l12: part 2 Flashcards
what is the explanation for developing autoimmune diseases after infections
molecular mimicry, in which epitopes relevant to the pathogen are shared with host antigens
Describe the aeitiology 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 anum
Treatment by injection of insulin and diet
Important to differentiate from:
-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
what is the evidence for autoimmune disease in t1 diabetes
- Islet cell antibodies detectable for months to years before the onset of clinical disease
- HLA associations
- Mouse model
- Early pancreatic biopsy shows infiltration with CD4/ 8 T cells
- Note that 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
what % of the pancreas has to be lost (and what other factor) for overt diabetes to be developed
90%
decrease in beta cell mass
describe the process of 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 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)
give some examples of molecular mimicry
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: 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
the paradigm remains rather theoretical
what are the genetics behind type 1 diabetes
HLA class II alleles are the major defined genetic risk factor
- DR3 or DR4 relative risk is 6
- DR3 and DR4 relative risk is 15
- Rather 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
what are the precipitating events to type 1 diabetes
Autoantibodies to islet cell antigens present for months-years before onset of clinical disease
Coxsackie virus
what is the evidence for coxsackie virus triggering type 1 diabetes
- 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)
summarise the development of AID in 4 steps
MHC background: Critical for some diseases in determining which peptides can be presented
T cell receptor repertoire: critical in determining whether the peptide-MHC complex can be recognised. Note: the gene segments are inherited, but the receptors are produced randomly and will differ even in identical twins
Infection: may influence the activation of T cells and B cells that are potentially auto reactive
Likely to be myriad other genetic and environmental factors
what are the cases in which antibodies have diagnostic value
(Autoimmune serology for diagnosis)
In some cases the antibodies are pathogenic
In others, they are simply a bystander effect
what are the 3 methods that you can do for Autoimmune serology for diagnosis
- Indirect immunofluorescence
- Solid-phase immunoassay
- Direct immunofluorescence
what is indirect immunofluorescence
- detecting antibodies in the blood, serum or other bodily fluids
- makes use of 2 antibodies while the primary antibody I unconjugated the second is Fluorophore-conjugated antibody is used for the detection of the source of the problem
describe the indirect immunofluorescence method
1- incubation )
patient serum containing (or not) relevant antibodies
It’s added to a glass slide with tissue of interest
2- detection)
Add detection antibody labelled with fluorescent marker
3-read) Look for fluorescence under microscope
sd: (Detection antibody sticks onto fc region
)
what is direct immunofluorescence
- it makes use of a single antibody to target the point of interest. The primary antibody is directly coupled with to a fluorophore
- looking for antibodies in the tissue biopsy
