Three essential biomarkers for measuring immune activation

The immune response is a coordinated process involving diverse chemicals and signaling pathways. When these pathways are activated, sick cells and pathogens are successfully eradicated in individuals with healthy immune systems. In some cases, the immune system can become overactive, leading to autoimmune disease. 

Image Credit: peterschreiber.media/Shutterstock.com 

Three critical molecules have been shown to play an important role in immune response control and modulation: High Mobility Group Box 1 (HMGB-1), neopterin (Np), and the soluble Interleukin-2 receptor (IL-2R).^1-15

There are similarities and distinctions among the immune system's three musketeers. They share functions across a wide range of immune-related disorders, and researchers must consider how they should be measured and when.

All three are valuable indicators for immunological activation, and their roles are outlined in this article (Figure 1).

Inflammatory mediators

HMGB-1 is a potent inflammatory mediator produced by activated immune cells and functions as a late mediator of inflammation.¹ Neopterin, a consequence of the GTP-metabolic pathway, is produced by activated macrophages/monocytes and serves as a marker of cellular immunological activation. sIL-2R, likewise released during immune activation, is a marker of T-cell activation and inflammation.^2,3

Biomarkers of disease activity

Elevated levels of HMGB-1, sIL-2R, and neopterin are found in a variety of inflammatory and autoimmune illnesses, making them possible biomarkers for disease activity and severity.^4-6

Prognostic indicators

High quantities of all three molecules have been linked to poor outcomes and disease progression in conditions like cancer, sepsis, and autoimmune diseases.^7-9

Immune regulation

HMGB-1 can act as a chemoattractant, activating and mobilizing immune cells.¹⁰ Neopterin has been demonstrated to modulate oxidative stress and apoptosis as part of its immune regulatory role.¹¹ Finally, sIL-2R regulates T-cell proliferation and activation, which helps maintain immunological homeostasis.¹²

Therapeutic targets

Strategies targeting HMGB-1, neopterin, and sIL-2R are being investigated as possible treatments for a variety of inflammatory and autoimmune disorders, including cancer, rheumatoid arthritis, and multiple sclerosis.^13-15

Researchers must determine whether they need to continuously measure all three markers or whether one would suffice. This depends on the specific disease state being researched. As a rule of thumb, the three molecules are all confirmed markers of immunological activation, so the researcher or clinician could begin by comparing the disease being studied, diagnosed, or treated with previous research in the field.

The second aspect to consider is that, if tests are performed in the clinic rather than in the research environment, the 'tiebreaker' is that the clinician must use an IVD-compliant test rather than a RUO (research use only) test.

To aid the selection of biomarker(s) to monitor illness status, this article will briefly outline the research on each type before consolidating how they may be quantified.

Figure 1. High Mobility Group Box 1 (HMGB-1), neopterin (Np), and soluble Interleukin-2 receptor (sIL-2R): three key molecules that play an essential role in the regulation and modulation of the immune response. Image Credit: IBL International GmbH, Part of Tecan Group

HMGB-1

Human HMGB-1 is required for cell stress response and plays a significant role in many infectious diseases, as well as ischemia, immunological disorders, neurological diseases, and cancers.¹⁶ It has received much attention in recent years for its potential as a biomarker for assessing inflammation and immune system dysfunction. The Tecan Blog series provides a more detailed explanation of HMGB-1’s mechanism of action in relation to COVID-19 infection.

HMGB-1 is a non-histone nuclear protein that can be released when cells are stressed, injured, or inflamed.¹⁷ Once released into the extracellular environment, it functions as a ‘danger-associated molecular pattern’ (DAMP) and can elicit inflammatory responses by attaching to pattern recognition receptors (PRRs) on immune cells.¹⁸

Elevated HMGB-1 levels have been found in individuals with rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, and inflammatory bowel disease (IBD), all of which are autoimmune diseases.¹⁹

In rheumatoid arthritis cases, HMGB-1 levels in synovial fluid and serum are associated with disease activity and severity, making it a possible biomarker for disease progression and therapy response.²⁰

HMGB-1 levels are elevated in both blood and urine in cases of SLE. These levels are associated with disease activity, organ damage, and the presence of specific autoantibodies.²¹ HMGB-1 has also been investigated as a biomarker for sepsis, a potentially fatal illness characterized by a massive immunological response to infection.²²

Elevated HMGB-1 levels have also been linked to the development and progression of several malignancies, including breast, lung, and colorectal cancer, possibly due to its involvement in promoting inflammation and tumor growth.²³

There are some significant benefits of using HMGB-1 as a biomarker, including its stability in bodily fluids and its direct involvement in the inflammatory and immunological responses that underpin multiple diseases.

It has been difficult to develop standardized methods for assessing HMGB-1 levels and to demonstrate its clinical value as a diagnostic and prognostic biomarker across a variety of disorders. However, ELISA tests are now available that allow us to standardize HMGB-1 assays and, hence, compare data across labs worldwide.

Figure 2. HMGB-1 plays a key role in the body's response to injury and infection. Image Credit: IBL International GmbH, Part of Tecan Group

Neopterin

Neopterin (Np) is produced by macrophages and dendritic cells in response to IFN-γ, a cytokine released by activated T-cells and natural killer cells during immunological reactions.^24-25

Np, also known as 2-amino-4-hydroxy-6-(D-erythro-1',2',3'-trihydroxypropyl)-pteridine, is classified as a pteridine.²⁶ This Np was first identified in 1963 from bee larvae, worker bees, and royal jelly.^{27 - 29} Researchers Sakurai and Goto first isolated Np in human urine in 1967.³⁰

It has since been intensively studied across a wide range of inflammatory disorders, including viral, bacterial, and parasitic infections, cardiovascular diseases, autoimmune diseases, and malignant tumors.^31-37 

Neopterin levels in bodily fluids, such as serum, urine, and cerebrospinal fluid (CSF), rise in response to various inflammatory and immune-mediated diseases.³⁸ Viral diseases such as HIV, hepatitis B and C, and CMV exhibit high Np levels, indicating that the cellular immune response to these viruses has been activated.²⁶

Neopterin levels correlate with disease activity and severity in autoimmune illnesses such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and multiple sclerosis, suggesting it could serve as a biomarker to track disease progression and therapeutic responses.³⁹

Neopterin levels are also elevated when some cancers develop, including leukemia, lymphoma, and solid tumors, probably due to immune cell activation by tumor antigens.⁴⁰

Elevated neopterin levels in allograft recipients can suggest acute rejection episodes or post-transplant infections, which help to monitor transplant outcomes.⁴¹

Neopterin has also been investigated as a biomarker for cardiovascular diseases, as it is linked to an increased risk of adverse outcomes and may reflect the underlying inflammatory processes that contribute to atherosclerosis.⁴²

The advantages of employing neopterin as a biomarker, like those of HMGB-1, include its stability in biological fluids, its direct relationship to cellular immunological activity, and the availability of well-established analytical methods for measuring it.

Again, ELISA is a simple and reliable method for assessing neopterin because it is sensitive, robust, and accurate, even in complex matrices such as serum, plasma, and urine.

Figure 3. Neopterin is an early marker for immune activation. Image Credit: IBL International GmbH, Part of Tecan Group

sIL-2 receptor

Similar to HMGB-1 and neopterin, Interleukin-2 (IL-2) is a major signaling molecule in the human immune system. IL-2 is a cytokine, a tiny, secreted protein produced by cells that has a unique effect on cell connections and communication. This assists in regulating the body's natural response to infection, allowing it to distinguish between foreign (‘non-self’) and ‘self’.⁴³

IL-2 binds to lymphocyte-expressed IL-2 receptors to exert its effects. The primary sources of IL-2 are activated CD4+ and CD8+ T cells.⁴³

When T-cells are activated, the soluble form of the interleukin-2 receptor (sIL-2R) is secreted, or ‘shed’, resulting in a greater-than-background concentration of sIL-2R in patients suffering from numerous illnesses associated with an ongoing immunological response (Figure 4).⁴³

Clinicians use quantification of soluble interleukin-2 receptor (sIL-2R) in serum or plasma in adults to assess immunological function in vivo and to explore and treat a variety of disorders.

Elevated sIL-2R levels are found in autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus (SLE), and multiple sclerosis, and they correlate with disease activity and severity.^44-45

In SLE, greater sIL-2R levels are associated with organ involvement and the presence of particular autoantibodies.⁴⁶ In rheumatoid arthritis, sIL-2R levels in serum and synovial fluid are linked to joint inflammation and erosion, making it a valuable biomarker for tracking disease progression and therapy response.⁴⁷

sIL-2R has also been identified as a biomarker for transplant rejection, as its levels increase during acute rejection episodes in organ transplants such as the kidney, liver, and heart.⁴⁸ sIL-2R levels are directly correlated to some hematological malignancies, such as hairy cell leukemia and adult T-cell leukemia/lymphoma, indicating malignant T-cell proliferation.⁴⁹

Sarcoidosis, biliary cirrhosis, chronic immune activation in common variable immunodeficiency (CVID), and hemophagocytic lymphohistiocytosis (HLH) are among the other immune-mediated disorders linked to elevated sIL-2R.^{50 - 54}

In infectious disorders, sIL-2R levels may rise due to T-cell activation in response to infections including HIV, CMV, and tuberculosis.⁵⁵

The stability of sIL-2R in bodily fluids, as well as its direct relationship with T-cell activation, a key mechanism in many immune-mediated diseases, makes it an attractive biomarker candidate.

The relative stability of sIL-2R levels throughout adulthood and its showing only small differences by gender contribute to sIL-2R's appeal as a biomarker.^{56 -57} However, sIL-2R levels can be altered by a number of factors, including age, renal function, and concurrent drugs, which should be taken into account during interpretation.⁵⁸

Soluble IL-2 receptor levels are often measured by enzyme-linked immunosorbent assay (ELISA) or chemiluminescent immunoassay (CLIA). Commercially accessible assays should be calibrated to the international reference standard, NIBSC 97/600.

Table 1. Soluble IL-2R is a reliable marker of an ongoing immune response. Credit: IBL International GmbH, Part of Tecan Group

sIL-2R:

• Associated with infection, autoimmune diseases, and inflammatory conditions
• Helps distinguish self from non-self
• Marker of T-cell activation

Use: measurable surrogate for T-cell activation in vivo as part of disease prognosis and management.

Measuring the ‘three musketeers’ of the immune activation pathway

All three immunological markers, HMGB-1, neopterin, and sIL-2R, have been established as indicators of ongoing immune response and, theoretically, as able to monitor a wide range of immune-mediated diseases; in essence, they can all be considered universal or generic markers of immune activation.

The researcher or clinician must next make an informed decision on which marker(s) would be most appropriate for the disease being investigated, diagnosed, or treated, based on the empirical evidence available in the literature and commercially accessible tests.

All three markers can be accurately assessed using immunoassays, most notably ELISA. The Tecan Blog articles describe the intimate relationship between ELISA tests and other accessible techniques, such as HPLC, RIA, and mass spectrometry.

ELISA is by far the simplest technique to apply. The following will outline an examination of current tests and determine how these ELISA tests may be scaled and automated to provide the most reproducible findings, therefore facilitating worldwide standardization.

Choosing and implementing ELISAs for immunology biomarkers

ELISA assays are widely available for the three outlined immune activation biomarkers (HMGB-1, neopterin, and sIL-2R).

Most of them are for research use only (RUO). This means that - even if their efficacy as a marker for a specific disease has been demonstrated through study and basic empirical evidence - their long-term usage in the clinical field cannot be guaranteed, necessitating the adoption of IVD-compliant tests.

Furthermore, most tests are intended for manual performance, but they should be easily automated and scalable to achieve optimal repeatability and inter-lab comparisons. These are only a few of the main criteria for using ELISA to assess immunological activation: a more detailed checklist may include:

• Ready-to-use assay reagents: dilution is not necessary
• Ready-to-use standard-curve reagents: no stock dilution is required
• Kit ready-calibrated against standard preparations and other methods
• Internal kit controls provided
• Easily automatable

Tecan ELISA kits can be run manually for initial testing and validation when used for IVD-compliant clinical use, or automated based on your lab’s specific standardization and throughput requirements.

Automation scripts are widely available and are ‘open system’, meaning they can be easily converted to your automation platform, and Tecan can also work directly with you to integrate them.

Many white papers and articles are offered for further study, depending on whether you want to learn more about the science behind these tests or use ELISA in your lab, with or without automation. Visit your country's website to learn more about buying ELISA testing and ongoing discounts.

Tecan's open approach to IVDR and automation is leading the way toward international standardization and the automation of ELISA, the main method for measuring immunology markers in clinical environments, opening new avenues for future research as the company continues to capitalize on the method’s enormous potential in diagnosing, treating, and monitoring disease.

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