13. Autoimmune diseases 2 Flashcards
Non-genetic factors in autoimmunity: infection
Some infections linked with subsequent development of autoimmune disease
Could be due to molecular mimicry, in which pathogen epitopes are shared with host antigens
Molecular mimicry
Viral infection: viral peptides presented to a CD4 T cell via MHC 2, causing T cell activation
The viral peptides happen to be similar to a host peptide; T cell normally recognises these peptides, but doesnt react to them
The activated T cell now reacts strongly to the self-peptide and initiates inflammation§
What predisposing factors are needed for molecular mimicry
The process depends on having the correct MHC molecules to present the critical epitope that is common to both virus and host (inherited)
Also need the correct T cell to recognise it (mainly bad luck)
Examples of molecular mimicry
Autoimmune haemolysis after mycoplasma pneumoniae
rheumatic ever after streptococcal infection to heart, joints, skin and brain
Target antigens not well defined
Autoimmune haemolysis
example of molecular mimicry
Happens after Mycoplasma pneumoniae
Mycoplasma antigen has homology to ‘I’ antigen on red blood cells
IgM antibody to mycoplasma may cause transient haemolysis
Rheumatic fever
example of molecular mimicry
inflammatory disease occurring after streptococcal infection affecting heart, joints, skin and brain
Anti-streptococcal antibodies believed to cross-react with connective tissue
Type 1 diabetes
Lack of insulin impairs cellular update of glucose, leading to polyuria, polydypsia, polyphagia and weight loss
Onset at any age, but typically childhood
Disease prevalence around 0.8%
Treatment by injection of insulin and diet
Not same as monogenic diabetes or Type II diabetes mellitus = older onset, insulin secretion, ketoacidosis less likely and insulin not necessarily required
Evidence for T1DM as an autoimmune disease
- Islet cell antibodies detectable for months to years before onset of clinical disease
- HLA associations
- Mouse model
- Early pancreatic biopsy shows infiltration with CD4/ 8 T cells
- even tho antibodies are present they do not appear to be directly relevant to pancreatic destruction
By the time patient has established diabetes, generally no active inflammation in pancreatic biopsy
Progression to type 1 diabetes
Genetic susceptibility Environmental trigger Autoantibodies insulitis Clinical onset Loss of C-peptide
by time overt diabetes has developed, over 90% of the pancreas has been destroyed
Genetic and type 1 diabetes
Conconcordance in monozygotic twins is almost 100% if they are observed for long enough
Major gentic risk factor: HLA class II alleles
- DR3 or DR4 relative risk is 6
- DR3 and DR4 relative risk is 15
these molecules are needed to present relevant islet cell antigens to CD4 T cells
Autoimmune response may occur if appropriate TCRs are present, together with other genetic and environmental co-factors
Precipitating events in type 1 diabetes
Autoantibodies to islet cell antigens present for months-years before onset of clinical disease
Some evidence for Coxsackie virus
- Stronger immune response to 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)
Factors in develping AID
MHC background: Critical in determining which peptides can be presented
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
Autoimmune serology for diagnosis
Broadly three methods for detection:
- Indirect immunofluorescence
- Solid-phase immunoassay
- Direct immunofluorescence
Some autoantibodies have diagnostic value: some are pathogenic some are bystanders
Indirect immunofluorescence
Glass slide with tissue of interested from animal source
- Incubate - add patient serum containing (or not) relevant antibodies to slide
- Detect - add detection antibody labelled with fluorescent marker
- Read - look for fluorescence under microscope
Detecting antibodies in blood by immunoassay (ELISA)
Add antibodies to a well coated in antigen, if specific then will bind
Enzyme linked antibody binds to the specific antibody
The substrate is assed and converted by enzyme into coloured product
The rate of colour formation is proportional to amount of specific antibody
…..being replaced by newer methods that are more automated eg particle bead suspension
ELISA practical
Well coated with tTG antigen , antibodies is added
Well is blocked using milk powder then excess milk solution is washed away
Samples are added to wells, incubated then given time
Excess antibody washed off
Secondary antibody is added, this antibody is an anti-IgA antibody which will bind to IgA Fc regions. Covalently linked to enxzyme like horse radhish peroxidase.
Substrate is added, reacts with peroxidase on secondary antibody bound to tTG antibody in patient sample -> colour change
colour change measured using a photocell
Direct immunofluorescence
Prepare tissue biopsy/slide: Take a biopsy of affected tissue eg skin, kidney; if damage mediated by antibody, antibody will already be stuck to its antigen in the tissue
Detect: Add detection antibody labelled with fluorescent marker
Read: Look for fluorescence under microscope
Bullous skin disease: pemphigoid
Thick-walled bullae, rarely on mucus membranes
Fulfils criteria for antibody-mediated disease
Target is antigen at dermo-epidermal junction
Linear deposition of antibody, which activates complement producing skin dehiscence and tense blister
Bullous disease: pemphigus
Thin-walled bullae on skin and mucus membranes, rupture easily
Fulfils critiera for antibody-mediated disease
Target is the intercellular cement protein desmoglein 3 in superficial skin layers
Coeliac disease diagnosis
Antibodies binding to the endomysium of smooth muscle fibres
target antigen is tissue tranglutaminase (tTG), which is expressed in recombinant systems to provide antigen for modern immunoassays
HLA typing – absence of HLA DQ-2/ 8 makes coeliac disease very unlikely (ie high negative predictive value)
Vitamin B12 and intrinsic factor
Vitamin B12 absorbed in terminal ileum
Absorption requires a co-factor called INTRINSIC FACTOR which is secreted by the gastric parietal cells
Pernicious anaemia
autoimmune destruction of the gastric parietal cells
Loss of intrinsic factor abrogates B12 absorption
Liver stores around 2 years supply of B12
Once depleted, multiple possible manifestations:
- Anaemia
- Neurological
- Subfertility
Why do we manage consequences of AID rather than treat teh cause?
Preferable to treating the immunology
Immunosuppressive drugs are toxic
By the time the disease is overt, the damage may already have been done and immunosuppression may be unhelpful
Treatment of AID: manage the consequences examples
Thyroxine for underactive thyroid
Carbimazole, surgery or drugs for thyrotoxicosis
Insulin for diabetes
B12 for pernicious anaemia
However, in some AID, particularly non organ-specific, treatment of the immune system is the best option
Some drugs for immunomodulation
Used particularly for ‘multi-system’ autoimmune diseases
- Systemic corticosteroids
- Small molecule immunosuppressive drugs (eg methotrexate, azathioprine, ciclosporin)
- High-dose intravenous immunoglobulin (mechanism poorly understood)
- Increasing interest in ‘biologics’
Plasmapharesis
Plasmapharesis removes antibodies from the bloodstream therefore may be useful in antibody-mediated diseases
