Journal of Clinical Immunology | 2021
Soluble Interleukin-2 Receptor Is a Promising Serum Biomarker for Granulomatous Disease in Common Variable Immune Deficiency
Abstract
To the editor: Common variable immune deficiency (CVID) is a primary antibody deficiency characterized by a marked decrease of immunoglobulin (Ig) G in combination with low IgA and/or IgM, an impaired response to immunization and recurrent infections [1]. Up to 68% of CVID patients have additional noninfectious complications (NIC), including autoimmune complications, malignancies, and granulomatous disease. These NIC are associated with increased morbidity and mortality [2–4]. Granulomatous disease, especially granulomatous and lymphocytic interstitial lung disease (GLILD), leads to a significant reduction in median survival in CVID patients [5]. Granuloma formation is thought to be initiated by CD4+ T lymphocytes that become activated after interaction with antigen presenting cells [6]. Activated CD4+ T lymphocytes secrete cytokines that subsequently stimulate macrophage activation and tumor necrosis factor (TNF)-α production, ultimately leading to the characteristic immune cell agglomerates (i.e., granulomas) in various organs. Several studies have tried to identify potential biomarkers for NIC in CVID. It has been shown that increased numbers of PD-1 high CCR7 low CD4+ T follicular-helper-lymphocytes are associated with autoimmune complications or granulomatous disease [7]. Furthermore, an association between elevated serum IgM and interstitial lung disease in CVID, which was related to B cell follicles within the lung parenchyma, is reported [8]. In pediatric CVID patients, it was observed that reduction in total B and NK lymphocytes with an increase in CD8+ T lymphocytes was associated with presence of bronchiectasis [9]. Hartono et al. [10] described a prediction model for the presence of GLILD in CVID. They showed that a medical history of splenomegaly, immune thrombocytopenia (ITP) and/or autoimmune hemolytic anemia (AIHA), IgA levels < 13 mg/dl, and CD21-low B lymphocytes > 5% of total CD21 B cells are to be predictive measures for GLILD in CVID [10].Wewere interested to seewhether these clinical and immunological features were also predictive for GLILD in our CVID cohort. Therefore, we collected data on the presence of splenomegaly, ITP, AIHA, the IgA levels, and the frequency of CD21-low B lymphocytes from our cohort of CVIDpatients, which resulted in a subgroup of 38CVIDpatients of which all these characteristics were available. In our cohort, only the presence of splenomegaly was found to be significantly increased in patients with GLILD when compared to CVID patients without GLILD. Moreover, also in patients with granulomatous complications affecting other organ systems, including spleen and lymph nodes, only splenomegaly positively correlated with the presence of granulomatous disease (Supplementary Table 1). However, it has to be taken into account that sample sizes used for analysis were small. These findings prompted us to search for a low-invasive biomarker to diagnose and monitor the progression of granulomatous disease in CVID. The soluble form of the interleukin-2 receptor (sIL-2R or sCD25), which is secreted by activated T lymphocytes, is frequently used to monitor immune cell activation. Elevated sIL-2R levels have been reported in various pathological conditions, including autoimmune diseases, infection, and malignancies [11–14]. Previous studies showed that sIL2R levels in CVID patients in general are higher than in healthy controls (HCs) [15–17]. Moreover, it has been demonstrated that sIL-2R levels are higher in CVID patients with NIC when compared to patients with infections-only (IO), or CVIDpatientswith Hanna IJspeert and Willem A. Dik contributed equally to this work.