CRP - science and pathophysiology

Introduction

C Reactive Protein is a key actor in the clearance of bacteria and dying cells and is an acute phase reactant with levels rising within 12 hours of most acute inflammatory states.
It is a member of the small pentraxins family which are are an evolutionary conserved family of proteins characterised by containing a pentraxin protein domain. This family includes pentraxin 3 (pentraxin 3 (PTX3)) from leukocytes, serum amyloid P component (SAP) and neural pentraxin I (NPTXI) and II (NPTXII).
- both SAP and CRP are evolutionary conserved in all vertebrates and also found in distant invertebrates such as the horseshoe crab
- see https://en.wikipedia.org/wiki/Pentraxins
initially identified and named based upon the finding of a substance in serum in patients with acute inflammation that reacted with the cell wall polysaccharide (C-polysaccharide) of pneumococcus.
CRP gene is located on chromosome 1 (1q23.2)
CRP protein is composed of 5 monomers, each monomer has 224 amino acids and assembles into stable pentameric structure with a discoid shape.
serum CRP levels are indicative of CRP production levels given elimination is a constant

CRP is produced from hepatocytes upon interleukin 6 (interleukin-6 (IL-6)) stimulation.
- IL-6 is produced from macrophages and adipocytes
CRP production may be less than expected in systemic lupus erythematosus (SLE) and viral infections due to:
- activation of IFN-α
- IFN-α dependent downregulation of CRP
  - Type I IFNs (eg. IFN-α ) are strong activators of the anti-viral immune response, and may also contribute to autoantibody production in several autoimmune conditions
  - IFN-α inhibits IL-6/IL-1β-induced CRP gene transcription and protein production from hepatocytes¹⁾
- over-expression of the CRP-lowering polymorphism rs1205 (this is more common in systemic lupus erythematosus (SLE) patients)
CRP production is dependent upon the interplay of:
- IL-6 levels (most inflammatory states, esp. bacterial infections)
- inhibitory effects of Type I IFNs activity (eg. IFN-α in viral infections, SLE as above)
- gene polymorphisms:
  - interleukin-1 family
  - interleukin 6,
  - polymorphic GT repeat of the CRP gene
  - CRP-lowering polymorphism rs1205
- hepatic function
  - CRP production may be greatly reduced in liver failure
CRP production is also reduced by:
- interleukin-6 (IL-6) inhibitors
- colchicine
- interleukin-1b (IL-1b) inhibitors (via reduced IL-6)

Its pentameric structure encompasses an effector face with affinity for C1q and Fcγ-receptors and a recognition face with the ability to bind phosphocholine on e.g., dying cells and pathogens, but also nuclear constituents exposed during apoptosis (i.e., snRNP and histones)
it can also bind phosphoethanolamine, a constituent of the cell membrane of Salmonella enterica
these enable CRP to contribute to efficient clearance of cell remnants and immune complexes by complement activation/modulation, opsonization, and phagocytosis

plasma half-life of CRP is 19 hours, and this is constant in all medical conditions
hence serum CRP levels are indicative of changes in production levels

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