Lecture 15: Autoimmune diseases Flashcards
What is molecular mimicry?
Epitopes relevant to the pathogen are shared with host antigens
Explain the mechanism of molecule mimicry for a viral infection?
- Presentation of viral peptides to a CD4 T cells via MHC 2 causing T cell activation
- The viral peptides happen to be similar to a host-derived peptides; the T Cell would normally recognise these peptides but would not react with them
- The activated T cell now reacts strongly to the self-peptides and initiates inflammation
What does the molecular mimicry depend on?
The process depends on having the correct MHC molecules to present this critical epitope that is common to both virus and the host
-Also depends on having the correct T cell to recognise it mainly
Can you give an example of molecular mimicry in action?
Autoimmune haemolysis after mycoplasma pneumoniae
- Mycoplasma antigen has homology to āIā antigen on RBC
- IgM antibody to mycoplasma may cause transient haemolysis
Can you give an example of molecular mimicry in action?
Rheumatic fever:
- Inflammatory disease occurring after streptocoocal infection affecting the heart, joints, skin and the brain
- Anti-streptococcal antibodies believed to cross-react with connective tissue
explain the how the symptoms of type 1 diabetes are caused?
Lack of insulin impairs cellular uptake of glucose, leading to: Polyuria Polydypsia Polyphagia and weight loss
What are the bases of the treatment?
injection of insulin and diet
Which other types of diabetes is type 1 important to differentiate from and why?
Monogenic diabetes: can present with similar phenotype but requires different management
Type 2 Diabetes: older onset, still some residual insulin secretion
ketoacidosis less likely and insulin not necessarily required
Explain the immunogenic evidence of type 1 diabetes?
- Islet cell antibodies detectable for months to years before the onset of clinical disease
- HLA association
- Mouse model
- Early pancreatic biopsy shows infiltration with CD4/8 T cells
Explain the evidence that may contradict the theory of immunogenic origin of type 1 diabetes?
- Although antibodies present, they do not appear to be directly relevant to destruction of the pancreas
- by the time clinical diabetes becomes apparent-no active inflammation in pancreatic biopsy
Explain the genetics link of type 1 diabetes?
- Monozygotic twins=100 concordance
- HLA class II alleles are the major defined risk factor
- DR3 OR DR4 relative risk is 6
- DR3 AND DR4 relative risk is 15
Compare the genetic link of type 1 diabetes to coeliacs?
Similar to coeliacs, the expression of DR3 or DR4 are required to present relevant islet ce;; antigens to CD4 T cell
- Auto-immune response may occur if appropriate T Cells receptors are present, together with other genetic and environmental co-factors
What are the precipitating events of type 1 diabetes?
-Auto-antibodies to islet cell antigens present fro month to years before onset of clinical disease
-Gap between initiation of disease and its presentation makes identification of triggers difficult
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Describe how the coxsackie virus is precipitating event for T1Dm?
- Stronger immune response tp virus compared to control
- Viral infection can cause pancreatitis in humans and mice and can precipitate autoimmune diabetes in mouse models
- Protein 2C from Coxsackie virus has homology with islet cells antigen glutamic acid decarboxylase (GAD)
Describe the summary steps of the development of AID multistep?
- MHC background- critical for some diseases in determining which peptides can present
- T cell receptor repertoire: critical in determining whether the peptide-MHC complex can be recognised
- Infection: may influence the activation of T cells and B cells that are potentially auto reactive
- Likely to be combination of genetic and environmental factors
What are the multi-system auto-immune diseases?
RA- predominantly a joint disease, but many extra-articular features
SLE
Sjorgrens
Explain the symptoms of SLE?
Skin- Butterfly rash (lupin) -photo-sensitivity -Hives Serositis: -pleurisy, pleural effusion -Pericarditis -Renal -nephritis -pulmonary fibrosis -joint pain auto-immune cytopenia
What are the causes of SLE?
deficient of classical complement component (C1, C4, C2)
-Some elements of the disease probably caused by immune complex deposition; others may be explained by disordered apoptosis
What are the immune complexes cleared by?
Phagocytes: process enhanced by phagocyte Fc receptors and C3b receptors
Why does the deficiency of C1q/c2/c4 predisposes to lupus?
Due to immune complexes can not be cleared effectively
How are the antibodies used for diagnosis?
-Some antibodies have diagnostic value: some are pathogenic and others are simply bystander
Describe the three methods for detection of antibodies?
- Indirect immunofluorescence
- Solid phase immunoassay
- direct immunofluoresence
Describe the detection process of antibodies using indirect immunofluorescence?
1) Incubate- patient serum containing (or not containing) antibodies
2) Detect :
Add detection antibody labelled with fluorescent marker
3) Read:
Look for fluorescence under microscope
Why is it important identify type 1 DM?
- Risk of ketoacidosis
- Requires insulin
- Monogenic diabetes and type II require different approach
Describe the detection process of antibodies using direct immunofluorescence?
1) Prepare tissue biopsy slide: Take a biopsy of affected tissue, e.g.skin (if damage mediated by antibody then it will be already stuck to the tissue
2) Detect: Add detection antibody labelled with fluorescent marker
3) Read)
Look for fluorescence under microscope
Describe the features of Bullous skin disease: pemphigoid?
- Thick walled bullae, rarely on mucus membrane
- Fulfils criteria for antibody-mediated disease
- Target antigen at dermo-epidermal junction
- Linear deposition of antibody, which activates complement producing skin dehiscence and tense blister
Describe bullous skin disease: pemphigus?
- Thin Walled bullae on skin and mucus membranes, rupture easily
- fulfils criteria for antibody-mediated disease
- Target is the intercellular cement protein desmoglein 3 in superficial skin layers
Describe the causes of pernicious anaemia?
- Vitamin B 12 is absorbed in the terminal ileum
- Absorption requires a co-factor called intrinsic factor which is secreted by the parietal cells
How is pernicious anaemia caused?
- Autoimmune destruction of gastric parietal cells
- Loss of intrinsic factor abrogates B12 absorption
- Liver stores around 2 year supply of B12
What are the manifestation of pernicious anaemia?
- anaemia
- neurological issues
- sub-fertility
What are the treatments options autoimmune disease?
- Strategy:
- manage the consequences
- Immuno-suppressive drugs are toxic and the damage is probably already done therefore immuno-suppressive therapy unhelpful
Give the examples of diseases in managing the consequences strategy is used?
- Thyroxine for under-active thyroid
- Carbimazole, surgery or drugs for thyrotoxicosis
- Insulin for diabetes
- B12 for pernicious anaemia
