Autoimmune Diseases Flashcards
1
Q
What is an Autoimmune disease?
A
an adaptive immune responses to self-antigens contribute to tissue damage
2
Q
Give an overview selection of the adaptive immune lymphocytes
A
3
Q
What is the outcome of too Rigorous or too Permissive Negative selection?
A
Too Rigorous
- Low risk of autoimmunity
- Poor repertoire pool
- Increased susceptibility to infection
Too Permissive
- Broad repertoire
- Lower risk of infection
- Higher risk of autoimmunity
4
Q
What are the main Peripheral tolerance mechanisms?
(6)
A
- Immunological hierarchy
- CD4 T cell will not be activated unless antigen is presented in an ‘inflammatory’ context with TLR ligation
- Antigen segregation
- Physical barrier to sequestered antigen
- Peripheral anergy
- Weak signalling between APC/ CD4 T cell without co-stimulation causes T cells to become non-responsive
- Regulatory T cells
- CD25+FoxP3 positive T cells and other types of regulatory T cells actively suppress immune responses by cytokine and juxtacrine signalling
- Cytokine deviation
- Change in T cell phenotype Th1 to Th2 may reduce inflammation
- Clonal exhaustion
- Apoptosis post-activation by activation-induced cell death
5
Q
What is the classification of Autoimmune Diseases?
(5)(3)
A
Organ-specific
- Type 1 diabetes mellitus
- Pemphigus, pemphigoid
- Graves disease
- Hashimoto’s thyroiditis
- Autoimmune cytopenias: anaemia, thrombocytopenia
Multi-system
- SLE: Systemic lupus erythematosis
- Rheumatoid arthritis
- Sjogrens syndrome
6
Q
What is Type 2 hypersensitivity according to Gell and Coombes?
- Criteria (3)
A
- refers to diseases where an antibody is pathogenic
- Disease can be transferred between experimental animals by infusion of serum, or during gestation to cause problems in fetus/ neonate
- Removal of antibody by plasmapharesis is beneficial
- A pathogenic antibody can be identified and characterised
7
Q
What is Grave’s disease (autoimmune hyperthyroidism)
- symptoms
A
- It’s an antibody-mediated autoimmune disease
- Symptoms of hyperthyroidism
- (tachycardia, palpitations, tremor, anxiety, heat intolerance etc)
- Goitre
- Grave’s ophthalmopathy due to poorly-understood retro-orbital inflammation
- Has all the characteristics of an antibody-mediated disease:
- Neonatal hyperthyroidism if mother is affected
- Serum transfers disease between experimental animals
- Antibody detected and characterised
8
Q
Explain the mechanism behind Graves thyroiditis
A
9
Q
What is Myasthenia gravis?
- symptoms
- underlying mechanism
A
- Muscle weakness and fatigability
- Eyelids, facial muscles, chewing, talking and swallowing most often affected
- Ptosis (drooping of the eyelids) at rest, becoming markedly worse after patient asked to close and open eyes repeatedly
10
Q
What is Spontaneous Urticaria?
A
- IgG FcεR1 antibody cross-links mast cell receptor causing degranulation, release of histamines –>
- Manifests with hives and swelling
11
Q
Give examples where non-pathogenic autoantibodies would be present?
- what type of antibody is it
- clinical relevance?
A
- Tissue transglutaminase antibody (coeliac),
- Islet cell antibody (diabetes),
- Gastric parietal cell antibody (pernicious anaemia)
- they can be useful for diagnosis
12
Q
What is Typer 4 hypersensitivity according to Gell and Coombs?
- criteria
A
- Tissue damage is directly mediated by T cell-dependent mechanisms
- T cells activate macrophages and other elements of innate immunity
- CD8 T cells damage tissue directly
13
Q
What is Hashimotos Thyroiditis (autoimmune hypothyroidism)?
A
- T cell-mediated autoimmunity
- the autoimmune destruction of thyroid
- organ infiltrated by CD4 and CD8 T cells
14
Q
AIRE gene
What is APCED- (Autoimmune polyglandular syndrome, candidiasis and ectodermal dystrophy)?
- cause
- aetiology
A
- a rare monogenic autoimmune disorder
- AIRE gene regulates ectopic expression of tissue-specific antigens in the thymus
- AIRE mutations result in failure of negative selection
- Strongly associated with organ-specific autoimmune diseases (type 1 diabetes, vitiligo, alopecia, autoimmune adrenal disease etc)
- Candidiasis results from antibodies to IL-17 – this cytokine seems to be important in host defence against fungi at mucosal surfaces
15
Q
What is DiGeorge syndrome?
- cause
- full phenotype effect
- presentation
A
- Failure migration 3th/ 4th branchial arches during embryogenesis
- Microdeletions in chromosome 22 (not a pure monogenic disorder)
- Full phenotype:
- Absent parathyroids (low calcium –> tetany)
- Cleft palate
- Congenital heart defects
- Thymic aplasia (low T cell no.–> immunodeficiency)
- Variable presentation
- May affect any of the above in isolation
- Huge spectrum of immunodeficiency from mild-SCID-like
- Autoimmunity is also common
16
Q
What is IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked)
- presentation
A
- Exceedingly rare X Linked mutation affecting Forkhead p3 (FoxP3) gene
- mainly found on the island of Sardinia
- Abrogates production of CD4+CD25+FoxP3+ regulatory T cells
- Key features:
- Inflammatory bowel disease
- Dermatitis
- Organ-specific autoimmunity
17
Q
Give an overview of the HLA System: Human Lymphocyte Antigen
(MHC)
- role
- genetics
- nomenclature
A
- APCs present processed peptide to T cells in combination with highly polymorphic MHC (HLA) molecules
-
Encoded by the HLA system on chromosome 6
- Class I: A, B, C (presents to CD8 T cells)
- Class II: DR, DP and DQ (presents to CD4 T cells)
- the nomenclature used to describe the tissue type in an individual
- Eg HLA B27=expresses serotype 27 at B locus of HLA class I
- Eg HLA DR2=expresses serotype 2 at locus 2 of HLA class II
19
Q
What is seen pathologically and genetically Coeliac disease?
A
- Total small bowel villous atrophy, crypt hyperplasia and lymphocyte infiltration in advanced disease
- virtually all affected individuals express
- HLA-DQ2
- HLA-DQ8
- or both
- DQ = MHC class 2
21
Q
Give an overview of Coeliac pathogenesis
A
- The damage is mediated by T cells;
- antibodies are produced, but do not contribute to tissue damage
- Inflammation resolves with strict gluten avoidance
23
Q
Explain Molecular mimicry
A
- Viral infection: presentation of viral peptides to a CD4 T cell via MHC 2, causing T cell activation
- The viral peptides happen to be similar to a host-derived peptide; the T cell would normally recognise these peptides, but would not react to them
- The activated T cell now reacts strongly to the self-peptide and initiates inflammation
- The process depends on having the correct MHC molecules to present this critical epitope that is common to both virus and host (inherited)
- Also depends on having the correct T cell to recognise it (mainly bad luck)
26
Q
What is the progression of type 1 diabetes?
A
- there is a genetic susceptibility
- then an environmental trigger which results in autoantibodies INsulitis
- by the time overt diabetes had developed over 90% of the pancreas has been destroyed
- Pre-diabetic pancreatic biopsy can show infiltration of CD8 T cells against the beta cells
31
Q
What is the link between Classical Complement deficiency and SLE?
A
- Immune complexes are cleared by phagocytes; process enhanced by phagocyte Fc receptors and C3b receptors
- Deficiency of C1q/ C2/ C4 predispose to lupus, presumably because immune complexes cannot be cleared effectively
33
Q
How are antibodies in the blood detected through Indirect immunofluorescence
(3)
A
- Incubate
- Detect
- Read
35
Q
How are antibodies in blood detected by Solid Phase Immunoassay
- example
- critique of the method
A
- ELISA test: Enzyme-linked peroxidase is the secondary antigen that binds to the antibody
- substrate to the enzyme is added, the rate of colour formation is proportional to the amount of specific antibody present
- washing has to be done between each stage to remove any unbound antibodies/enzymes
- very labour intensive and need to be done as runs (so batches together)
- being replaced by more automated methods - particle bead suspension
36
Q
How are antibodies bound to tissue detected via direct immunofluorescence
(3)
A
- Prepare tissue biopsy/slide
- Detect Read
37
Q
Give an example of when direct immunofluorescence would be used?
A
- In Bullous skin disease: Pemphigoid
- Thick-walled bullae, rarely on mucus membranes
- Target antigen is at the dermo-epidermal junction which can be seen on fluorescence
- In Bullous skin disease: Pemphigus
- Thin-walled bullae on skin and mucus membranes rupture easily
- Target is the intercellular cement protein desmoglein 3 in superficial skin layers
43
Q
What is Plasmapheresis
- when is it indicated?
A
- Plasmapharesis removes antibodies from the bloodstream
- useful in antibody-mediated diseases
