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MEDSCI 314 > Lecture 24; Autoimmunity > Flashcards

Lecture 24; Autoimmunity Flashcards

1
Q

What are the events required for an autoimmune disease?

A
  • Escape of autoreactive clones from thymus
  • Autoreactive clones encounter self-antigens
  • Peripheral tolerance failure
  • Autoreactive tissue damage
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2
Q

What are the mechanisms that self reactive lymphocytes can be removed from the body by?

A

Clonal deletion
Clonal anergy
Immunological ignorance
Suppression

Learnt all about this in another lecture

Clonal Deletion (central)
• Bone marrow and thymus
Clonal Regulation (peripheral)
• No co-stimulation - Anergy
• Suppression (Regulatory T cells)
Suppression (peripheral)
• Tregs control self-reactive cells
Ignorance
• Privileged sites
• Sequestered antigens
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3
Q

Describe niave t cell activations;

Shouldve learnt this in other lectures…

A
  • TCR on naïve Th cells binds antigenic peptide displayed on MHC class II molecules on DCs
  • Signals sent to nucleus and CD40L upregulated on Th cell that binds CD40 on DC leading to upregulation of B7 molecule on DC
  • Signal 2 sent to Th cell nucleus when B7 molecules bind costimulatory CD28 on the Th cell
  • Th cells express IL-2 and its receptor
  • IL-2/IL-2R signalling results in 3rd signal to Th cell nucleus
  • Th cell is now activated and proliferates to generate Th effector cells
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4
Q

What is anergization of T cells?

A

It is when autoreactive t cells binds a tolergenic DC (no danger signal as no infection, immature thus no co recptors), this will lead to T cell anergization (no prolif).

Therefore when the anergized autoreactive t cell encounters a Mature, DC with antigen, it will bind but wont proliferate as doesnt have the co-receptors.

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5
Q

Describe B cell activation

You should know this too

A
  • Signal 1 delivered following antigen binding to surface BCR
  • Antigen bound to the BCR complex is internalised/processed to generate peptide-MHC class II complex that binds TCRs
  • CD40L binds to CD40 on B cell resulting in costimulatory signal 2 to induce cytokine receptor expression
  • Cytokines expressed by Th cell bind receptors on B cell leading to signal 3 and B cell activation
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6
Q

How do autoreactive B cells become anargized?

A

Either they receive no stimulatory signal -> anargise and apoptosis

Or receive Anergised Th cell binding (no co stim here either) = anergy = apoptosis

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7
Q

Write some general notes on autoantibodies;

A
  • Natural autoantibodies are common
  • Most IgM and low affinity
  • May be against sequestered antigens
  • Products of a subset of B cells produced early in life (B-1 or CD5+)
  • Can directly regulate tissue activity
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8
Q

What are two noteable autoimmune diseases as a result of sequestered antigen exposure?

A

Sympathetic opthalmia
- Damage to eye exposes hidden antigens and causes immune damage to good eye

Autoimmune orchitis
- Damage to testicle by trauma or mumps exposes hidden antigens and causes immune damage to good testicle.

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9
Q

What is a molecular mechanisms that autoimmunity can evolve from?

A

Molecular Mimicry

- Where T cells think that present bacterial and self peptides look the same (even though they might not be)

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10
Q

Give two examples of autoimmune diseases and the origin of the peptide that is mimicked;

A

Rheumatic Fever ; Streptococcus cell wall protein -> Human myosin chain

Multiple Sclerosis ; Epstien barr virus protein -> Human myelin basic protein

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11
Q

In Acute Rheumatic fever, what are the peptides specifically that get confused / mimicked?

A

• Group A streptococcal post-infection complication
• M proteins share epitopes with proteins in synovium,
heart muscle, and heart valve

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12
Q

What sort of hyp. reaction of autoimmunity causes the symptoms of Rheumatic Fever?

A

• Antibody-mediated Type II hypersensitivity generates tissue damage and inflammation
• Arthritis, heart valve
damage

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13
Q

What are a lot of autoimmune diseases triggered by and why?

A
  • Viral infection
  • As these cause interferon up regulation which upregulates Class 2 HLA (abnormal MHC expression)
  • This can results in situations where the cell doesnt normally express these MHC receptors

= Abnormaly MHC expression which can lead to autoimmunity if the cell starts presenting autoantigens

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14
Q

What does abnormal MHC presentation lead to?

A
  • Possibility of autoantigen presentation
  • Exposure of intracellular (sequestered) antigens
  • T cells activated and provide support for autoreactive B cells
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15
Q

What are some examples of autoimmune diseases that result from abnormal MHC expression;

A
  • Autoimmune thyroiditis (thyroid gland)
  • Rheumatoid arthritis (synovial cells)
  • Psoriasis (keratinocytes)
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16
Q

What sort of reaction is organ specific autoimmunity typically?

A

Typically a type two hypersensitivity reaction

17
Q

What are some examples of organ specific autoimmunity?

A

Goodpastures syndrome

Myasthenia Gravis

Pemphigus

Idiopathic Thrombocytopenic Purpura (ITP):

Addisons Disease:

Hashimotos Thyroiditis:

Diabetes mallitius type one

18
Q

Write some notes on goodpastures syndrome;

A

Goodpastures Syndrome:
• Antibodies against type IV collagen in basement membrane (glomeruli and alveoli)
• Kidney dysfunction, bleeding in lungs

19
Q

Write some notes on MG

A

Myasthenia Gravis:
• Antibodies block acetylcholine receptors
• Muscle weakness

20
Q

Write some notes on pemphigus

A
  • Antibodies against intercellular adhesion molecule (desmogleins) between keratinocytes causing blisters
  • Can lead to fatal infections
21
Q

Write some notes on ITC

A

Idiopathic Thrombocytopenic Purpura (ITP):
• Antibodies against platelets
• Increased tendency to bleed

22
Q

Write some notes on addinsons disease

A

Addisons Disease:
• Destruction of adrenal cortex
• Decrease in steroid hormones

23
Q

Write some notes on Hashimotos Thyroiditis:

A

Hashimotos Thyroiditis: (hypothyroidism)
• Antibodies and T cells destroy thyroid tissue

( it binds TSH receptor and decreases is response)

24
Q

What happens in graves disease?

A

Hyperthyroidism (type2 reaction)

  • autoAB binds TSH receptor and enhances its activity
25
Q

What happens in type one diabetes?

A

Autoantibodies can recognise epitopes on

  • Glutamic acid decarboxylase
  • Tyrosine phosphotase

In the beta cells, auto reactive cytotoxic t cells then can come kill these cells that have these expressed on MHC class one.

26
Q

Whats a type three hypersensitivity reaction of an autoimmune disease?

A

SLE

27
Q

What causes SLE on a molecular level?

A

Immune complexes form, (ABAg) compliment becomes activated and these can result in complex entry tissue and inflammation, mediators release which destory tissue

This is all covered in another lecture so should know

28
Q

What are the effects of SLE?

A

• Inflammation in the skin, joints, blood vessels, kidneys
- can be widespread
• Photosensitivity

29
Q

What drives SLE?

A

• Antinuclear antibodies (ANA), anti-DNA, anti-RNA, anti-nuclear proteins

Due to defective clearance of neutrophils ec traps; (as these are made from DNA/RNA proteins)

30
Q

What genetically normally causes autoimmunity?

A

defects in peripheral tolerance mechanisms

Due to;
- Drugs, environement, pathogens, chemicals, toxins

31
Q

What genetically can cause autoimmune disease?

1 and 2

A

Antigen receptor genes:
• Immunoglobulin and TCR
Antigen presentation genes:
• Associations with class I (e.g. HLA-B27, ankalysing spondylitis) and class II (e.g. HLA-DR2, DR3 and DR4)

32
Q

What genetically can cause autoimmune disease?

3 and 4

A 
Complement genes:
• Impaired immune complex clearance 
Regulatory genes:
 • Cytokines and co-stimulators
Treatment possibilities:
Proinflammatory cytokine (TNFα and IL-1) antagonists

also non-hla associations due to other receptors

33
Q

What are the two treatment possibilities of autoimmune disease?

A

Replace

Suppression

34
Q

What diseases can be treated by replacement?

A
  • T1D = replacement of insulin
  • Hashimotos = thyroxin replacement
  • Addisons = replacement of glucocorticoids and mineralcorticoids
35
Q

How is SLE treated?

A
  • immunosuppressive drugs
    i. e
  • corticosteroids
  • azathioprine
  • cyclophosphoamide
36
Q

How is Rheumatoid arthritis treated?

A

Immunosuppressive drugs;

  • corticosteroids
  • NSAIDS
  • Anti-TNF and Anti-IL1 antagonists

MEDSCI 314 (28 decks)

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