Mechanism

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Background

 Sepsis is a complex, multifactorial and rapidly progressing disease characterized by an excessive inflammatory response to infection that can lead to organ failure and eventual death. In the United States, sepsis is the second-leading cause of death in non-coronary ICU patients and the tenth-most-common cause of death in general. To reduce the mortality rate, it is necessary to diagnose and start therapy for patients with a predicted poor outcome as early as possible.
For this purpose, the most widely used diagnosis is a combination of parameters, including clinical signs, a scoring system, and levels of CRP, IL-6 and PCT. From the viewpoint of specificity and accuracy, however, better biomarkers are still needed in clinical practice.

CD14

 CD14, a cluster-of-differentiation (CD) marker protein, is found on the surface membranes of mononuclear cells. It serves as a specific high-affinity receptor for lipopolysaccharide (LPS). It is known that membrane-bound CD14 is absent in patients with paroxysmal nocturnal hemoglobinuria (PHN), whereas soluble CD14 (sCD14) can be detected in the plasma of patients with PHN. Generally, sCD14 is detected at microgram concentrations as both a 49-kD and a 55-kD molecule. Interestingly, several diseases, including sepsis, AIDS, acute respiratory distress syndrome, and systemic lupus erythematosus, are associated with elevated sCD14 plasma levels.

Presepsin

 Presepsin (sCD14-ST) is a fragment of CD14 (13kDa polypeptide) which is found with N-terminal sequence of CD14. Presepsin lacks the ability of LPS-binding and cannot be detected by anti-CD14 antibodies. A recent study revealed that Presepsin increases in plasma with bacterial infection and levels of Presepsin show significantly high in septic patients and severe septic patients.
 Preliminary in vivo studies with two rabbit sepsis models revealed that Presepsin was not secreted via endotoxin-stimulated sepsis model but by cecal ligation and puncture (CLP) sepsis model. In addition, in vitro studies with rabbit granulocytes revealed that phagocytosis inhibitors curbed the production of Presepsin. These data suggest that the secretion mechanism of Presepsin depends on phagocytosis. Moreover, the production of Presepsin from granulocytes is prevented by asparagine protease inhibitor and treatment of sCD14 with Cathepsin D enzyme produces a 13kDa fragment of CD14, which can be detected by Presepsin ELISA [1].
Presepsin induction is very rapid. In the CLP model, Presepsin was detected within 2 hours after operation. The kinetics of Presepsin, however, is currently unclear, especially in the absence of appropriate cases to determine reactions in humans [1].

Comparison of Presepsin with CD14

Property Presepsin
(Soluble CD14 subtype)
CD14
Molecular weight Approximately 13kDa Approximately 55kDa
Form Soluble type Membrane and soluble type
Peptide structure Fragment of CD14 356 amino acids
LPS binding ability No Yes
Biological ability Unknown Endotoxin receptor
Anti-CD14 antibody binding No Yes
Anti-Prespsin antibody binding Yes No
Normal concentration
in human blood
0.048-0.171ng/mL(95%CI)*1 1200-3100ng/mL(Range)*2
Disease specificity Infection and Sepsis Sepsis and other diseases
Induction mechanism Degradation of CD14 by enzymes Protein synthesis and shedding
*1: Internal data of Mitsubishi Chemical Medience
*2: Normal EDTA plasma samples (34) were determined by human CD14 immunoassay (data from R&D Systems catalog).

 In vivo and in vitro data suggest that phagocytosis caused by bacterial infection is essential for Presepsin production. In lysosome of leukocyte, cathepsin D digests not only bacteria fragment but also CD14. Digested CD14 turns into Presepsin and is released into blood [1].

Clear Production Mechanism(Fig3)

[1]  Katsuki Naitoh et al.,
The new sepsis marker, sCD14-ST (PRESEPSIN), induction mechanism in the rabbit sepsis models.
Presentation of SEPSIS 2010