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
18
Q
What is Coeliac disease?
- aetiology
- cause
- presentation
A
- A very common inflammatory disease of the small bowel with gastrointestinal and extra-gastrointestinal features
- Up to 1% UK population affected
- 30-50% of Europeans express HLA-DQ2 and/ or HLA-DQ8 – not clear which additional genetic
- More common in women
- Majority undiagnosed
- Characteristics of an autoimmune disease, but unusually triggered by an exogenous antigen (gluten) in predisposed individuals
- Main manifestations are malabsorption
- loose stool, weight loss, vitamin deficiency, anaemia, poor growth in children
- But can present with chronic fatigue, subfertility issues, constipation
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
20
Q
Explain how HLA causes coeliac disease
A
- Dietary gliadin (wheat, rye and barley) is degraded by gut tissue transglutamine 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
- has to fit very tightly and this only occurs with the specific DQ2/8 HLA (and the right t cell receptor)
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
22
Q
How is infection linked with autoimmunity?
A
- some infections linked with subsequent development of autoimmune disease
- this could be due to Molecular mimicry
- an epitope relevant to the pathogen are shared with host antigens
- so the immune system produces antibodies against the pathogen epitope but also recognises the self-antigen
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)
24
Q
What are examples of Molecular Mimicry?
- disease- infection
A
-
Autoimmune haemolysis after Mycoplasma pneumoniae
- __mycoplasma antigen has homology to ‘I’ antigen on red blood cells
- IgM antibody to mycoplasma may cause transient haemolysis
-
Rheumatic fever after streptococcal infection
- an inflammatory disease affecting the heart, joints, skin and brain
- anti-streptococcal antibodies cross-react with connective tissue
25
What is Type 1 diabetes?
- cause
- presentation/effect
- aetiology
- treatment
* caused by autoimmune destruction of insulin-producing beta cells in the pancreas
* leads to a lack of insulin
* Causes: polyuria, polydypsia, polyphagia and weight loss
* Onset at any age, but typically childhood
* Disease prevalence around 0.8%; rising by around 5% per anum
* Treatment by injection of insulin and diet
26
What is the progression of type 1 diabetes?
* 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
27
What are the Genetic factors of Type 1 diabetes?
* HLA Class II alleles are the major defined genetic risk factors
* DR3 _or_ DR4 relative risk is 6
* DR3 _and_ DR4 relative risk is 15
* like in coeliac disease HLA molecules need to present relevant islet cell antigens to CD4 T cells
* autoimmune response may occur if the appropriate T cell receptors are present, along with other genetic and environmental co-factors
28
What are the precipitating events before autoantibody insulitis occurs?
* autoantibodies to islet cell antigens are present month- yeas before the onset of clinical disease
* the gap between the initiation of disease and its presents makes it difficult to identify the triggers
* some evidence of **Coxsackie virus**
* Stronger immune response to the virus in cases compared to controls
* Viral infection can cause pancreatitis in mice and humans, and precipitate autoimmune diabetes in mouse models
* Protein 2C from Coxsackie virus has homology with islet cell antigen glutamic acid decarboxylase (GAD) (?molecular mimicry mechanism)
29
Where does Systemic lupus erythematosus (SLE) affect?
- locations and symptoms
* Skin
* Butterfly (‘lupine’ rash)
* Photosensitivity
* Hives
* Serositis (inflammation of the serous membrane)
* Pleurisy, pleural effusion
* Pericarditis
* Renal
* Nephritis
* Pulmonary fibrosis
* Joint pain
* Autoimmune cytopenias
30
What is Systemic Erythematosis (SLE)?
- aetiology
- cause/ common co- foundaries
* A true multi-system autoimmune disorder
* Mostly women of reproductive age, rare in men
* More common in people of Asian and African decent
* Associated with the presence of anti-nuclear antibodies
* a collection of antibodies that react with cell nuclei and cell division apparatus;
* however, these don’t seem to directly cause disease and are probably an epi-phenomenon
* Some elements of disease probably caused by immune complex deposition;
* others may be explained by disordered apoptosis
* Some patients have a deficiency of _classical complement components (C1, C4, C2)_
31
What is the link between Classical Complement deficiency and SLE?
* 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
32
What are the 3 Broad methods of detecting autoantibodies?
* Indirect immunofluorescence
* Solid-phase immunoassay
* Direct immunofluorescence
33
How are antibodies in the blood detected through **Indirect immunofluorescence**
(3)
* Incubate
* Detect
* Read
34
How is indirect immunofluorescence useful in Type 1 diabetes?
- why is it important to identify them
- critique of method?
* Important to identify type 1 DM as:
* Risk of ketoacidosis
* Requires insulin
* Monongenic diabetes and type 2 diabetes require a different approach
* Distinction between type 1/ type 2 and monogenic diabetes not as straightforward as once thought on clinical grounds
* This method now being replaced by immunoassays for specific islet cell antigens (GAD, IA2, insulin)
35
How are antibodies in blood detected by Solid Phase Immunoassay
- example
- critique of the method
* 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
How are antibodies bound to tissue detected via **direct immunofluorescence**
(3)
* Prepare tissue biopsy/slide
* Detect Read
37
Give an example of when direct immunofluorescence would be used?
* 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
38
What are the different type of Bullous Skin disease?
- where do they present
- what symptoms do they produce
- severity?
* Pemphigoid
* Thick-walled bullae, rarely on mucus membranes
* linear deposition of antibody: activates complement _producing dehiscence and tense blisters_
* Target antigen is at the dermo-epidermal junction which can be seen on fluorescence
* Pemphigus (more serious disease)
* Thin-walled bullae on skin and mucus membranes rupture easily
* more serious as it affects the mucous membranes which make nutrition and hydration difficult
* large areas of open skin so high risk of infection dehydration and electrolyte abnormalities
* Target is the intercellular cement protein desmoglein 3 in superficial skin layers
39
What factors are used to diagnose Coeliac disease?
* Subsequently target antigen found to be **tissue transglutaminase (tTG),** which is now expressed in recombinant systems to provide antigen for _modern immunoassays_
* HLA typing also increasing utilised – absence of HLA DQ-2/ 8 makes coeliac disease very unlikely (ie high negative predictive value)
40
What is Pernicious Anaemia?
- how does it manifest itself (3)
* Vitamin B12 malabsorption in the _terminal ileum_
* caused by **autoimmune destruction** of **gastric parietal cells** resulting in lack of co-factor **intrinsic factor** which is needed for absorption
* Manifests as
* anaemia
* neurological presentation
* subfertility
41
Why is the treatment of Autoimmune diseases through managing the disease consequences preferable?
- give examples (4)
* Immunosuppressive drugs are toxic
* By the time the disease is overt, the damage may already have been done and immunosuppression may be unhelpful
* Examples:
* **Thyroxine** for an _under-active thyroid_
* **Carbimazole**, **surgery or drugs** for _thyrotoxicosis_
* **Insulin** for _diabetes_
* **B12** for _pernicious anaemia_
42
When is the treatment of Autoimmune diseases through drugs preferable?
- give examples
* when it is a 'multi-system' AID
- Systemic corticosteroids
- Small molecule immunosuppressive drugs (eg methotrexate, azathioprine, ciclosporin)
43
What is Plasmapheresis
- when is it indicated?
* Plasmapharesis removes antibodies from the bloodstream
* useful in antibody-mediated diseases
