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Module 204 MSK & Immune system > T1 L12 & 13 Autoimmune diseases > Flashcards

T1 L12 & 13 Autoimmune diseases Flashcards

1
Q

What is autoimmunity?

A

Immune responses to self antigens

Also known as auto-reactivity

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2
Q

What is an autoimmune disease?

A

Adaptive immune responses to self-antigens contribute to tissue damage

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3
Q

What is tolerance?

A

State of immunological non-reactivity to an antigen

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4
Q

Why isn’t inflammatory bowel disease an autoimmune disease?

A

While it involves the immune system it doesn’t involve adaptive immune responses to self antigens

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5
Q

What is the mechanism for immunological hierarchy tolerance?

A

CD4 T-cells aren’t activated unless antigen is presented with an ‘inflammatory’ context with TLR ligation

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6
Q

What is the mechanism for antigen segregation?

A

Physical barriers to sequestered antigen

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7
Q

What is the mechanism for peripheral anergy?

A

Weak signalling between APC / CD4 T-cell without co-stimulation causes T-cells to become non-responsive

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8
Q

What is the mechanism for regulatory T-cells?

A

CD25+ Foxp3 positive T-cells and other regulatory T-cells actively suppress immune responses by cytokine and juxtacrine signalling

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9
Q

What is the mechanism for cytokine deviation?

A

Changes in T-cell phenotype e.g. Th1 to Th2 may reduce inflammation

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10
Q

What is the mechanism for clonal exhaustion?

A

Apoptosis post-activation by activation-induced cell death

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11
Q

Give examples of organ-specific autoimmune diseases?

A 
Type 1 diabetes mellitus
Pemphigus, pemphigoid
Graves disease
Hashimoto's thyroiditis
Autoimmune cytopenias - anaemia, thrombocytopenia
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12
Q

Give examples of non-organ specific autoimmune diseases

A

Systemic lupus erythematosus

Rheumatoid arthritis

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13
Q

What does type II hypersensitivity refer to?

A

Diseases where antibody is clearly pathogenic i.e. causes disease / tissue damage directly

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14
Q

What is the criteria for autoimmune antibody-mediated disease?

A

Diseases can be transferred between experimental animals by infusion of serum or during gestation to cause problems in foetus / neonates
Removal of antibody by plasmapheresis is beneficial
Pathogenic antibody can be identified and classified

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15
Q

What are the signs and symptoms of autoimmune hyperthyroidism?

A 
Tachycardia
Palpitations
Tremor
Anxiety
Heat intolerance
Goitre
Grave's ophthalmopathy
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16
Q

Describe the physiology of the thyroid in Grave’s disease

A

Autoimmune B cell makes antibodies against TSH receptor that also stimulates thyroid hormone production
Thyroid hormones shut down TSH production but have no effect on autoantibody production which continues to cause excess thyroid hormone production

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17
Q

What is affected in myasthenia gravis?

A

Muscle weakness and fatigability

Eyelids, facial muscles, chewing, talking and swallowing are most often affected

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18
Q

How does spontaneous urticaria occur?

A

IgG FceR1 antibody cross-links mast cell receptor leading to degranulation.
This causes hives and swelling

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19
Q

What is type IV hypersensitivity?

A

Tissue damage directly mediated by T-cell dependent mechanisms

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20
Q

Give examples of T-cell mediated autoimmunity

A

Autoimmune hypothyroidism
Coeliac
Type 1 diabetes mellitus

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21
Q

What is the evidence for genetics in autoimmunity?

A

Rare monogenic disorders of immune system that are associated with autoimmune diseases
Mouse models rely on genetically susceptible strains
Enrichment in families, most attributable to HLA assocations

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22
Q

What is the evidence that environment has a role in autoimmunity?

A

Littermates in group of non-obese diabetic mice have identical genetic background and similar environment but there is variability in the development of type 1 DM

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23
Q

What is APACED?

A

Autoimmune polyglandular syndrome candidiasis and ectodermal dystrophy

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24
Q

What gene is involved in APACED?

A

AIRE gene mutation leading to failure of negative selection

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25
What does the AIRE gene normally do?
Regulates ectopic expression of tissue-specific antigens in thymus
26
Why is candidiasis a feature of APACED?
Antibodies to IL-17 which is an important cytokine in host defence against fungi at mucosal surfaces
27
What is DiGeorge syndrome?
Migration failure of 3rd/4th branchial arches
28
What are the signs of DiGeorge syndrome in a full phenotype?
Absent parathyroids leading to low calcium and tetany Cleft palate Congenital heart defects Thymic aplasia leading to low numbers of T-cells and immunodeficiency
29
What is IPEX?
Immune dysregulation polyendocrinopathy enteropathy X-linked Rare X-linked mutation affecting Foxp3 gene Abrogates production of CD4+, CD25+, FoxP3, regulatory T-cells
30
What are the key features of IPEX?
Inflammatory bowel disease Dermatitis Organ-specific autoimmunity
31
What does HLA B27 mean?
Expresses serotype 27 at B locus of HLA class I
32
What are the 2 classes of the HLA system?
Class I: A, B, C | Class II: DR, DP, DQ
33
What does HLA DR2 mean?
Expresses serotype 2 at locus 2 of HLA class II
34
What is coeliac disease?
Common inflammatory disease of small bowel with GI & extra-GI features Characteristics of autoimmune disease but triggered by exogenous antigen (gluten) in pre-disposed antigens
35
What are the main manifestations in coeliac disease?
Malabsorption - Loose stool - Weight loss - Vitamin deficiency - Anaemia - Poor growth in children
36
Describe the histological features in advanced coeliac disease
Total villous atrophy Crypt hyperplasia Lymphocyte infiltration
37
What HLA do those with coeliac express?
HLA-DQ2, HLA-DQ8 or both
38
What happens to HLA molecules in coeliac disease when gluten is consumed?
``` Dietary gliadin (wheat, rye, barley) is degraded by gut tissue transglutaminase 2 enzyme during digestion to produce gliadin peptides HLA DQ2/8 molecules can present these gliadin peptides to T-cells if the appropriate T-cell receptors are present ```
39
Describe molecular mimicry
Epitopes relevant to pathogen are shared with host antigens 1) Viral infection 2) Presentation of viral peptides to CD4 T-cell via MHC II leads to T-cell activation 3) Viral peptides are similar to host-derived peptide 4) Activated T-cell now reacts strongly to self peptide and initiates inflammation
40
What does molecular mimicry depend on?
MHC molecules to present this critical epitope that is common to both virus and host T-cell to recognise it
41
What are some examples of molecular mimicry?
Autoimmune haemolysis after mycoplasma pneumonia | Rheumatic fever
42
How is autoimmune haemolytic after mycoplasma pneumonia an example of molecular mimicry?
Mycoplasma antigen has homology to 'I' antigen on RBC | IgM antibody to mycoplasma may cause transient haemolysis
43
How is rheumatic fever an example of a molecular mimicry?
Inflammatory disease occurring after streptococcal infection | Anti-streptococcal antibodies believed to cross-react with connective tissue
44
Describe the pathophysiology of type I diabetes
Lack of insulin --> impaired cellular uptake glucose --> polyuria, polydipsia, polyphasic, weight loss
45
Why is it important to differentiate type 1 diabetes from monogenic diabetes?
Can present with similar phenotype but require different management
46
Why is it important to differentiate type 1 diabetes from type II diabetes?
Type II DM has older onset, some insulin secretion, ketoacidosis is less likely Insulin isn't necessarily required
47
What is the evidence that type 1 DM is an autoimmune disease?
Islet cell autoantibodies are detectable for months to years before onset of clinical disease HLA associations Mouse model Early pancreatic biopsy shows infiltration with CD4/8 T cells
48
Describe the genetics of autoimmune type 1 DM
Concordance in monozygotic twins is almost 100% HLA class II alleles are major defined genetic risk factor - DR3 or DR4 has relative risk of 6 - DR3 and Dr4 has relative risk of 15
49
Describe the evidence for Coxsackie virus being a trigger for type 1 DM
Stronger immune response to virus in cases compared to controls Viral infection can cause pancreatitis in mice and humans Protein 2C Coxsackie virus has homology with islet cell antigen glutamic acid decarboxylase
50
What are the 3 detection methods for immunology?
Indirect immunofluorescence Solid-phase immunoassay Direct-immunofluorescence
51
What are the 3 stages of indirect immunofluorescence?
1) Incubate - glass slide with tissue of interest, harvested from animal source - patient serum that does (or doesn't) contain antibodies 2) Detect - add detection antibody labelled with fluorescent marker 3) Read - look for fluorescence under microscope
52
Why is it important to identify type 1 diabetes?
Risk of ketoacidosis Requires insulin Monogenic diabetes and type 2 diabetes require different approach
53
What are the 6 stages of solid-phase immunoassay?
1) Coat each well of plastic 96-well plate with tTG antibody 2) Block well using milk-powder solution 3) Add patient samples to wells 4) Add secondary antibody 5) Add substrate 6) Compare colour change to calibration curve
54
Why is the well in solid-phase immunoassay blocked using milk-powder solution?
Gets rid of spare spaces on plastic that biological molecules can bind to.
55
Why are the samples incubated in solid-phase immunoassay?
To allow time for tTG antibody in sample to react with tTG antibody
56
What is the secondary-antibody in solid-phase immunoassay?
Anti-IgA antibody which binds to IgA Fc regions | Covalently linked to enzyme such as horse radish peroxidase
57
What is the colour change in solid-phase immunoassay measured with?
Photocell
58
How is calibration curve set uo?
Set up wells with known concentrations of tTG antibody Done by serial dilution Photocell readings from each well used to create standard curve
59
What are the steps of direct immunofluorescence?
1) Prepare tissue biopsy / slide - take biopsy of affected tissue, if damage is mediated by antibody the antibody will already be stuck to its antigen in the tissue. 2) Detect - add detection antibody labelled with fluorescent marker 3) Read - look for fluorescence under microscope
60
Describe the bullous skin disease pemphigoid
Thick-walled bullae, rarely on mucous membranes Fulfils criteria for antibody-mediated disease Linear deposition of antibody which activates complement to produce skin dehiscence and tense blister
61
What is the target in pemphigoid?
Antigen at demo-epidermal junction
62
Describe the bullous skin disease pemphigus
Thin-walled bullae on skin and mucus membranes. Rupture easily Fulfils criteria for antibody-mediated disease
63
What is the target in pemphigus?
Intercellular cement protein desmoglein 3 in superficial skin layers
64
How is coeliac disease diagnosed?
Target antigen is tissue transglutaminase (tTG) HLA typing increasingly used - absence of HLA DQ2/8 makes coeliac disease very unlikely - presence of HLA DQ2/8 isn't indicative of coeliac disease
65
What is pernicious anaemia?
Autoimmune destruction of gastric parietal cells Vitamin B12 absorbed in terminal ileum - requires intrinsic factor Once liver store is depleted it causes anaemia, neurological and sub fertility issues
66
Why is the aim of AID treatment often just to manage consequences and not treat immunology?
Immunosuppressive drugs are toxic | By time disease is over, damage may have already been done and immunosuppression would be unhelpful
67
Give examples of treatments for AID
Thyroxine for underachieve thyroid Carbimazole, surgery or drugs for thyrotoxicosis Insulin for diabetes B12 for pernicious anaemia
68
Give examples of immunomodulation drugs
``` Systemic corticosteroids Small molecule immunosuppressive drugs - methotrexate - azathiprine - ciclosporin High dose IV immunoglobulin ```
69
What does plasmapheresis do?
Removes antibodies from bloodstream | May be useful in antibody-mediated diseases

Module 204 MSK & Immune system (44 decks)

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