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Infections and autoimmunity; molecular mimicry versus bystander activation dr. M. Bergman 11:00-12:45 WN-D107 Helicobacter pylori & Autoimmune Gastritis, HLA / chronic infections / T cells

18 important questions on Infections and autoimmunity; molecular mimicry versus bystander activation dr. M. Bergman 11:00-12:45 WN-D107 Helicobacter pylori & Autoimmune Gastritis, HLA / chronic infections / T cells

What is the role of HLA in autoimmunity?

The risk of developing AID highly depends on the ability of HLA/MHC to present autoantigen peptides to autoantigen-specific T cells

Give an example of the role of HLA in autoimmunity

Example 1 = Coeliac Disease: 
HLA-DQ2 or DQ8  -> MHC II molecules are able to present deaminated gliadine peptidesApple-tabwhite-space -> Increased risk to develop Coeliac Disease
Apple-tabwhite-space
Non-DQ2/8 allotypes “protect” from development of Coeliac Disease -> reliable negative prediction of disease!

Example 2 = IDDM:HLA-DQ8 or DQ2 -> increased risk to develop IDDMHLA-DQ6 ->decreased risk (RR=0.02), “protective"

How can microogranisms be involved in autoimmunity?

Microorganisms can be involved through:

1)“Bystander activation” of T lymphocytes
2) pathogeen-specifiek activation of lymphocytes :“Moleculaire Mimicry”

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What are the 3 “Ingredients” for autoimmune disease?

- Escape of autoreactive T cells from negative selection in the thymus
- Presentation of autoantigens in MHC molecules
- Activation of autoreactive T cells as a consequence of infection with                          (pathogenic) microorganism(s)
-> Possibilities: Apple-tabwhite-space
- suppression by Tregs succumbs / is overruled       Apple-tabwhite-space
- pathogen-non-specific (bystander) activation  Apple-tabwhite-space
- pathogen-specific stimulation

What is  Bystander activation of autoreactive T cells?

Abnormal or excessive presentation of self-antigens because of ectopic expression of MHC class II induced by pro-inflammatory cytokines (picture on the slide before):  Combined with:
- Tissue damage caused by inflammation induced by infection   
           ->more self-antigens come available for presentation in MHC Class II                        Molecules
- co-stimulation of autoantigen-specific T cells    by professional APC’s in the neighbourhood

- Local disturbance of – or shift in - cytokine profiles

Explain how B cell epitopes can have molecular mimicry

BCR and antibodiesrecognize complexantigenic structures

Example: GBS

Explain how T cell epitopes can have molecular mimicry

T cells recognizesmall peptide fragments(presented in MHC)!

Examples: Type 1 diabetes, autoimmune gastritis

What is the prevalence of Helicobacter pylori infection?

Colonizes the stomach for life !
50 % world population is infected
100 % inflammation (gastritis)
10-15 % peptic ulcer disease
Corpus atrophy (destruction of gastric glands)
2 % gastric cancer

How much infected patients of H. pylori get autoantibodies and to what?

H. pylori leads to autoantibodies in 30-50% of infected patients

Binding site is the H+,K+-ATPase (proton pump) in parietal cell canaliculi that make gastric acid

Anticanalicular autoantibodies are associated with development of corpus atrophy

Which cells are present in human AIG?

H+K+-ATPase-specific CD4+ T cells are present in human AIG and secrete Th1/Th0 cytokines

What is the mechanism of target-cell destruction in AIG?

 Fas-FasL mediated apoptosis by H+K+-ATPase-specific T cells is one mechanism of target-cell destruction in AIG 

Where does AIG stands for?

Autoimmune Gastritis 

What is (are) the epitope(s) of H+,K+-ATPase-specific T cells

Smal linear peptides derived from protein antigens

Presented to T cells by APC

In peptide binding groove of MHC molecules on APC

Recognition by TCR-complex depends on both peptide and HLA molecule

What are the steps for identification of epitopes recognized by H+,K+-ATPase-specific T-cells

Steps: 
1) Isolate and identify T cell clones specific for H+,K+-ATPase
2) Syntesize linear, overlapping peptides that together comprise the intact H+,K+-ATPase
3) Make pools of peptides and measure proliferation of T cells against single pools
4) Measure proliferation against single peptides from a pool that is positive

What is the strategy in identification of putative cross-reactive epitopes in H pylori. And what is the method?

Strategy: look for homologies/similarities to sequence 43-44 in H. pylori genome 
Method: do a BLAST search for that amino acid sequence against H. pylori ORFs

What is epitope spreading?

during the development of an autoimmune disease the number of different B and T cell epitopes increases 
specificity spreads to other autoanatigen epitopes:  - within the original antigen and - outside the original

Experimentele AIG  vb. intramolecular epitope spreading reactiviteit tegen 261-274 van HK-ATPase  b-keten, breidt uit naar ander eptiopen op ook a-keten

IDDM  vb. intermolecular epitope spreading reactiviteit tegen: GAD65  HSP-60  insuline
SLE  intermolecular epitope spreadingzie figure 13-36 (Parham 3e editie)


Several autoimmune diseases are associated with specific allotypes of HLA (predominantly MHC Classe II !) Why?!

Opzoeken


The risk of getting an autoimmune disease after infection is also largely dependent on the HLA allotype. Why?! 

Opzoeken

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