Autoimmune diseases 2 Flashcards
What is molecular mimicry?
Epitopes relevant to pathogen are shared with host antigens
Which cells and molecules are involved in molecular mimicry?
Viral infection:
Presentation of viral peptides to CD4 T cell via MHC 2 -> T cell activation.
viral peptides happen to be similar to host-derived peptide, T cell would normally recognise it but not react. activated T cell now reacts strongly to self-peptide + initiates inflammation.
process depends on having correct MHCs to present critical epitope that is common to virus + host (inherited) + having correct T cell to recognise it (mainly bad luck).
What is an example of molecular mimicry?
Autoimmune haemolysis after Mycoplasma pneumoniae.
mycoplasma antigen has homology to ‘I’ antigen on RBCs. IgM to mycoplasma may cause transient haemolysis.
Rheumatic fever: inflammatory disease occurring after streptococcal infection affecting heart, joints, skin + brain.
anti-streptococcal antibodies cross-react with connective tissue.
What is the evidence that suggests that type 1 diabetes is an autoimmune disease?
Islet cell antibodies detectable for months to years before onset of disease.
HLA associations
Mouse model
Early pancreatic biopsy shows infiltration with CD4/ 8 T cells.
Antibodies present, but aren’t directly relevant to destruction of pancreas.
By the time diabetes is established, generally no active inflammation in pancreatic biopsy.
Which alleles are associated with type 1 diabetes?
HLA class II alleles -> major defined genetic risk factor
DR3 or DR4 relative risk is 6x
DR3 and DR4 relative risk is 15x
These molecules are required to present relevant islet cell antigens to CD4 T cells.
Autoimmune response may occur if appropriate T cell receptors are present with other genetic + environmental co-factors.
The development of autoimmune diseases depend on which factors?
MHC background -> determines which peptides are presented in some diseases.
T cell receptor repertoire -> determines whether peptide-MHC complex can be recognised. gene segments are inherited, but receptors are produced randomly + differs even in identical twins.
Infection -> may influence activation of T + B cells that are potentially auto reactive.
Myriad other genetic + environmental factors.
Give examples of multi-system autoimmune diseases
Rheumatoid arthritis, SLE, Sjogrens
What are the signs and symptoms of SLE?
Skin -> butterfly (‘lupine’ rash), photosensitivity, hives.
Serositis -> pleurisy, pleural effusion, pericarditis
Renal, nephritis, pulmonary fibrosis, joint pain, autoimmune cytopenia.
Outline the features and pathogenesis of SLE
Mostly women of reproductive age + Asian and African decent.
Anti-nuclear antibodies react with cell nuclei + cell division apparatus but don’t directly cause disease (epi-phenomenon).
Some elements caused by immune complex deposition, others by disordered apoptosis.
Some have deficiency of classical complement components (C1, C4, C2).
What is classical complement deficiency?
Immune complexes cleared by phagocytes + enhanced by phagocyte Fc receptors and C3b receptors.
Deficiency of C1q/ C2/ C4 predispose to lupus because immune complexes can’t be cleared effectively.
Which 3 methods are used to detect autoantibodies?
Indirect immunofluorescence
Solid-phase immunoassay
Direct immunofluorescence
Outline the process of indirect immunofluorescence
Incubate -> patient serum containing (or not) relevant antibodies.
Detect -> add detection antibody labelled with fluorescent marker.
Read -> look for fluorescence under microscope.
Why is it important to detect type 1 diabetes?
Risk of ketoacidosis, requires insulin, monogenic diabetes + type 2 DM require different approach.
Outline the process of immunoassay
Plastic well coated with antigen e.g. diabetes -> pancreatic islet cell antigen.
Serum added to well, antibody present sticks to antigen.
Secondary antibody anti-IgA binds to IgA Fc regions, covalently linked to enzyme horseradish peroxidase -> sticks to specific antibody that’s bound to antigen.
Excess secondary antibody washed away.
Trigger added -> reacts with horse radish peroxidase that’s bound to secondary antibody, which is bound to antibody tTG present in patient sample -> colour change measured using photocell.
How are values provided for the samples produced in immunoassay?
Need to be compared:
set up wells containing known concentrations of tTG antibody.
photocell readings from each well used to create standard curve.
Positive + negative controls run to show that assay has worked correctly.
Outline the process of direct immunofluorescence
Prepare tissue biopsy/slide: take biopsy of affected tissue. if damage mediated by antibody, it will already be stuck to its antigen in tissue.
Detect: add detection antibody labelled with fluorescent marker.
Read: look for fluorescence under microscope.
Outline the features of 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 -> activates complement producing skin dehiscence + tense blister.
Outline the features of bullous skin disease - pemphigus
Thin-walled bullae on skin + mucus membranes, rupture easily.
Fulfils criteria for antibody-mediated disease.
Target is intercellular cement protein desmoglein 3 in superficial skin layers.
How is coeliac disease diagnosed?
Strongly associated with antibodies binding to endomysium of smooth muscle fibres.
Target antigen is tissue transglutaminase (tTG) -> expressed in recombinant systems to provide antigen for modern immunoassays.
HLA typing –> absence of HLA DQ-2/ 8 makes coeliac disease very unlikely.
Indirect immunofluorescence with monkey oesophagus shows characteristic endomysial staining pattern.
Outline the pathophysiology of pernicious anaemia
Vit B12 absorbed in terminal ileum -> requires intrinsic factor secreted by gastric parietal cells.
Autoimmune destruction of gastric parietal cells.
Loss of intrinsic factor abrogates B12 absorption.
Once B12 liver stores depleted, manifestations -> anaemia, neurological, subfertility.
How are autoimmune diseases treated?
Manage consequences -> immunosuppressive drugs are toxic. when disease is overt, damage may already been done, immunosuppression may be unhelpful.
Examples:
Thyroxine for under-active thyroid
Carbimazole, surgery or drugs for thyrotoxicosis
Insulin for diabetes
B12 for pernicious anaemia
Non organ-specific AID -> best option is treating immune system.
Which drugs can be used for immunomodulation?
Used esp for ‘multi-system’ AIDs:
Systemic corticosteroids
Small molecule immunosuppressive drugs -> e.g. methotrexate, azathioprine, ciclosporin.
Biologics.
What is plasmapharesis?
Removes antibodies from bloodstream so may be useful in antibody-mediated diseases
