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3rd Year Biomed > Immunology (Liz - Autoimmunity) > Flashcards

Immunology (Liz - Autoimmunity) Flashcards

1
Q

What 3 factors contribute to the development of an autoimmune disease?

A

1) Genetics
2) Immune regulation
3) Environment

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2
Q

What is central tolerance?

A

Self-reactive B and T cells produced in the bone marrow and thymus respectively undergo negative selection where they are destroyed

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3
Q

How do some cells escape central tolerance?

A
  • Not all self antigens are found in the thymus or bone marrow where negative selection takes place
  • Weakly self-positive cells can escape detection
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4
Q

Antigens may be immunogenic or?

A

Tolerogenic

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5
Q

Exposure of a mature lymphocyte to a tolerogenic or immunogenic antigen causes what?

A

Tolerogenic - apoptosis of lymphocyte

Immunogenic - activation and proliferation of lymphocyte

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6
Q

What factors can cause tolerance?

A
  • High antigenic dose
  • Persistence of antigen in host
  • Intravenous or oral exposure
  • Lack of co-stimulation
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7
Q

What is peripheral T cell tolerance?

A

Tolerance induced in the periphery i.e. occurs once the T cells have migrated out of the thymus and into local lymph nodes

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8
Q

What type of T cell can help control self-reactive T cells?

A

T reg cells

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9
Q

What happens to Immature T cells with high affinity for self antigens?

A

They are destroyed in the thymus

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10
Q

What happens to Immature T cells with low affinity for self antigens?

A

May be released into the body, but can be controlled by T reg cells

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11
Q

What happens to Immature T cells with intermediate affinity for self antigens?

A

Upregulate expression of transcription factor Foxp3 and become T reg cells
- suppress reaction to self antigens at sites of inflammation

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12
Q

What is the role of IL-17 producing T helper cells and how does it carry out this role?

A
  • To cause inflammation

Stimulates TNF-alpha, IL-1 and IL-6 and inflammatory cytokine production which promotes the recruitment of neutrophils and macrophages

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13
Q

What happens if you delete Foxp3 from T cell?

A

You get severe systemic autoimmunity

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14
Q

What are the 5 main causes of autoimmune reactions to self antigens?

A

1) Release of normally hidden antigens
2) Molecular mimicry between foreign and self antigens
3) Inappropriate MHC class II expression on non-APCs (due to high levels of IFN-gamma in tissue - promotes MHC activation)
4) Polyclonal activation of B and T cells by superantigens produced by bacteria and viruses
5) Genetic haplotype (MHC molecules inherited from both parents)

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15
Q

How mat infectious organisms cause the release of normally hidden antigens?

A

Disruption of cell or tissue barrier

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16
Q

How may infectious organisms cause molecular mimicry?

A

Production (by chance) of cross-reactive antibodies or T cells

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17
Q

Give some examples of autoimmunity to normally hidden antigens

A

1) Immune response to sperm after vasectomy

2) Proteins from the eye after injury

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18
Q

Describe the process of autoimmunity to eye antigens after injury?

A

1) Trauma to 1 eye causes release of sequestered intraocular antigens
2) Antigens carried to lymph nodes and activates T cells
3) Effector T cells return via the bloodstream and attack antigens in BOTH eyes

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19
Q

Give an example of molecular mimicry caused by a specific bacteria

A

Streptococcus pyogenes injection:

  • Streptococcal cell wall stimulates antibody production
  • Some antibodies cross-react with heart valve tissue due to antigen mimicry
  • Causes Rheumatic fever
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20
Q

Name a disease that can be caused by inappropriate MHC II expression on non APCs

A

Type I diabetes

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21
Q

How was it shown experimentally that autoimmunity can cause diabetes?

A
  • Introduction of IFN-gamma transgene on an insulin promoter
  • Leads to the production of high IFN-gamma in the pancreas
  • Upregulates MHC II expression on islet cells causing T cells to differentiate and destroy beta islet cells that produce insulin
  • Any newly grafted normal islets cells also get destroyed (genetically identical but lack IFN-gamma transgene)
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22
Q

Describe how polyclonal B-cell activation can cause autoimmunity

A
  • Viruses and bacteria can induce non-specific B cell activation without need for T helper cells
  • If B cells that recognise self antigens are activated this way, auto-antibodies will be produced
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23
Q

Give an example of a disease in which auto-antibodies are made against T and B cells

A

Infectious mononucleosis (glandular fever) by the Epstein-Barr Virus

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24
Q

What other types of auto-antibodies can be made?

A

1) Rheumatoid factors (bind to self IgG)

2) Antinuclear antibodies (bind to self DNA and phospholipids)

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25
Q

What are superantigens?

A
  • Produced by pathogenic organisms
  • Can override T cell specificity
  • Can activate up to 25% of total T cell population
  • Does this by binding to all TcRs with a Vbeta sequence
26
Q

Where do superantigens bind?

A

Bind to both the T cell receptor and the MHC complex on the outer edge

27
Q

What type of molecule is a bacterial and viral superantigen?

A 
Bacterial = soluble exotoxin
Viral = membrane-embedded protein
28
Q

What is another name for MHC?

A

The Human leukocyte antigen (HLA) complex

29
Q

Almost all patients with type I diabetes express which 2 MHC class II haplotypes?

A

HLA-DR3 and HLA-DR4

30
Q

Which haplotype is said to be protective against diabetes?

A

HLA-DR2

31
Q

In the normal HLA-DQbeta chain (MHC class II), what amino acid is there at position 57?

A

A charged aspartic acid (Asp-57)

32
Q

This charged Asp-57 allows the formation of what?

A

A salt bridge to an arginine in the adjacent alpha chain

33
Q

In patients with type 1 diabetes, the charged Asp-57 is commonly changed to what?

A

An uncharged, valine, serine or alanine

34
Q

How does this amino acid change affect the MHC?

A
  • Disrupts the salt bridge
  • MHC becomes less selective in binding of self peptides
  • Increases chance of type 1 diabetes
35
Q

What is ‘relative risk’ in terms of allele frequency?

A
  • The number of patients carrying the allele compared to the number that would be expected, given how common that particular HLA allele is in the general population
36
Q

What does a relative risk of 1 mean?

A

The same as found in the general population

37
Q

In the US, how many people have autoimmune diseases and what % are female?

A

~50 million

78% female

38
Q

Why is it thought that women are more susceptible to autoimmune diseases?

A
  • Women have a more vigorous immune system

- Possibly due to oestrogen

39
Q

What finding supports the suggestion that autoimmune disease is linked to oestrogen?

A

Lupus flares up during pregnancy (high oestrogen) and goes into remission during the menopause (low/no oestrogen)

40
Q

What are microglial cells?

A

The brains immune cells - macrophages in the brain

41
Q

What evidence suggests that there is a link between microglial cells and schizophrenia?

A

Microglial cells are hyperactive in people at risk of schizophrenia and in the early stages of the disease

42
Q

Name some autoimmune diseases

A
  • Antibody-mediated autoimmunity
  • Graves disease
  • Hashimotots thyroiditis
  • Myasthenia Gravis
  • Multiple sclerosis
  • Rheumatoid arthritis
  • Retrovirus and rotavirus infection
  • Type 1 diabetes mellitus
43
Q 
Name the what the antibodies are produced against in the following diseases:
A) Graves disease
B) Type I diabetes
C) MS
D) Myasthenia Gravis
E) Rheumatoid arthritis
F) Guillian-Barre syndrome
E) Systemic lupus erythematosus
A

A) Thyroid-stimulating hormone receptor on thyroid cells

B) Pancreatic beta cell antigens

C) Myelin on CNS neurons

D) Acetylcholine receptor of motor endplate

E) Collagen

F) Myelin of PNS neurons

E) Intracellular nucleic acid protein complexes (antinuclear antibodies)

44
Q

Give an example of a systemic autoimmune disease

A

Systemic lupus erythematosus (SLE)

45
Q

What is the characteristic symptom of SLE?

A

Butterfly rash over womens cheeks

46
Q

What is the diagnostic test for SLE?

A

Testing for antinuclear antibodies in patients serum

- Staining with anti-human secondary antibody labelled with fluorescein

47
Q

What is the ratio of women to men that get SLE?

A

9:1

48
Q

What causes the symptoms in SLE?

A

Autoantibodies made to DNA, histone, RBCs, platelets, leukocytes, blood clotting factors

49
Q

What are the general symptoms of SLE?

A
  • Fever
  • Weakness
  • Skin rashes
  • Arthritis
  • Kidney dysfuntion

From autoantibodies to RBCs and platelets and clotting factors:

  • Anemia
  • Poor blood clotting after injury
50
Q

What occurs in Graves’ Disease?

A
  • Autoantibodies bind to TSH receptor, mimicking action of TSH
  • Leads to uncontrolled action of adenylate cyclase
  • Results in overproduction of thyroid hormones due to lack of negative feedback (hyperthyroidism)
51
Q

What happens in Hashimoto’s thyroiditis?

A
  • Autoantibodies generated to thyroid antigens (thryroglobulin and thyroid peroxidase)
  • T cells respond to thyroid antigen causing influx of immune cells
52
Q

What is the result of Hashimotos thyroiditis?

A

a) Enlarged thyroid
b) Antibody binding interferes with iodine uptake leading to decreased production of thyroid hormone
c) the effect of b) leads to decreased production of thyroid hormones (hypothyroidism)

53
Q

Who is affected by Hashimotos thyroiditis?

A

Middle aged women

54
Q

What occurs in Myasthenia gravis?

A
  • Binding of autoantibodies to the nicotinic acetylcholine receptor blocks acetylcholine binding
  • Receptor-mediated endocytosis of the receptor occurs and is degreaded
  • Antibodies also activate complement which damage motor endplate
55
Q

What are the symptoms of Myasthenia gravis?

A 
- Progressive muscle weakness:
> droopy eyelids
> Slurred speech
> Weak arms and legs
> Problems chewy
Can eventually be fatal
56
Q

What occurs in Rheumatoid arthritis?

A
  • Autoreactive T helper cells activate macrophages with cytokines
  • Macrophages produce IL-1, IL-6 and TNF-alpha
  • Activated fibroblasts produce matrix metalloproteinases (MMPs) which lead to tissue destruction
  • Fibroblasts and T cells in the joint produce RANK ligand (a cytokine) to activate bone-destroying osteoclasts
  • B cells produce antibody to collagen
57
Q

What are the symptoms of rheumatoid arthritis?

A

Pain, stiffness and swelling of the joints due to collagen breakdown and inflammation

58
Q

What are the 2 phages of MS pathogenesis?

A

Inflammatory and neurodegenerative phases

59
Q

Describe the inflammatory phase of MS

A
  • T cells, B cells and APCs enter CNS and secrete cytokines that damage the oligodendroglial cells

(These cells manufacture myelin)

  • Lymphocytes extravasate into the CNS through receptor binding (the alpha4-integrin)
  • Once the BBB has been breached, other inflammatory cells accumulate in white matter of brain
  • In the brain, T cells, macrophages and microglial cells release osteopontin (OPN), IL-23, IFN-gamma and TNF which DAMAGE THE MYELIN SHEATH
  • B cell produce myelin specific antibodies, which activate the classical pathway of complement
  • Complement produces membrane-attack complexes (MACs) that punch holes in the myelin and the oligodendroglial cells
60
Q

Describe the neurodegeneration phase of MS

A
  • T cells and APCs produce glutamate which injures oligodendroglial cells and underlying axons
61
Q

Name some ways in which MS can be treated

A

1) Statins - inhibit metalloprotease secretion
- May therefore block T cells from entering the CNS
- Block T cell activation

2) Altered peptide ligands (APLs)
- Block T cell activation

3) Antibodies for alpha4-integrin
- block T cell movement into brain

62
Q

What has been suggested as a trigger for autoimmune diabetes?

A

1) Retrovirus infection
- Retrovirus superantigen discovered in patient with diabetes

2) Rotavirus
- May be due to molecular mimicry
- Amino acid sequences of some rotavirus proteins is similer to pancreatic islet proteins

3rd Year Biomed (44 decks)

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