Bio-Markers

Question 1

What is a Bio-Marker?

Answer 1

A characterisation that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological response to a therapeutic

Question 2

Name 4 Examples of Genetic Bio-Markers

Answer 2

DNA (ie SingleNucleotidePolymorphisms) , Epigentic modifications to DNA such as methylation, mRNA, miRNA

Question 3

Name 5 Examples of Protein Biomarkers

Answer 3

(Auto)Antibodies, cytokines, chemokines, signalling molecules, other (ie C-reactive Protein)

Question 4

Name 2 Examples of Cellular BioMarkers

Answer 4

Infiltrate (ie immune cells) and Cell phenotypes (eg CD40)

Question 5

Name 3 examples of other biomarkers

Answer 5

Lipids, carbs, metabolites

Question 6

What are descriptive BioMarkers?

Answer 6

Reflect state of disease but are not directly involved in disease pathogenesis (eg markers of inflammation such as ESR and C-reactive protein). Usually not disease specific and have low diagnostic/prognostic value

Question 7

What are Mechanistic Biomarkers?

Answer 7

These are generated from the biological mechanism of a disease and reflect dysregulation of molecular pathways directly involved in disease pathogenisis (eg presence of (Auto)Antibodies. They have high treatment predictive value

Question 8

What are diagnostic BioMarkers?

Answer 8

These are used to monitor disease activity and help guid therapeutic interventions

Question 9

What are treatment predictive biomarkers?

Answer 9

Used to predict a persons responce to a specific treatment, Ie matching the correct drug with specific individuals

Question 10

What Is RA?

Answer 10

Rheumatoid Arthritis is a chronic inflammatory disease mediated by T-cells due to a breakdown in tolerance and T-cell responce to self autoantigen. Also involves B-cells recognising autoantibodies

Question 11

What are some genetic risk factors for RA?

Answer 11

Susceptibility Genes: Eg HLA-DRB1
Epigenetic Modifications (40% of risk)
Smoking, Sex, Microbiota, Ethnic factors, western diet

Question 12

Why are Biomarkers needed for RA?

Answer 12

1) RA is a complex Heterogenous disease which vaires between patients. Many factors increase susceptibility to RA, how the disease presents and patients response to treatments. Presence of immune cells important for Pathogenesis, for some people its T-cells others its B-cells
2) Early diagnostic improves outcomes. Effective treatments require rapid and accurate diagnostic and the window of opportunity maybe short (up to 12 weeks). Faster diagnostic allows modulation of disease course and decrease in joint damage.

Question 13

What are some of the current Bio-markers used for RA diagnosis?

Answer 13

Inflammatory markers such as C-Reactive-Protein and ESR (these not specific to RA)
Autoantibody rheumatoid factorn RF (not specific to RA)
Autoantibody anti- citrullinated peptide antibodies (ACPA) - specific to RA
Aprox 40% of RA patients are ACPA negative and hard to diagnose

Question 14

What are some diagnostic biomarkers in CD4 T-Cells?

Answer 14

You can take monocyte derived CD4 T-cells from patients, purify them, extract the RNA and look at gene expression.
IL-6 Important for RA

Question 15

How many genes signal development for RA?

What are some genes you can focus on?

Answer 15

12

STAT3 inducible genes such as BCL3, SOCS3 PIM1

Question 16

Why do we need to understand the biological mechanisms for individual biomarkers?

Answer 16

Eg- IL-6 can bind to IL-6R but can ALSO bind to soluble Csl IL-6 reseptors (SIL-6R) which can bind to gp130 and cause Jak phosphorylation which causes STAT Phosphorylation which can lead to STAT Translocation to the nucleus and cause transcription of of genes such as BCC3, SOCS3 and PMI1. These genes can effect T-cell function ie proliferation , activation and cytokine profile.
We know IL-6 dysregulates CD4 T-Cells function but it is not useful for ACPA-Negative RA patients.