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INVITED COMMENTARY

Measuring (and Manipulating) Cellular ImmuneActivation

Daniel Y. Sze, MD, PhD

Figure. Activated T lymphocytes and NK cells responding toinfectious, malignant, or other immune stress produce IFN-g, acytokine that stimulates macrophages and dendritic (antigen-presenting) cells. Macrophages and dendritic cells produce anarray of other cytokines and by-products, including neopterin,tumor necrosis factors (TNF), interleukins (IL), and reactiveoxygen species (ROS). These products and the macrophagesthat produce them serve to disarm and control pathogens and

The immune system serves to protect us from both

infectious agents and malignancy. Normal homeostasis

requires a constant iterative process of recognition of

threats, recruitment and deployment of appropriate defend-

ers, and vigilance against reprisal attacks. Activation of the

immune system when we are under attack may manifest as

fever; leukocytosis; and elevated circulating cytokines,

antibodies, and complement. Although these manifesta-

tions are associated with discomfort, they represent a

reassuring counteroffensive.

Neopterin is a pteridine found in humans and primates,

produced from guanosine triphosphate by macrophages and

dendritic cells activated by gamma interferon (IFN)-g(1,2). IFN-g is produced mainly by activated T lympho-

cytes (CD4þ and CD8þ) and natural killer (NK) cells.

Neopterin levels reflect the level of activation of the entire

cellular immunity cascade, including macrophages, T cells,

and NK cells. In contrast to IFN-g and other cytokines,

neopterin is biochemically stable in humans and can be

measured in serum, urine, and other body fluids without

artifacts from binding, neutralization, or degradation. It is

eliminated by simple renal filtration. Although originally

believed to be a silent by-product only, neopterin may also

play a regulatory role in the metabolism of reactive oxygen

species in macrophages (3) (Figure).

Neopterin levels are elevated in a huge variety of

pathologic conditions, basically reflecting any condition

that elicits cellular immune activation. These include infec-

tions by viruses, intracellular bacteria, fungi, and parasites;

sepsis; autoimmune diseases; rejection of transplanted

allografts; neurodegenerative diseases; cardiomyopathies;

atherosclerosis; infarctions; preeclampsia; malignancies of

the lung, pancreas, ovary, cervix, uterus, breast, prostate,

colon, kidney, and liver; myeloma; lymphoma; and mela-

noma. Elevated neopterin is also associated with cachexia,

anemia, fatigue, and depression. An elevated neopterin

level is of very limited worth as a diagnostic tool because

of lack of specificity. However, increasing data suggest that

tumors. These products also serve to stimulate more macro-phages but also stimulate other cells in the cellular immunitysystem, including regulatory T lymphocytes (Treg). Treg cellsmay inhibit other parts of the immune system, including Tlymphocytes and NK cells. Overactive regulation may compro-mise the ability to fight pathogens and tumors. All of thesecytokines and signaling metabolites can be measured in serum,but most are reactive and subject to metabolism. Neopterin isrelatively inert, eliminated only by renal filtration, and a morestable gauge of overall cellular immune activation.

Volume 24 ’ Number 6 ’ June ’ 2013 873

it can be useful for prognostication and may exceed the

utility of other nonspecific tests of immune activation, such

as C-reactive protein and erythrocyte sedimentation rate.

However, measurement of neopterin is not offered in most

clinical laboratories and requires timely centrifugation and

freezing of serum and radioimmunoassay.

If immune activation represents our counteroffensive

against infectious or malignant threats, it seems that an

elevation of neopterin level should be an encouraging sign.

In their article in this issue, Yilmaz et al (4) describe the

opposite prognosis—pronounced elevation of the serum

neopterin level was associated with a poor outcome in

patients undergoing percutaneous drainage of malignant

biliary obstruction from a variety of different cell types.

This finding confirms what has been found in nearly every

other study on neopterin in malignancy or infection,

showing correlation of neopterin elevation with tumor

aggressiveness and poor patient survival. Are we to

conclude that cellular immune activation is harmful in

patients with cancer or infection? No. A moderate eleva-

tion in neopterin, similar to a moderate fever or moderate

leukocytosis, probably represents the immune system

getting the job done. An extreme elevation of neopterin,

such as a fever of 431C with a heart rate of 150 beats/min,

represents the desperate last paroxysms of an overwhelmed

and defeated immune system.

If extreme elevation of neopterin level is a death knell,

how can it be useful in clinical practice? Frequently, there

are other signs of impending demise that may be quicker

and cheaper to measure and to interpret. What remains

under investigation is whether the cellular immune system

gone awry can be effectively modulated to improve its

function and whether this function can be monitored using

neopterin as a metabolomic gauge. Immunomodulation,

specifically immunosuppression in circumstances of infec-

tious, inflammatory, or malignant stress, is not an alien

concept; for instance, corticosteroids have been shown to

improve the outcome in severe sepsis, when intuitively,

immunosuppression could worsen the infection and the

outcome (5). Yilmaz et al (4) have described a model in

which immunomodulation may potentially be attempted in

an identified patient population carrying an extremely

grave prognosis.

REFERENCES

1. Sucher R, Schroecksnadel K, Weiss G, Margreiter R, Fuchs D,

Brandacher G. Neopterin, a prognostic marker in human malignancies.

Cancer Lett 2010; 287:13–22.

2. neopterin_e.pdf. Available at: http://www.neopterin.net. Accessed March

4, 2013.

3. Murr C, Widner B, Wirleitner B, Fuchs D. Neopterin as a marker for

immune system activation. Curr Drug Metab 2002; 3:175–187.

4. Yilmaz B, Parildar Z, Bozkaya H, et al. Prognostic utility of serum

neopterin in obstructive jaundice secondary to malignant lesions treated

by percutaneous transhepatic biliary drainage. J Vasc Interv Radiol 2013;

24:865–871.

5. Skrupky LP, Kerby PW, Hotchkiss RS. Advances in the management of

sepsis and the understanding of key immunologic defects. Anesthesiol-

ogy 2011; 115:1349–1362.