L13: Autoimmune diseases 2 Flashcards
Molecular mimicry - 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 process depends on having the correct MHC molecules to present this critical epitope that is common to both virus and host (inherited)
Effect of T cell activation
- The activated T cell now reacts strongly to the self-peptide and initiates inflammation
What are some examples of molecular mimicry
- Autoimmune haemolysis after mycoplasma pneumoniae
- Rheumatic fever
What is autoimmune haemolysis
- Mycoplasma antigen has homology to ‘I’
- IgM antibody to mycoplasma may cause transient haemolysis
Rheumatic fever
- Inflammatory disease occurring after streptococcal infection affecting heart, joints, skin and brain
- Anti-streptococcal antibodies believed to cross-react with connective tissue
- Even for these ‘best examples’ the target antigens are not well-defined; for other diseases, the paradigm remains rather theoretical
Features of 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%; rising by around 5% per annum
- Treatment by injection of insulin and diet
What is monogenic diabetes
- Can present with a similar phenotype but requires different management
Type II diabetes mellitus
- Older onset, insulin secretion, ketoacidosis less likely and insulin not necessarily required
Immunology of type 1 diabetes
- Islet cell antibodies detectable for months to years before the onset of clinical disease
- HLA associations
- Early pancreatic biopsy shows infiltration with CD4/8 T cells
- Although antibodies present, they do not appear to be directly relevant to destruction of the pancreas
- By the time patient has established diabetes, generally no active inflammation in pancreatic biopsy
Relevance of genetics - type 1 dm
- Genetic background definitely important - concordance in monozygotic twins is close to 100% if they are observed for long enough
Major defined genetic risk factors - T1DM
HLA class II alleles:
- DR3 or DR4 relative risk is 6
- DR3 and DR4 relative risk is 15
- Relative like coeliac disease, believed that 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, together with other genetic and environmental co-factors
Precipitating events
- Autoantibodies to islet cell antigens present for months-years before onset of clinical disease
- Gap between initiation of disease and its presentation makes identification of triggers difficult
- Much of the data is epidemiological
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)
Development of AID
MHC background - critical for some diseases in determining which peptides can be presented
T cell receptor repertoire - critical in determining whether 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 myriad of other genetic and environmental factors
Autoimmune serology for diagnosis
Some autoantibodies have diagnostic value
- In some cases, the antibodies are pathogenic
- In others, they are simply a bystander effect
