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Immunology > Autoimmunity > Flashcards

Autoimmunity Flashcards

1
Q

How do autoimmune diseases differ?

A

Specificities vary greatly from organ specific (Grave’s) to systemic (SLE)

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2
Q

Name examples of autoimmune diseases in order of organ specific to systemic

A
  • Grave’s Disease
  • Hashimoto’s Thyroiditis
  • Pernicious Anaemia
  • Addison’s Disease
  • Insulin dependent DM
  • Goodpasture’s syndrome
  • Myasthenia Gravis
  • Multiple sclerosis
  • Autoimmune haemolytic anaemia
  • Idiopathic thrombocytopenic purpura
  • Rheumatoid arthritis
  • Scleroderma
  • Systemic Lupus erythematosis (SLE)
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3
Q

What causes grave’s disease?

A

Type II HS reaction; cytotoxic reaction against TSH receptors in thyroid

Causes inflammation of eyes due to TSHr on fibre optics of eyes; mediated by T cells

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4
Q

What are HLA associated Spondyloarthropathies?

A

Group of autoimmune diseases: Ankylosing spondylitis, undifferentiated spondyloarthropathy, reactive arthritis, psoriatic arthritis, urethritis, iritis

Spectrum of severity and HLA B27 association

Associated with bowel inflammation

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5
Q

What is SLE?

A

Systemic lupus erythematosus (SLE) is a multi-system disease

Characterised by autoantibodies to nuclear antigens
eg double stranded DNA

Relapse and remission occurs

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6
Q

What is autoimmunity?

A

Immune system regulatory controls prevent it from attacking self proteins and cells
Failure of controls results in immune attack of host components

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7
Q

Give examples how tolerance is developed against autoimmunity

A

Characteristics eg:

  • Sex
  • Genetics
  • Environment
  • Mechanisms of autoimmune disease e.g T cells, autoantibodies
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8
Q

What is meant by immune tolerance?

A

Immune system does not attack self proteins or cells – it is tolerant to them

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9
Q

What are the 2 types of immune tolerance?

A
  • Central tolerance

- Peripheral tolerance

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10
Q

What is central tolerance?

A

Destruction of self-reactive T or B cells before they enter circulation

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11
Q

How is Peripheral tolerance achieved?

A

Destroy / control any self reactive T or B cells which enter circulation

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12
Q

How is central tolerance achieved?

A

If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered

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13
Q

How do T cells recognise antigens?

A

T cells recognise antigens that are presented to them by MHC proteins

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14
Q

Which TCRs are selected for immunity?

A

Need to select for T cell receptors which are capable of binding self MHC

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15
Q

What is the consequence of weak self MHC binding to TCRs?

A

May not be enough to allow signalling when binding to MHC with foreign peptides bound in groove

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16
Q

What is the effect of too strong MHC binding of TCRs?

A

If binding to self MHC is too strong, may allow signalling irrespective of whether self or foreign peptide is bound in groove

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17
Q

Which TCRs are not selected for?

A

If cell doesn’t bind to any self-MHC at all

Death by neglect (apoptosis)

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18
Q

When can T cells be dangerous (autoimmune?)

A

Binds self MHC too strongly

Apoptosis triggered – negative selection

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19
Q

Outline characteristics of useful T cells that are selected for

A

Binds self MHC weakly

Signal to survive – positive selection

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20
Q

How do T cells become tissue specific?

A

T cells developing in thymus encounter MHC bearing peptides expressed in other parts of the body

Due to a specialised TF that allows thymic expression of genes expressed in peripheral tissues

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21
Q

How is autoimmunity regulated?

A

AIRE - Autoimmune Regulator

promotes self tolerance by allowing the thymic expression of genes from other tissues

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22
Q

What is the consequence of mutations in AIRE?

A

Mutations in AIRE result in multiorgan autoimmunity

Autoimmune Polyendocrinopathy Syndrome type 1
Autoreactive T cells that survive central tolerance control

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23
Q

What are the 3 types of peripheral tolerance?

A
  • Ignorance
  • Anergy
  • Regulation
24
Q

What is Ignorance in peripheral tolerance?

A

Antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering

25
Q

Where is peripheral tolerance ignorance commonly seen?

A

Immunologically privileged sites e.g. eye, brain

26
Q

What is anergy (peripheral tolerance)?

A

If naive T cell sees it’s MHC/peptide ligand without appropriate costimulatory protein it becomes anergic – i.e. Less likely to be stimulated in future even if co-stimulation is then present

27
Q

What do naive T cells require to be activated?

A

Naive T cells need costimulatory signals in order to become activated

28
Q

Why does anergy arise?

A

Most cells lack costimulatory proteins and MHC class II

29
Q

What causes Regulation Peripheral tolerance?

A

A subset of helper T cells known as Treg (T regulatory cells) inhibit other T cells

Defective Treg have been observed in multiple sclerosis

30
Q

What markers are used to detect Treg?

A

Treg is detected using markers such as FOXP3, CD4 and CD25

Treg express transcription factor FOXP3

31
Q

What does FOXP3 mutations lead to?

A

Mutation in FOXP3 leads to severe and fatal autoimmune disorder - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome

32
Q

Which region of the genome is associated with disease the most?

A

MHC is associated with more disease than any other region of the genome

33
Q

Outline the genetics of MHC molecules

A

Each copy of chromosome 6 carries 3 different MHC class I and 3 different MHC class II genes

High levels of genetic variation (polymorphism)

34
Q

How does gender affect SLE epidemiology?

A

SLE is >10 times more common in females than males

35
Q

Describe MS epidemiology in men and women

A

MS is approximately 10 times more common in females than males

36
Q

Outline the prevalence of Ankylosing spondylitis between genders

A

Ankylosing spondylitis is approximately 3 times more common in males than females

37
Q

What is the hygiene hypothesis of autoimmune diseases

A

Early childhood exposure to particular microorganisms (e.g. gut flora and helminth parasites) protects against allergic + autoimmune diseases by contributing to immune system development

38
Q

What causes self tolerance breakdown?

A
  • Loss of/problem with regulatory cells
  • Release of sequestered antigen
  • Modification of self
  • Molecular mimicry
39
Q

What is citrulline?

A

Citrulline is an amino acid, not coded for by DNA

40
Q

How is citrulline generated?

A

Arginine can be converted to citrulline as a post-translational modification by peptidylarginine deiminase (PAD) enzymes

41
Q

What increases citrulline levels?

A

Citrullination may be increased by inflammation

42
Q

Describe presence of citrulline in rheumatoid arthritis

A

Autoantibodies to citrullinated proteins seen in rheumatoid arthritis. Now used for clinical diagnosis

43
Q

Describe the molecular mimicry causing rheumatic fever

A

Disease triggered by Streptococcus pyogenes infection

Antibodies to strep cell wall antigens may cross react with cardiac muscle

44
Q

How does Grave’s disease occur?

A

Auto-antibodies bind Thyroid stimulating hormone (TSH) receptor and stimulate it, resulting in hyperthyroidism
Disease can be transferred with IgG antibodies

45
Q

Describe the mechanism of myasthenia gravis

A

Autoantibodies bind to nAchR and block ability of Ach to bind

46
Q

What is the consequence of nAchR blockage in myasthenia gravis?

A
  • Leads to receptor internalisation and degradation

- muscle weakness

47
Q

How are immune complexes formed in SLE and vasculitis?

A

Autoantibodies to soluble antigens form immune complexes

48
Q

Where are immune complexes deposited in vasculitis and SLE?

A

Deposited in tissue e.g. blood vessels, joints, renal glomerulus

=> activation of complement and phagocytic cells
=> renal failure

49
Q

How can AI disease in a mother affect the foetus?

A

Autoimmune diseases mediated by IgG can be transferred across the placenta

50
Q

How do T cells contribute to autoimmunity?

A

Direct killing by CD8+ CTL

Self-destruction induced by cytokines such as TNFα

Recruitment and activation of macrophages leading to bystander tissue destruction

51
Q

What is the role of CD4 cells in autoimmunity?

A

CD4 cells providing help for Ab and cytotoxicity

52
Q

Give examples of autoimmune diseases caused by T cells

A
  • Multiple sclerosis

- Insulin dependent diabetes mellitus

53
Q

What are Th17 cells?

A

Th17 cells are helper T cells that produce the cytokine IL-17
implicated in AI diseases including spondyloarthropathy, MS and diabetes

54
Q

What is the effect of Th17 activation?

A

Highly inflammatory

Produce cytokines which are involved in the recruitment, migration and activation of immune cells

55
Q

What therapeutic strategies are used to overcome AI diseases?

A

Anti-inflammatories
- NSAID, corticosteroids

T & B cell depletion
- RA: anti-CD4, anti-CD20

Therapeutic antibodies

  • anti-TNF; anti-VLA-4
  • blocks adhesion

Antigen specific therapies

  • (in development)
  • Glatiramer acetate
  • increases T-regs.
56
Q

What is the role of central and peripheral tolerance?

A

Central and peripheral tolerance mechanisms eliminate and control autoreactive T cells

57
Q

What is the defining genetic factor in AI disease?

A

The major histocompatibility complex is the most important genetic factor in autoimmune disease

Immunology (14 decks)

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