Introduction to Inflammation Markers

Georgina Grimsey

Nov 21, 2019

Inflammation markers

Inflammation is the body’s generic response to pathogens,
irritants, or damaged cells, and it is considered a hallmark of the innate
immune response. Its function is to eliminate the initial causes of cell
damage, to remove necrotic cells and tissues and to initiate tissue
repair.  The classical signs of acute
inflammation are heat, pain, redness and swelling caused by the release of
molecular signalling products resulting in dilated vasculature. The increased
supply of neutrophils and macrophages assist in the process. Subdued
inflammation could lead to progressive tissue destruction caused by the harmful
stimulus. Persistent, chronic inflammation leads to a shift in cell types such
as mononuclear cells at the inflammation site, and may lead to diseases like
allergies, atherosclerosis, cancer, neurodegenerative or autoimmune diseases. Inflammation
is therefore closely regulated by the body.

As a response to inflammation, IL6 triggers the increase of
the so-called Acute Phase protein levels in the circulatory system, such as
CRP, SAA and AAT. PCT levels indicate bacterial or viral origin of
inflammation, while faecal Calprotectin is commonly used to diagnose intestinal
inflammations. NGAL is commonly known as a renal injury marker, but IL8 is a
more generic inflammation marker. Finally, Trypsonogen-2 levels are monitored
to detect acute pancreatitis and its severity.

C-Reactive Protein (CRP)

CRP is secreted in response to a variety of inflammatory
cytokines, and its main biological role is the activation of the complement
system and other proinflammatory processes. Its binding capacity to molecules
like phosphocholine, widely distributed in cellular membranes and in
polysaccharides of pathogens, makes CRP recognize a range of pathogenic targets
as well as membranes of damaged and dying host cells. Therefore, this marker is
a widely used indicator of either infection or inflammatory conditions.

Serum Amyloid A (SAA)

Like CRP, also levels of the SAA proteins increase within
hours in response to inflammatory signals as part of the acute phase
response.  Both SAA1 and SAA2 expression
is regulated by proinflammatory cytokines IL1, IL6 and TNF-alpha. The
significance of chronic inflammation in the development and progression of many
other severe diseases, such as various cancers and cardiovascular diseases,
suggests SAA might be a useful prognostic marker. The proteins are highly
conserved across species throughout vertebrates and invertebrates.

Calprotectin

Calprotectin is secreted by neutrophils at the site of
inflammation. It is a calcium binding heterodimer existing of S100A8 and S100A9
monomers with capacity to bind metals such as manganese or zinc. These
properties give Calprotectin antimicrobial activity. Calprotectin levels in plasma
are substantially increased in infectious or inflammatory conditions. Elevated
faecal calprotectin levels indicate migration of neutrophils into the
intestinal mucosa, which occurs during intestinal inflammation. Analysis of faecal
calprotectin is commonly used to diagnose intestinal inflammations, especially
inflammatory bowel disease (IBD). Information about faecal calprotectin levels
provides valuable support for treatment decisions as it can consistently
differentiate IBD from irritable bowel syndrome.

Procalcitonin (PCT)

PCT is the precursor for Calcitonin and Katacalcin, both
hormones lower calcium levels in the blood. 
The remaining propeptide, left after maturation, is the N-terminal PCT
with unknown function. The serum PCT levels are normally below detection, but
increase upon inflammatory cues from bacterial infection, while the levels
remain low when these cues are from viral or non-infectious origin. Thus, PCT
serves as a marker to decide if antibiotics are required, especially when sepsis
is suspected.

Neutrophil gelatinase-associated lipocalin (NGAL)

Neutrophil gelatinase-associated lipocalin (a.k.a.
Lipocalin-2) is a small glycoprotein involved in innate immunity by limiting
bacterial growth in epithelial tissues. Elevated levels of blood and urine NGAL
are associated with acute or chronic renal failure, and elevated serum levels
indicate active inflammatory bowel disease (IBD) and cardiovascular events.

Alpha-1 Antitrypsin (AAT)

Alpha-1 Antitrypsin is a member of the Serine Protease Inhibitors
(Serpins) and it is in relative high abundance in blood (1.5-3.5g/l). It
protects tissues from enzymes of inflammatory cells, especially neutrophil
elastase, and its levels increase manifold upon acute inflammation. In its
absence (AAT deficiency), elastase is free to break down elastin, which
contributes to the elasticity of the lungs, resulting in respiratory
complications such as emphysema, or COPD in adults and cirrhosis in adults and
children.

Interleukin 6 (IL6)

IL6 is an interleukin that acts as both a pro-inflammatory
and anti-inflammatory cytokine. T cells and macrophages secrete IL6 to
stimulate immune response to trauma, especially burns or other tissue damage
leading to inflammation. IL6 is an important mediator of increased temperature
both locally (at inflammation site) and of the entire body upon infection
(fever). IL-6 is responsible for stimulating acute phase protein synthesis
(such as CRP, SAA and AAT), as well as the production of neutrophils in the
bone marrow. It supports the growth of B cells and it is antagonistic to
regulatory T cells. Its role in a large variety of diseases, including
autoimmunity and cancer, has led to clinical applications both as a marker (for
example in advanced/metastatic cancer patients) and as a therapeutic target
(already FDA-approved anti-IL6 therapy for Rheumatoid Arthritis).

Interleukin 8 (IL8)

IL8 is an interleukin produced by macrophages and other cell
types such as epithelial cells, airway
smooth muscle cells and endothelial cells as an important mediator of the innate immune
response. It serves as a chemical signal that attracts neutrophils and
other granulocytes at the site of inflammation. Its levels increase as a
response to inflammation-associated oxidative stress and therefore IL8 serves
as generic inflammation marker.

IL-8 is also known to be a potent promoter of angiogenesis,
and it is implicated in the pathogenesis of bronchiolitis, a common respiratory
tract disease caused by viral infection. Raised IL8 levels are associated to
many pathologies and would serve as a first indicator upon which further
specific diagnostic tests would be required.

Trypsinogen-2

Trypsinogens are the precursor forms of the pancreatic
trypsins. Although there are three genes, encoding for three trypsin
precursors, their homology among each other is so high that they are indistinct
in detection by most antibodies. Trypsinogens are activated by enteropeptidase
in the intestinal mucosa to form trypsin. Once activated, the trypsin can
activate more trypsinogen in addition to its role to digest any protein and
peptide by cleaving peptide bonds on the carboxyl side of basic amino acids. High
serum trypsinogen levels are seen with acute pancreatitis, and with cystic
fibrosis.  Determination of urine trypsinogen-2 is a useful test to detect
acute pancreatitis and to evaluate disease severity. Trypsinogen-2 serum levels
are also implicated in pancreatic cancer.

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