Soluble IL-2R as a Marker of T Cell Activation in Immune-Mediated Diseases: Review and Case-Based Interpretation

Abstract

The soluble interleukin-2 receptor (sIL-2R) is a novel biomarker associated with a variety of immune-mediated diseases. It is produced through the proteolytic cleavage of the membrane-bound interleukin-2 receptor α-chain on activated T lymphocytes; hence, its increase reflects T-cell activation and immune dysregulation. Elevated sIL-2R levels are frequently documented in conditions such as rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, relapsing polychondritis, histiocytosis, hemophagocytic lymphohistiocytosis, lymphomas, and graft-versus-host disease, suggesting a potential role in monitoring disease activity and progression. However, sIL-2R levels may increase in the context of immune response to infections and malignancies, requiring careful interpretation. It is essential to determine whether elevated levels of this marker within specific ranges could suggest a specific entity, due to the implications this may have for the management of patients. This case-based review presents five patients with different immune-mediated diseases, highlighting how these different conditions can present with characteristic ranges of sIL-2R elevation. By integrating clinical findings with sIL-2R measurements, we emphasize the biomarker’s utility in guiding diagnosis, as well as monitoring disease activity and determining prognosis, which can enhance clinical decision-making and patient management in rheumatology and related fields.

1. Introduction

The soluble sIL-2R, also known as soluble CD25 (sCD25), is the α-chain of the high-affinity interleukin-2 (IL-2) receptor complex. It is primarily produced through the proteolytic cleavage of the membrane-bound IL-2 receptor α-chain on activated T lymphocytes, a process mediated by specific proteases such as ADAM family metalloproteinases. Additionally, alternative splicing of IL-2 receptor mRNA generates isoforms that lack the transmembrane domain, enabling their direct secretion into circulation [1,2]. Its precise mechanisms of action remain only partially elucidated. Studies propose both agonistic and antagonistic roles in influencing lymphocyte proliferation and activation, some suggesting that it may promote autoimmune processes by enhancing Th17 generation through sequestration of IL-2 that normally inhibits early Th17 differentiation. Alternatively, sIL-2R complexed with IL-2 may extend the half-life of IL-2, enhancing its immune-stimulatory properties, even by activating low-affinity dimeric IL-2 receptors. It has also been proposed that sIL-2R can present IL-2 to CD4(+) T lymphocytes, inducing differentiation into regulatory T cells (TRegs) rather than into T-helper 1 (Th1) or Th17 lymphocytes, subsequently suppressing immune activity [1].

Measurement of soluble s-IL2R levels has significant clinical applications as a valuable biomarker for assessing immune activation, disease activity and disease progression across a spectrum of immune-mediated conditions, including hematological malignancies and autoimmune disorders [1,2,3,4,5,6]. However, the interpretation of sIL-2R levels is hindered by their nonspecific nature, raising important considerations regarding its utility in discriminating overlapping clinical presentations. For example, studies have noted that elevated sIL-2R levels may occur in lymphoma and severe infections, where T-cell activation is prominent but unrelated to autoimmune pathology [1,3,7].

Understanding the relationship between specific ranges of sIL-2R and diseases is essential for developing diagnostic and prognostic strategies in clinical practice. Research suggests that the magnitude of sIL-2R elevation can be correlated with particular entities, aiding in differential diagnosis and guiding clinical decision-making [4,8]. For instance, mild to moderate elevations (700–1500 U/mL) may be seen in autoimmune conditions such as rheumatoid arthritis. In sarcoidosis, moderate to high elevations of s-IL2R (1500–3000 U/mL) correlate with disease activity and pulmonary involvement, helping in diagnosis and evaluating response to treatment [5,9]. In lymphomas, especially T-cell lymphomas, markedly elevated sIL-2R levels (>3000 U/mL) reflect a high tumor burden and can be used as a means to assess disease progression and response to treatment [10]. Histiocytosis and hemophagocytic syndromes often present with extremely high sIL-2R levels, sometimes exceeding 10,000 U/mL, serving as a diagnostic marker and indicating severe immune activation [1,3,6]. In graft-versus-host disease (GVHD), increased s-IL2R levels indicate immune activation following transplantation and can aid in the early detection and management of GVHD [8].

Consequently, studies are focused on understanding the mechanism of sIL-2R activity and validating its diagnostic potential in a broader spectrum of diseases. This case-based review aims to illustrate how the range of sIL-2R elevation can aid in accurately identifying diseases as well as in monitoring them. By combining clinical findings with sIL-2R measurements, the goal is to improve clinical decision-making and enhance patient outcomes within rheumatology and related fields.

2. Clinical Cases

Refer to

Table 1. Summary of laboratory findings in patients included in the case reports. Levels of sIL-2R were assessed by solid phase chemiluminescent immunoassay on the SIEMENS Immulite (R) 2000 XPi platform. The analytical inter-assay coefficient of variation for this technique was 3.9% for concentrations of 207 U/mL and 21% for concentrations of 957 U/mL, with a measurement range of 50–7500 U/mL and a reference range of 158–623 U/mL.

Case	Age (Years)	Diagnosis	CRP (mg/dL)	ESR (mm/h)	Ferritin (ng/mL)	sIL-2R Level (U/mL)	IL-6 (pg/mL)
Normal Value			<0.5	<20	12–150	158–623	≤7
1	31	Still’s Disease	6.27	34	1140	1024	23.6
2	65	Castleman’s Disease	7.25	22	4830	2820	14.9
3	67	Axial Spondyloarthritis	0.4	45	153	364	3.2
4	29	Inflammatory Bowel Disease	15.48	58	7063	656	35.7
5	61	Diffuse Large B-Cell Lymphoma	9.11	53	380	5062	-

for detailed information on laboratory findings.

2.1. Case 1

A 31-year-old woman presented with a history of persistent fever, abdominal pain, diarrhea, muscle weakness, and skin lesions resembling flagellate erythema. Physical examination revealed erythematous linear lesions on the skin. Laboratory tests showed elevated inflammatory markers with a C-reactive protein (CRP) level of 6.27 mg/dL and an erythrocyte sedimentation rate (ESR) of 34 mm/h. Liver function tests demonstrated a hepatocellular pattern with seven-fold elevation in ALT and AST levels, without hyperbilirubinemia. Ferritin levels were markedly elevated at over 1100 ng/mL. Her serum soluble interleukin-2 receptor (sIL-2R) level was moderately elevated at 1024 U/mL and her interleukin-6 (IL-6) was elevated at 23.6 pg/mL (normal < 7 pg/mL). A positron emission tomography (PET) scan revealed nonspecific lymphadenopathies in the neck and groin regions. Based on the clinical presentation and laboratory findings, she was diagnosed with adult-onset Still’s disease (AOSD).

Still’s disease, also known as adult-onset Still’s disease (AOSD), is a systemic inflammatory disorder characterized by excessive activation of immune cells, particularly T lymphocytes and macrophages [11,12]. The activation of CD4(+) T helper cells leads to increased expression of the IL-2 receptor α-chain (CD25) on their surface, and proteolytic cleavage of this receptor results in elevated levels of sIL-2R in the serum [1]. The moderate elevation of sIL-2R reflects the heightened T-cell activation and cytokine production (e.g., IL-1β, IL-6, IL-18) associated with the disease’s inflammatory processes [11,12], evidenced in this case by elevated IL-6.

2.2. Case 2

A 65-year-old woman presented with asthenia and inflammation of the right hand, characterized by swelling, morning stiffness of the metacarpophalangeal (MCP) joints, and neuritic pain in the extremities, predominantly affecting the upper limbs. Her symptoms worsened, leading to hospitalization due to general deterioration and vomiting associated with episodes of headache. Physical examination revealed an erythematous lesion on the left thigh and jaundice. Laboratory tests showed lymphocytosis, anemia, and mild neutropenia with normal platelet count. Liver function tests were abnormal, displaying a mixed pattern without hyperbilirubinemia. Ferritin levels were markedly elevated at ≥3000 ng/mL (normal 12–300 ng/mL). The PET scan revealed mild hepatosplenomegaly with increased diffuse uptake of the spleen, small hypermetabolic lymph nodes both above and below the diaphragm, and mild diffuse uptake of the bone marrow. Her sIL-2R level was 2820 U/mL, indicating significant elevation, while her IL-6 was elevated at 14.9 pg/mL (normal < 7 pg/mL). Based on the clinical presentation and investigative findings, she was later diagnosed with Castleman’s disease of the multicentric type.

Castleman’s disease is a lymphoproliferative disorder characterized by non-clonal proliferation of lymphoid cells and excessive cytokine production [13,14]. The patient’s elevated CRP and ESR are indicative of systemic inflammation. Hyperferritinemia reflects macrophage activation and chronic inflammation [15]. Exaggerated activation of the immune system occurs, with increased production of cytokines such as IL-6 leading to systemic symptoms and further immune cell activation [16]. Activated CD4(+) T cells express high levels of CD25, and shedding of CD25 results in elevated sIL-2R levels [1]. Therefore, sIL-2R levels reflect intense immune activation and correlate with disease activity [16].

2.3. Case 3

A 67-year-old man presented with persistent fatigue, abdominal pain, low-grade fever (~37.5 °C in the afternoons), and musculoskeletal symptoms including back stiffness and arthralgias in the knees and ankles. Physical examination revealed decreased spinal mobility (Schober test: 2 cm), reduced cervical range of motion, bilateral dactylitis of the second and third fingers and enthesitis at multiple sites. Laboratory tests showed an elevated ESR of 45 mm/h, slightly elevated CRP at 0.4 mg/dL, and ferritin at 153 ng/mL. His sIL-2R level was 364 U/mL, within normal limits. IL-6 was 3.2 pg/mL. Imaging studies, including PET, revealed arthritis in the sternoclavicular and bilateral acromioclavicular joints, as well as sacroiliitis. Based on the clinical presentation and findings, he was diagnosed with axial spondyloarthritis. Disease activity scores (ASDAS) were consistently high, reflecting severe disease activity.

Axial spondyloarthritis involves inflammation of the spine and sacroiliac joints. The disease is associated with activation of the innate immune system and involvement of Th17 cells producing interleukin-17 (IL-17) [17]. While there is some T-cell activation, it may not be as pronounced as in other systemic inflammatory conditions [17]. The normal sIL-2R level suggests minimal systemic CD4(+) T-cell activation and a predominantly localized inflammatory process.

2.4. Case 4

A 29-year-old man was hospitalized due to general deterioration, persistent fever, abdominal pain, and diarrhea. He also reported mild discomfort in his right knee. His medical history included surgery in 2020 for an inguinal fistula and perianal abscess. He had a long-standing history of hidradenitis suppurativa, characterized by severe, somewhat monomorphic acne outbreaks, partially responsive to isotretinoin and antibiotics. On physical examination, there was mild joint effusion in the right knee with slight local warmth. Laboratory tests revealed elevated inflammatory markers: CRP at 15.48 mg/dL and ESR at 58 mm/h. Liver function tests were abnormal. Ferritin was markedly elevated at 7063 ng/mL. His serum-soluble interleukin-2 receptor (sIL-2R) level was 656 U/mL, indicating a mild elevation. IL-6 was elevated at 35.7 pg/mL. An abdominal and pelvic CT scan showed segmental thickening of the ileum with local lymphadenopathy, suggestive of Crohn’s disease. Colonoscopy revealed aphthous ulcers in the terminal ileum, and biopsy confirmed the diagnosis.

Crohn’s disease is an inflammatory bowel disease (IBD) characterized by chronic inflammation of the gastrointestinal tract, involving both the innate and adaptive immune systems [18]. Activation of CD4(+) T cells, particularly Th1 and Th17 subsets, leads to increased expression and shedding of CD25, resulting in elevated serum sIL-2R levels [1,19]. The mild elevation of sIL-2R reflects moderate T-cell activation associated with disease activity. Elevated CRP and ESR indicate systemic inflammation, while hyperferritinemia may result from chronic inflammation and anemia of chronic disease [15,18].

2.5. Case 5

A 61-year-old man presented with generalized lymphadenopathy, unexplained weight loss, and night sweats. A lymph node biopsy confirmed diffuse large B-cell lymphoma (DLBCL). His sIL-2R level was markedly elevated at 5062 U/mL.

DLBCL is an aggressive B-cell non-Hodgkin lymphoma [20]. Although the malignant cells are of B-cell origin, the tumor microenvironment involves significant interaction with the immune system [21]. T-cell activation occurs in response to the tumor, leading to increased expression and shedding of CD25 from activated CD4(+) and CD8(+) T cells [1]. Additionally, some lymphoma cells may aberrantly express CD25 [22]. The markedly elevated sIL-2R levels reflect a high tumor burden and extensive immune activation, correlating with disease aggressiveness and prognosis [10].

3. Discussion

Measuring serum sCD25 levels has become a valuable tool, not only for demonstrating T-cell activation, but also for guiding the diagnostic evaluation of non-infectious diseases characterized by specific or nonspecific immune activation, including neoplastic processes [1,2]. However, the nonspecific elevation of sCD25 presents a diagnostic challenge, as increased levels are not exclusive to immune-mediated diseases. Infections, such as Epstein–Barr virus or cytomegalovirus, and malignancies, particularly hematologic ones like lymphomas, can also lead to significantly elevated sCD25 due to lymphocyte activation. Additionally, transient immune activation or physiological variations may contribute to fluctuations in sCD25 levels. Therefore, interpreting sCD25 values requires clinical context and should be complemented with other biomarkers, such as CRP, to improve specificity.

The cases we present highlight the value of sIL-2R to differentiate between immune-mediated conditions and suggest potential mechanisms that lead to the elevation of this marker, which can orientate to a specific diagnostic. For example, in case 1 (adult Still’s disease), moderate elevation of sIL-2R (700–1500 U/mL) correlated with significant T cell activation and systemic inflammation. In case 2 (Castleman disease), high levels of sIL-2R (1500–3000 U/mL) reflected intense immune activation and overproduction of cytokines such as IL-6, indicating involvement of both innate and adaptive immunity [15,16]. In case 3 (axial spondyloarthritis), normal sIL-2R levels despite active disease suggested a predominantly localized inflammatory process with minimal systemic T cell activation. Case 4 (Crohn’s disease) showed mild elevation of sIL-2R (up to ~700 U/mL) associated with moderate activation of T cells in the gastrointestinal tract. Case 5 (diffuse large B-cell lymphoma) illustrated how markedly elevated levels of sIL-2R (>3000 U/mL) indicate extensive immune activation, which correlates with high tumor burden and aggressive disease. Elevated sIL-2R evidence both the activation of malignant B cells and reactive T cells in the tumor microenvironment [10,22].

Additionally, these cases emphasize the utility of sIL-2R levels in shaping clinical decisions. For example, in case 1, sIL-2R elevations supported the initiation of corticosteroid therapy to control systemic inflammation. In case 2, high sIL-2R levels corroborated the diagnosis of multicentric Castleman’s disease and guided targeted therapeutic strategies. In case 5, elevated sIL-2R levels, coupled with clinical and imaging findings, were instrumental in diagnosing diffuse large B-cell lymphoma, directly influencing the oncologic management plan.

In light of the previously discussed findings and pathophysiological models, measuring sIL-2R levels can help to narrowing down diagnoses in patients presenting with nonspecific symptoms and without evidence of any current infection. By evaluating sIL-2R alongside other inflammatory biomarkers (CRP and ES), the accuracy of diagnosis orientation can be enhanced.

We propose the following framework and scenarios based on our observations (Figure 1).

1.

High CRP and sIL-2R levels

This pattern suggests conditions involving activation of antigen-presenting cells (APCs) and the innate immune system reflecting systemic inflammation (high CRP), along with active CD4+ T-cell responses, which elevate sIL-2R. Diseases such as granulomatous conditions (e.g., sarcoidosis), hemophagocytic lymphohistiocytosis (HLH), and autoinflammatory syndromes like Crohn’s disease can present with this profile [1,5,6,19].

2.

High CRP and low sIL-2R levels

This combination indicates primarily activation of innate immunity, with less involvement of adaptive T-cells. It suggests inflammatory conditions where there is low activation of tissue-resident APC [15].

3.

Low CRP and high sIL-2R levels

This pattern may be seen in hematological malignancies or conditions with constitutive activation of lymphocytes (CD4+ or CD8+ T cells/B cells) or macrophages without significant systemic inflammation [10,15].

4.

Low CRP and sIL-2R levels

This scenario could represent inflammatory conditions in resolution or patients responding to treatment. Both markers being low suggests minimal ongoing systemic inflammation and immune activation.

As was mentioned previously, combining sIL-2R levels with other laboratory parameters can provide insights into the underlying pathophysiology of various conditions, helping in the assessment of differential diagnosis. For patients with febrile syndromes of insidious onset, elevated ESR, and absence of a protein gap (indicating no significant hypergammaglobulinemia), the combination of CRP and sIL-2R levels becomes particularly useful [15]. Nevertheless, one aspect that must be considered when evaluating the utility of sIL-2R measurement as a pivotal element in the assessment of autoinflammatory conditions is its availability in resource-limited settings. As this is a novel biomarker, accessibility in developing countries or less specialized healthcare facilities may be constrained, thereby hindering the implementation of the diagnostic algorithm presented above. The aforementioned limitation also hinders the possibility of gathering a substantial number of representative cases of diverse pathologies to establish specific and individualized reference ranges for sIL-2R, which could become a future focus of investigation as access to its determination becomes more widespread.

Further research is needed to better define cutoff values and understand the dynamics of sIL-2R levels in various diseases.

4. Conclusions

Analyzing sIL-2R levels offers insights beyond merely indicating T-cell activation. It aids in guiding the diagnostic process in non-infectious diseases involving both specific and nonspecific immune activation, including neoplastic conditions. By combining sIL-2R levels with clinical findings and other biomarkers such as CRP and ESR, clinicians can narrow down the differential diagnosis, guide management decisions, and potentially improve patient outcomes.