Lecture 15 - Organ-specific autoimmunity Flashcards
What is T1D pathogenesis from the thymus to beta cell destruction?
Thymus
>Developing T cells undergo selection
>positive selection to progress further and enter the periphery, or negative selection because they react to self-antigens and should be deleted (central tolerance)
>Those at risk of developing T1D have T cells that are self-reactive to beta cell antigens (failure of negative selection)
> organ specific autoimmune disease
represents a failure of self from non-self discrimination (basically a fundamental task of the immune system)
> Pancreatic lymph node
In the periphery, these naive t cells become activated, presumably in the draining lymph node or in the pancreatic islets themselves
due to the high conc of beta cell antigens present in both these places presented by the APCs that picked them up in the beta cells and moved back to the draining lymph nodes
activate the naive t cells that have escaped the thymus and these self-reactive t cells go on to infiltrate the islets and mediate the destruction of beta cells, resulting in dysregulation of glucose homeostasis
What is the role of the human leukocyte antigen (HLA) locus on chromosome 6?
HLA Class II molecule:
>(alpha chain + beta chain)
>present peptides to CD4+ T cells
HLA Class I molecule:
>(alpha chain + beta-2-microglobulin chain (chr15))
>present peptides to CD8+ T cells
- Alleles for genes encoding MHC molecules confer the highest risk of T1D
What are the functions of T cells in T1D?
CD8+ T cells recognise peptides presented by HLA Class I molecules
>cytotoxic function
>directly kill the cells presenting that peptide on the HLA class I molecule
CD4+ T cells recognise peptides presented by HLA class II molecules
>usually from a professional APC
>will activate the APC to go on to do other functions e.g might be a B cell which goes on to produce (in the case of T1D) autoantibodies
>helper function
What is the DQ locus?
DQ locus consists of 2 genes
>gene that encodes the beta chain
>gene that encodes the alpha chain
>DQ2 and DQ8 is shorthand nomenclature to tell you what those alleles are for those 2 genes
What is the odds ratio for the HLA/MHC class II molecules?
HLA class II alleles confer the highest risk for type 1 diabetes
HLA/MHC class II Odds Ratio
DQ2; DQ8 >16.6
DQ8; other >11.4
DQ2; other >3.6
DQ2; DQ8 heterozygosity confers the highest risk of T1D
How do high risk alleles present beta-cell antigen-derived peptides to T cells?
- HLA class II molecules shape the T-cell repertoire during T cell development
- HLA class II molecules also activate the CD4+ T cells in the periphery
Why is the HLA class II locus associated so strongly with T1D (and other autoimmune diseases)?
- Beta cell antigens may not be presented efficiently in the thymus by particular HLA molecules
- This enables the escape of low affinity T cells from the thymus and subsequent activation by beta cell antigens that are present at high concentration in the pancreas and draining lymph nodes
How are genetic polymorphisms for insulin associated with thymic expression and T1D risk?
Key concept = Dysregulation of negative selection generates a peripheral pool of anti-self T cells displaying increased avidity/affinity and likely an enhanced pathogenic potential
A lot of self antigens are expressed in the thymus and presented by various cells in the medullary, so when the T cells interact with them, it sends out a signal to them to be deleted before they can get out into the periphery
Insulin (INS) = a key autoantigen for human T1D
> VNTR upstream element of INS (variable number of tandem repeats)
»>Class I (26-63 repeats) = predisposing allele
»>Class III (140-210 repeats) = protective allele
o Genetic polymorphisms that affect thymic insulin expression are associated with T1D
Decreased thymic expression = increased T1D risk
Increased thymic expression = decreased T1D risk
What is the effect of reduced thymic insulin expression?
Reduce negative selection of insulin-specific single positive thymocytes (precursor to the developed T cell that leaves and enters periphery)
Limit thymic development of beta cell-specific regulatory T cells (FOXP3+ CD4+ T cells)
What is PTPN22?
PTPN22 is a negative regulator of T cell receptor (TCR) signalling
Is expressed in developing thymosites that become t cells in the thymus)
>genetic variant (R620W, 1858C>T mutation associated with increased phosphatase activity and increased T1D risk
What is elevated phosphatase activity (PTPN22) predicted to do?
Reduce TCR signalling and diminish apoptosis induction in beta cell-specific thymocytes
>autoreactive T cells escape to the periphery
> similar to insulin, limits thymic development of beta cell-specific regulatory T cells (FOXP3+ CD4+ T cells)
o Alter BCR signalling that results in defective B cell tolerance and allows autoreactive B cells to escape into the periphery
What is the association between PTPN22 and INS in terms of defective negative selection and T1D risk?
During negative selection
>strong signal to developing thymocytes
>cause them to undergo apoptosis and die
> when you have PTPN22 allele, get increased phosphatase activity
reduce TCR signalling
reduces apoptosis induction in thymocytes that recognise B cell antigen and escape into periphery
> When you have reduced insulin expression in thymus
thymocytes who have low affintty for insulin can escape
once they get to pancreas lymph nodes, high amount of insulin makes up for that low affinity
cause immune response
What are the beta-cell antigen-specific autoantibodies?
Autoreactive B and T cells in the periphery that have escaped negative selection
Islet cell auto-antibodies (ICAs)
What are some islet self-antigens and what is their significance?
Present in serum of people with T1D
Insulin: hormone produced by pancreatic beta cells
GAD65: glutamic acid decarboxylase; expression not exclusive to pancreatic beta cells
IA-2: tyrosine phosphatase-like protein islet antigen 2; not exclusive to pancreatic beta cells
ZnT8: zinc transporter 8; zinc plays a role in storage and secretion of insulin; highly expressed in the endocrine, but absent in exocrine pancreas, also detected in extra-pancreatic sites
These are antigens expressed by the beta cells
What are the beta cell antigens?
Insulin granule
>insulin
>IA-2 (islet antigen 2)
>ZnT8 (zinc transporter 8)
Not in insulin granule
>GAD65 (glutamate decarboxylase)