

A

1) organs affected
- SLE is systemic; Grave’s is specific

2) the involvement of specific autoantigens
e. g. autoimmune haemolytic anaemia

3) the type of immune response involved (hypersensitivity reaction)

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9
Q

what is type 2 hypersensitivity?

Give 2 examples of AI diseases of this type

A

Antibody dependent reaction:

  • antibody response to cellular or ECM antigen
  • antigen is insoluble, usually a cell surface protein

1) Goodpasture’s syndrome:
• Autoantigen
– non-collagenous domain of BM collagen T4.
• Consequence
– glomerulonephritis, pulmonary haemorrhage.

2) Grave’s disease:
• Autoantigen 
– TSH receptor.
• Consequence
 – stimulation of TSHR by autoantibody so lots of T4 production.
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10
Q

what is type 3 hypersensitivity? Give examples of AI diseases of this type

A

immune complexes (by antibodies being formed against soluble antigens)

1) SLE – immune complex deposition in glomerulus

• Autoantigen
– DNA, histones, ribosomes, snRNP, scRNP.
• Consequence – glomerulonephritis, vasculitis, arthritis.

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11
Q

what is type 4 hypersensitivity?

Give examples of AI disease, their autoantigen and the consequent of targeting the antigen

  • Diabetes
  • Rheumatoid Arthritis
  • MS
A

T-cell mediated
(delayed type hypersensitivity)

– CD8+(cytotoxic) and CD4+ (T-cell) responses may become involved as well as B-cell responses

1) Diabetes mellitus:
• Autoantigen
 – pancreatic beta cell antigen.
• Consequence
 – beta-cell destruction.

2) Rheumatoid arthritis:
• Autoantigen – synovial joint antigen.
• Consequence – join inflammation & destruction.

3) Multiple sclerosis:
• Autoantigen
– myelin basic protein, proteolipid protein.
• Consequence
– brain degeneration (demyelination), weakness/paralysis.

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12
Q

examples of type 2 hypersensitivity diseases

A

Graves

Goodpasture’s Syndrome

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13
Q

name a type 3 hypersensitivity disease

A

SLE

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14
Q

name type 4 hypersensitivity diseases

A

T1DM
RA
MS

o Chronic graft rejection.
o Graft-versus-Host disease (GVHD).
o Coeliac disease.
o Contact hypersensitivity.

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15
Q

autoantigen and consequence in Goodpastures Syndrome

A
  • Autoantigen – non-collagenous domain of BM collagen T4.

* Consequence – glomerulonephritis, pulmonary haemorrhage.

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16
Q

what is the autoantigen and consequence of antibodies against it Graves?

A
  • Autoantigen – TSH receptor.

* Consequence – stimulation of TSHR by autoantibody so lots of T4 production–> hyperthyroidism

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17
Q

autoantigen and consequence in SLE

A

Immune complex deposition in glomerulus (type 3)
• Autoantigen – DNA, histones, ribosomes, snRNP, scRNP.
• Consequence – glomerulonephritis, vasculitis, arthritis.

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18
Q

autoantigen and consequence in T1DM

A
  • Autoantigen – pancreatic beta cell antigen.

* Consequence – beta-cell destruction.

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19
Q

what is the autoantigen and consequence in RA?

A
  • Autoantigen – synovial joint antigen.

* Consequence – join inflammation and destruction.

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20
Q

autoantigen and consequence in MS

A
  • Autoantigen – myelin basic protein, proteolipid protein.

* Consequence – brain degeneration (demyelination), weakness/paralysis.

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21
Q

what is the main MHC (HLA) molecule involved in most AI disease? therefore which T cell?

A

MHC II–> CD4+ (T helper cells)

these alleles are the dominant genetic factor affecting susceptibility to AI disease
e.g. HLA-DR3–> SLE

22
Q

what are the MHC molecules and the classes they contain? what T cells bind to them?

A

o MHC II (DP, DQ, DR)
–> CD4+ TCR.

o MHC I (A, B, C)
–> CD8+ TCR.

23
Q

what are the two important evidences for self-tolerance in the body?
mice model

A
  • timing of tolerance
    neonate mice given cells from donor accept grafts better from the same donor, than if they were to accept at adulthood
  • specificity of tolerance
    the neonate as an adult will only accept the graft from the donor that gave the cells in the first place (as neonate)
24
Q

what is immunological tolerance?

A

the acquired inability to respond to an antigenic stimulus.

Defined by “The 3 As”

25
Q

what are the 3 A’s that describe immunological tolerance?

A

1) acquired (learned as part of acquire immune system)
2) antigen-specific
3) active process (in neonates) - effects maintained throughout life

26
Q

what are the 2 types of tolerance?

A

1) central (during lymphocyte development)

2) peripheral (control of self reactive lymphocytes by 3 mechanisms)

27
Q

what are the 3 mechanisms involved in peripheral tolerance?

A

1) anergy
2) active suppression/regulation by Tregs
3) ignorance of antigen

28
Q

where do T cells and B cells mature?

A

T–> thymus

B–> bone marrow

29
Q

how does T cell selection occur in central tolerance?

A

1) T-cells recognise peptides presented on MHC in the thymus
– Thymic epithelial cells (TEC) or DC: production of:

MHC II (DP, DQ, DR)
–>CD4+ TCR.
MHC I (A, B, C)
–> CD8+ TCR.

2) Thymus selection – end results:

Useless
– can’t see MHC
-therefore apoptosis.

Useful
– see MHC weakly
- therefore +ve selection.

Dangerous
– see MHC strongly
- -ve selection and signal to apoptose

3) Only 5% of thymocytes survive the process.

30
Q

where does B cell selection occur in central tolerance?

what are the fates of the B cells during selection?

A

Takes place in the bone marrow

o No self-reaction –> migration to periphery –> mature B-cell

o Multi-valent self-molecule–> clonal deletion or receptor editing–> apoptosis or mature B-cell.

o Soluble self-antigen–> migrate to periphery–> anergic B-cell.

o 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.

31
Q

which kind of immature B cell has the potential to become auto reactive?

A

Low-affinity, non-crosslinking self-molecule

32
Q

what is the consequence of central tolerance failure?

A

APECED
– Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy

complex AI response to endocrine glands: kidneys, thyroid, gonadal failure, DM, pernicious anaemia, chronic mucocutaneous candidiasis

33
Q

what is the mechanism that causes APECED (Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) when central tolerance fails?

A

mutation in transcription factor AIRE
– Autoimmune Regulator

AIRE is important for expression of “tissue-specific” genes in the thymus and is therefore involved in negative selection of self-reactive T-cells.

NB. FOXP3 is for Treg development

34
Q

what is AIRE’s function?

A

AIRE is important for expression of “tissue-specific” genes in the thymus and is therefore involved in negative selection of self-reaction T-cells

MHC can present all kinds of body peptides to develop the repertoire of T cells
NB not Tregs

35
Q

what is the consequence of AIRE Tf mutation?

A

poor selection of T cells against peptides so they will go into the periphery and cause auto reactivity

36
Q

what are some examples of genes and encoded proteins that are associated with most AI diseases?
What are the roles of these proteins normally and how does the defect cause central tolerance failure?

A

o SLE
– 40-50 genes implicated in genetic susceptibility involved in:

1) Induction of tolerance
– failure of tolerance.
•CD22, SHP-1.

2) Apoptosis
– failure of cell-death.
• Fas, Fas-L mutations.

3) Clearance of antigen
– abundance of autoantigen.
• C1q, C1r, C1s complement proteins.

37
Q

what are roles of the genes involved in central tolerance?

what is the consequence if they fail?

A
  • induce tolerance
  • induce apoptosis
  • clear antigens

failure of these functions leads to AI disease

38
Q

why is peripheral tolerance essential?

A

Some antigens may not be expressed in the thymus or BM and may only be expressed after maturity of the immune system therefore is required to prevent auto-immunity as this stage

39
Q

what is anergy?

A

lack of co-stimulation–> no activation (NOT ignorance)

  • normally naïve T-cells require co-stimulation alongside the MHC interaction for activation
  • without co-stimulation, cell proliferation wouldn’t proceed.
  • subsequent stimulation then leads to a refractory state termed – anergy.
40
Q

what are some examples of co-stimulatory molecules? where are they present?

A

o Co-stimulatory molecules – CD80, 86, 40.

o These are absent on most cells of the body

41
Q

when and where does ignorance of an antigen occur?

  • antigen
  • APC
  • sites
A

o Occurs when antigen concentration is too low

o Occurs when relevant APC is absent i.e. appropriate MHC
– most cells in periphery are MHC II –ve.

o Occurs at immunologically privileged sites
– immune cells cannot penetrate as an immune reaction could do more harm than good e.g. the brain, gonads, eyes, CNS

42
Q

how is trauma to the eye an example of failure of ignorance of antigens

A

Sympathetic Ophthalmia:

  • Trauma to an eye leads to release of intraocular proteins which trigger immune system.
    An antigen has suddenly become available to cause auto reactivity
43
Q

what cells mediate the suppression of auto reactivity in the periphery?

A

regulatory T cells (Treg) for when there are bad boy T cells around but they don’t respond to autoantigens

1) CD25
 – IL-2 receptor.
2) CTLA-4 
– binds to B7 and sends a –ve signal.
3) FOXP3 
– TF required for T-reg cell development.
44
Q

what is the consequence of the FOXP3 Treg mutation?

A

IPEX= Immunodysregulation polyendocrinopathy enteropathy X-linked

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.

The Tregs don’t develop properly and allow the accumulation of the bad boys (auto reactive T cells)

45
Q

how can infections evade peripheral tolerance?

A

o Molecular mimicry of self-molecules
– i.e. Grave’s disease

o Induce changes in expression and recognition of self-proteins.

o Induction of co-stimulatory molecules or inappropriate MHC II expression.

o Failure of regulation
– effects in T-reg cells.

o Immune deviation
– shift in type of immune response – e.g. Th1 –>Th2.

o Tissue damage at immunologically privileged sites such as the eye.

46
Q

name two infections that cause MS, an AI disease

A

EBV & Measles

47
Q

compare type 2 and type 3 hypersensitivity

A

both cause the activation of complement and recruitment of inflammatory cells like neutrophils

but type 3 is more widespread as it involves soluble antigens and is driven by immune complexes

type 2 is antibody dependent

48
Q

what sort of B cell has the potential to become auto reactive?

A

Low-affinity, non-crosslinking self-molecule

49
Q

what is FOXP3 required for?

A

TF required for T-reg cell development.

50
Q

what T cell is positively selected?

A

Those able to see MHC weakly

MCD Immunology (5 decks)

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