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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

1. Incubate - add patient serum containing (or not) relevant antibodies to slide
2. Detect - add detection antibody labelled with fluorescent marker
3. 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 removes antibodies from the bloodstream therefore may be useful in antibody-mediated diseases