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Unit 9 > Week 1: Diseases of the Immune system 2 > Flashcards

Week 1: Diseases of the Immune system 2 Flashcards

1
Q

What selection processes to T and B cell undergo whilst maturing?

A

T cell: positive selection and negative selection
B cell: negative selection

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2
Q

Describe how tolerance in T cells confers tolerance in B cells?

A

B cell require (normally) a T cell activation signal in order to carry out their function.
If a self recognising B cell survives, it is unlikely that the complimentary self recognising T cell has also survived, therefore the B cell will likely never become activated

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3
Q

Where can negative selection of B cell occur?

A

Bone marrow
Some negative selection may also occur in the spleen as B cell continue to mature.

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4
Q

What is the co-stimulation reaction between a T reg, Th and an APC?

A

T reg - CTLA4
T help - CD28
APC - B7

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5
Q

What is the difference between an autoimmune condition and an auto-inflammatory condition?

A

Autoimmune condition - known specific self antigen that is targeted by the immune system
Autoinflammatory - specific antigen is not know, general inflammatory response causes unnecessary damage.

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6
Q

Is a response to self normal?

A

Yes, normally there is a small response to self, but this is normally of a lower quality or requires a high concentration of antigen to be activated

The damaging effector response in autoimmunity is not normal - it is pathological

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7
Q

What are some examples of diffuse autoimmune diseases?

A

Diffuse - spread over a large area.

Rheumatoid arthiritis
Systemic Lupus Erthyematosus

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8
Q

What are some examples of organ specific autoimmune diseases?

A

Type 1 diabetes
Multiple Sclerosis
Crohns disease
Psoriasis
Graves disease
Hashimoto thyroiditis

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9
Q

How does chronic autoimmune disease develop through a positive feedback loop?

A
  1. Insult or injury leads to inflammation
  2. Macrophage phagocytosed necrotic material (self cells) hence presents cell antigen contained within phagosome onto MHC1
  3. Self reaction T cell recognises presented antigen and can trigger an immune response
  4. Immune response attempts to clear the antigen causing more damage, hence creating an endless supply of antigen.
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10
Q

In basic terms, what processes are involved in developing autoimmunity?

A

Genetic factors - creates hypersensitive immune signalling or turns off tolerance factors. Is a predisposing factor
Combined with an environmental exposure - smoking etc that causes damage releasing self antigen. Acts as the trigger.
This causes an immune regulation by breaching tolerance
Leads to autoimmunity.

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11
Q

How can autoimmune diseases be classified by cause?

A

Monogenic (mainly genetic - one gene- small interaction with enviro)
Polygenic (require large interaction with environment and many genes)

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12
Q

Is autoimmunity genetic?

A

Has a genetic componenet - acts as a pre-disposing factor
Autoimmunity (but not always the same autoimmune condition) tends to be familial, shown in monzygotix twins

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13
Q

What do the mutation of genes tend to cause in order to lead to an autoimmune condition?

A
  • disrupt tolerance
  • disrupt apoptosis
    -promote inflammation
  • promote cell activation
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14
Q

What is a monogenic autoimmune disease?

A

Predominant genetic risk factor with minor additional genetic and environmental factors (IPEX and APECED)

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15
Q

What is a complex autoimmune disease?

A

Multiple genetic and environmental factors influcne the cause
(MS and RA)

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16
Q

How is the mutated AIRE gene involved in an autoimmune condition?

A

Caused APECED
AIRE gene - allows thymus to express self antigens, expose developing T cell to self antigens, allows for negative selection

When mutated - decreased expression of self antigens in the thymus, results in defective negative selection of self reactive T cells, so enter periphery

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17
Q

How is the mutated CTLA4 gene involved in an autoimmune condition?

A

Functional CTLA4 used by Treg cells to complete for co-stimulatory molecule B7 from other T cell phenotypes,.
Mutation in CTLA4 decreases T reg function, by reducing the activation threshold of self reacting T cell - hence failure of T cell energy

Associated with type 1 Diabetes and Graves disease

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18
Q

How is the mutated FOXP3 gene involved in an autoimmune condition?

A

Causes IPEX syndrome
Normal gene acts as a transcription factor for nTreg and iTregs
Mutated T regs are unable to carry out their function.

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19
Q

How is the mutated Fas gene involved in an autoimmune condition?

A

Results in Autoimmune lymphoproliferative syndrome

When mutated - Failure to induce apoptosis in self reactive T and B cells

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20
Q

How is the mutated C1q gene involed in an autoimmune condition?

A

Mutated results in defective complement activation results in defective clearances of immune complexes and apoptotic cells

Associated with systemic lupus arythematosus

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21
Q

Describe the structure of MHC (HLA) genes?

A

MHC is a group of genes resulting in HLA proteins
MHC gene can be split into class 1, class 2 and class 3 genes
Each class is polygenic - contains multiple different genes
Each gene is polymorphic - multiple possible copies of each allele to inherit.

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22
Q

What different HLA genes are included in the class 1 section?

A

HlA-B
HLA-C
HLA-A

23
Q

What different HLA genes are included in the class 2 section?

A

HLA-DM
HLA-DP
HLA-DO
HLA-DQ
HLA-DR

24
Q

How does having different alleles of HLA effect the overall MHC molecule?
How does this link to autoimmunity?

A

Different alleles will have different binding affinities for peptide (making it harder/easier to present)
Different alleles will results in MHC that finds it easier/harder to interact with TCR
Hence certain HLA types contribute to autoimmunity

25
Q

What is the structure of a MHC1 molecule and an MHC2 molecule regarding the components that make it up?

A

MHC1 - alpha chain with 3 sections - 2 of which make up peptide binding groove, and an additional beta2 microglobulin

MHC2 - made of an alpha chain (2 section) and a beta chain (2 sections), the first section of each chain contributes to the peptide binding groove.

26
Q

What HLA types can contribute to autoimmunity?

A

B27 - contributes to ankylosing spondylitis
DR4 - RA
DR3/DR4 - Type 1 diabetes
DR3 - Graves disease
CQ2/DQ8 - coeliac disease

27
Q

What regions of the world tend to have higher levels of autoimmune disease?

A

Developed countries - europe, North america, China and Australia
Due to higher level on environmental risk factors such as smoking

28
Q

Why are females more suspecetible to autoimmune diseases than men?

A

Women tend to have a stronger humoral response than men despite having same number of lymphocytes.
Oestrogen at low conc enhances B cell response (although is anti-inflammatory in high conc)
Prolactin in pregnancy - is pro-inflammatory
Screwed X inactivation in peripheral blood cells is shown in Graves and Hashimoto disease

29
Q

Why are males less susceptibile to autoimmune diseases than females?

A

Testosterone negatively regulates BAFF gene expression

Inhibits cytokine signalling for B cell survival and maturation

30
Q

Give an example of an cytokine receptor gene that may be involved at increasing the risk of autoimmunity?

A

Mutation is IL-23R associated with th17 development
Lots of Th17 is associated with an autoimmune disease

31
Q

What is some experimental evidence to show that autoimmune diseases have an environmental link?

A

Mice all with CTLA4 mutation and genetically identical - predisposed for type 1 diabetes - but all developed at different ages

EBV and Hep C infect B cells - experiment on soldiers all with MS were previously infected with EBV, but not all infected with EBV got MS

32
Q

What is thought to be the link between EBV and MS?

A

EBV antigen is structurally similar the antigen on myelin sheath.
When immune reaction raised against EBV, antibodies produced, once infection cleared, antibodies may target Myelin sheath antigens but in a lower affinity.

33
Q

What are the different methods of overcoming peripheral tolerance (leading to an autoimmune disease)?

A

Adjuvant effect
Cryptic antigens
Molecular mimicry
Bystander activation
Epitope spreading
Antigen is also a DAMP

34
Q

What is the adjuvant effect to overcome peripheral tolerance?

A

When self antigens are adminstered alongisde a danger signal (the adjuvant) an inflammatory response can be triggered, increasing change of autoimmunity

35
Q

What is meant by cryptic antigens as a mechanism to overcome peripheral tolerance?

A

‘Self antigens’ T cells and B cells are negatively selected against during development appear differently in the periphery.
Different environments in the periphery such as hypoxia, inflammation or chopped up on MHC differently, hence T cells that see this version are not selected against so trigger an immune response as non-self

36
Q

What is meant by molecular mimicry as a mechanism to overcome peripheral tolerance?

A

Some pathogens have antigens that are structurally similar to self antigens and may bind to TCR/BCR with higher affinity.
In thymus low affinity to self antigen is insufficient to activate the immune response.
Higher affinity in periphery and accompanied by PAMPs/DAMPS with pathogen is sufficient to activate the cell - once activated modest low affinity engagement is sufficient to cause response and damage
Antibodies produced against these pathogens can cross react with self antigens.

37
Q

What are some examples of pathogens/autoimmune diseases that show molecular mimicry as a method to overcome peripheral tolerance?

A

Ankylosing spondylitis - antibodies against K.pneumonia can cross-react with HLA-B27
Guillain-Barre syndrome - antibodies against C.jejuni antigens can cross react with gangliosides
MS - antibodies against EBV cross react with myelin sheath

38
Q

What is meant by bystander activation as a mechanism of overcoming peripheral tolerance to cause autoimmunity?

A

T and B cell with low affinity for self antigen escape central tolerance mechanisms
Antigen alone cannot activate cells
Inflammation in the area causes co-stimulatory molecules to be expressed by APC.
THis overcomes T cell energy, so it can be activated and attack.

39
Q

What is meant by epitope spreading as a mechanism to overcome peripheral tolerance to cause autoimmunity?

A

Immune reaction against infections or self antigens leads to damage to self cells
releases and presents more self antigens (at high conc) or cryptic self antigens
Triggers an immune response when recognised by T or B cell

40
Q

Does thymus negativly select against all self reactive T cells?

A

No, only ones with a high affinity

41
Q

What is meant by antigen is also a DAMP as a mechanism of overcoming peripheral tolerance to cause autoimmunity?

A

Self antigen may act as a DAMP by binding to surface TLR, as well as binding to BCR on B cell.
Binding to TLR causes B cell to receive a strong signal which cross links to BCR to the PRR activating the signalling cascade to activate the B cell.

42
Q

How is the proportion of T helper subtypes related to autoimmune diseases?

A

Increased activity of Th17 associated with RA, MS and other autoimmune diseases
This may be coupled with decreased T reg activity
Resulring in unresolved chronic inflammation and continued damage and expansion of Th17 cells

43
Q

How may IL-17 be targeted by therapies trying to stop autoimmune disease?
Why?

A

Disrupt interaction of IL-17 and receptor - IL-17 normally promotes MMP and pro-inflammatory mediator release

44
Q

How may IL-6 be targeted by therapies trying to stop autoimmune disease?
Why?

A

Tocilizumab target IL-6 receptor - acts as an inhibitor, prevents IL-6 binding and promoting pro-inflammatory actions such as differention of Th17 cells

45
Q

What is the autoimmune mechanism behind Graves disease?

A

Stimulates over production

Autoantibodies to the TSH receptor stimulate thyroid hormone production
High levels of thyroid hormone gives negative feedback to pituitary gland to produce less TSH but can’t effect antibody levels
Continues to produce high levels of thyroid hormone - cause damage.

46
Q

What is the autoimmune mechanism behind Myasthenia Gravis?

A

Inhibits receptor function

Autoimmune antibodies to acetylcholine receptor precvent acetylcholine from interacting with receptor
Because Acetylcholine receptors are internalised and degraded.
No muscle contraction

47
Q

What diseases are examples of antibody mediated autoimmune damage?

A

Graves disease
Myasthenia Gravis

48
Q

What diseases are an example of cytotoxic T cell mediated autoimmune damage?

A

Type 1 diabetes

49
Q

What is the mechanism of autoimmunity in type 1 diabetes?

A

Islets of langerhan cells express self antigen on MHC1
CD8+ recognises antigen on Beta pancreatic cells and targets for killing
Glucagon can still be produced but insulin is no longer secreted
Leads to high blood glucose.

50
Q

What is the mechanism of autoimmunity of rheumatoid arthiritis?

A

Unknown inflammatory trigger attracts leukocyte to tissue.
Self reactive T cells response to antigen released by damage and stimulate macrophage to cause sustained inflammation
Macrophage release MMPs
Fibroblasts also stimulated to release MMPs and RANKL osteoclasts, this degrades into bone producing a constant supply of antigen.

51
Q

Why are immunodeficiencies affecting the adaptive immune system more problematic than those affecting the innate immune system?

A

Innate - has great redundancy, as none specific so many cell types can overlap on function for many pathogens

Adaptive - very low redundancy due to high specificity of cell function, therefore loss of one gene function can be detrimental to the overall immune response

52
Q

Give an example of a antigen also acting as a DAMP in B cell activation

A

CpG nucleic acid
However CpG nuclei acid is normally only present during apoptosis of a cell
If CpG is not cleared fast enough, it may bind to TLR on a B-cell and the BCR - this provides enough activation signals to activate the B cell without the corresponding T cell.

53
Q

What is meant by MHC genes are polygenic?

A

The MHC gene locus contains several different MHC class 1 and 2 genes (3 genes per class in total, 6 alleles - 3 from each parent)

54
Q

What is meant by MHC genes as polymorphic?

A

Multiple different version of each allele (2 or more).
So large variation in a population

Unit 9 (14 decks)

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