|Year : 2016 | Volume
| Issue : 3 | Page : 132-139
Interleukin-17 and interleukin-27 in newly diagnosed multiple myeloma patients: interrelationship and correlation with leukocyte differential counts
Mervat A Al-Feky1, Rasha A El-Gamal MD 1, Ghada M El Gohary2, Gihan M Kamal2
1 Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||06-May-2016|
|Date of Acceptance||07-May-2016|
|Date of Web Publication||27-Dec-2016|
Rasha A El-Gamal
Department of Clinical Pathology, Faculty of Medicine, Ain Shams University Hospitals, Ramses St., Abbasia, Cairo 11566
Source of Support: None, Conflict of Interest: None
Objectives Efforts to uncover factors affecting multiple myeloma (MM) prognosis are unremitting. Recently, white blood cells differential (WBCD) counts were reported to affect MM prognosis. Cytokines, including interleukin-17 (IL-17) and IL-27, are known to influence the bone marrow microenvironment. The interrelation between both cytokines in previous studies is conflicting and their correlations to WBCD have not been investigated in MM. Our aim was to study the relationship between IL-17 and IL-27 in newly diagnosed MM patients, and to investigate possible association with the newly introduced prognostic WBCD.
Materials and methods Patients were classified according to the International Staging System (ISS). Plasma levels of IL-17 and IL-27 were assessed using the solid-phase sandwich enzyme-linked immunosorbent assay.
Results IL-17 and IL-27 median values showed no significant difference between patients and healthy controls, and a significant positive correlation between both cytokines was observed (P=0.001). IL-17 was significantly higher in International Staging System stage III and morphologically group II patients. IL-17 was significantly correlated with various prognostic parameters. However, on using multivariate analysis, monoclonal immunoglobulin concentration and absolute lymphocyte count/absolute monocyte count ratio continued to be correlated with IL-17 (P=0.007; 0.009, respectively). IL-27 was positively correlated with monoclonal immunoglobulin (P=0.001), negatively correlated with absolute lymphocyte count (P<0.001), and its higher levels were associated with circulating plasma cells.
Conclusion IL-17 and IL-27 were positively correlated and variably linked to prognostic markers of MM. Their relation to WBCD introduces an area of investigation as to assess its potential use in newer modalities of treatment.
Keywords: interleukin-17, interleukin-27, multiple myeloma, white blood cell differential
|How to cite this article:|
Al-Feky MA, El-Gamal RA, El Gohary GM, Kamal GM. Interleukin-17 and interleukin-27 in newly diagnosed multiple myeloma patients: interrelationship and correlation with leukocyte differential counts. Egypt J Haematol 2016;41:132-9
|How to cite this URL:|
Al-Feky MA, El-Gamal RA, El Gohary GM, Kamal GM. Interleukin-17 and interleukin-27 in newly diagnosed multiple myeloma patients: interrelationship and correlation with leukocyte differential counts. Egypt J Haematol [serial online] 2016 [cited 2019 Dec 9];41:132-9. Available from: http://www.ehj.eg.net/text.asp?2016/41/3/132/196216
| Introduction|| |
Multiple myeloma (MM) is one of the prevalent blood malignancies, being described as the second-most common cancer of the blood. Despite the progress made in the disease management, the outcome of MM patients has been found to be highly diverse when most patients fail to achieve or maintain remission of the disease with low survival rates . However, a number of independent indicators of survival were recognized, and many of them were adopted to form the basis of the two most widely implemented grading systems: Durie–Salmon classification  and the International Staging System (ISS) .
In the last decade, newer prognostic factors were introduced to MM that showed greater appreciation of the biology of the tumor. Researchers demonstrated correlations between MM prognosis and certain components of the white blood cell differential, including absolute lymphocyte count (ALC) ,, absolute monocyte count (AMC), ALC/AMC ratio , absolute neutrophil count (ANC), ANC/ALC ratio , and circulating plasma cells (CPCs) .
The synergy between myeloma cells and the components of their microenvironment is viewed as having an important role in conducting the malignant path , of which are the bone marrow (BM) stromal cells, whose role in supporting MM plasma cells (PCs) were extensively studied. The interaction between PCs and stromal cells were reported to govern PC-homing, growth, survival, and resistance to chemotherapy .
Being secreted in the BM microenvironment, different cytokines, proangiogenic factors, including interleukin-6 (IL-6), transforming growth factor-β, vascular endothelial growth factor and insulin-like growth factor-1, have been known to promote MM cell growth ,. Recently, more attention has been paid to the effects of IL-17 on the pathogenesis of MM. IL-17 is a proinflammatory cytokine, evolving primarily from activated CD4+ T-helper cells (Th17) . However, a considerable population of IL-17-producing T cells that were isolated from tissues or body fluids of numerous types of human carcinomas and autoimmune diseases was considered as IL-17-producing CD8+ T cells (Tc17) ,,. In addition, recent studies revealed that in several diseases, IL-17 is secreted by different cells involved in innate immune response, e.g., neutrophils, γ/δ T cells, natural killer (NK1.1) cells, and monocytes ,.
Increased levels of IL-17 in peripheral blood (PB) and BM of MM patients have been detected , and its levels were found to correlate with disease severity ,, as well as angiogenesis mediators . In addition, Prabhala et al.  had suggested that Th17 cells and IL-17 may represent a key therapeutic target to achieve anti-MM response, as well as to enhance immune function.
Another cytokine, IL-27, is a heterodimeric cytokine belonging to the IL-12 family of cytokines. IL-27 was recognized as an inflammatory cytokine ,, inducing the expansion of type 1 helper T (Th1) . On the other hand, immunosuppressive activity of IL-27 has been reported in the literature . Thus, both proinflammatory and anti-inflammatory functions were clearly defined for IL-27. Yet, the suggested therapeutic benefit to control diseases, such as bronchial asthma , collagen-induced arthritis , and tumor progression , reflects the anti-inflammatory effects of IL-27. In respect to MM, Cocco et al.  demonstrated that IL-27 strongly inhibited tumor growth of primary MM cells and MM cell lines.
Several studies have explored the interrelationship between IL-17 and IL-27 in MM and other diseases, and conflicting results were obtained –. Thus, we were motivated to study the relationship between IL-17 and IL-27 in newly diagnosed untreated MM patients and to investigate their association with the newly introduced prognostic determinants of white blood cell differential counts. We attempted to state a potential use of the effortless, routinely available, leukocyte differentials in implying the applicability of the two cytokines in MM therapy.
| Materials and methods|| |
The study population included 35 newly diagnosed MM patients (16 men and 19 women; median age 55 years, range 49–65 years) admitted to the Hematology Oncology Unit, Internal Medicine Department, Ain Shams University Hospitals, Cairo, Egypt, in the period from October 2013 to October 2014. According to the ISS , 12 patients were classified as having stage II disease, and 21 had stage III disease (only two patients had stage I of the disease at time of presentation). Twenty-six patients had monoclonal immunoglobulin (Ig) IgG-κ and nine patients had IgG-λ. Serum monoclonal Ig of patients had a median value of 1.9 g/dl [interquartile range (IQR): 1.1–2.7]. Plasma samples from 35 age and sex-matched healthy volunteers were included as controls. Informed consent was obtained from patients and controls for their approval to use their samples for research purposes.
| Methods|| |
All patients were evaluated and treated following the British Committee for Standards in Haematology and UK Myeloma Forum Guidelines for the Diagnosis and Management of MM . In this setting, sufficient PB samples were collected from the patients to perform the following tests: complete blood count using a Coulter LH 750 Hematology Analyzer (Beckman Coulter Inc., Fullerton, California, USA), with morphologic examination of leishman-stained PB smear and erythrocyte sedimentation rate; serum urea, creatinine, calcium, and albumin using UniCelDxC600 Synchron Clinical Systems (Beckman Coulter Inc., Brea, California, USA); β2-microglobulin (β2-MG) using the IMMULITE Automated Analyzer (DPC, Los Angeles, California, USA); and electrophoresis of serum proteins together with immunofixation, and quantification monoclonal protein in serum, using Helena Rep Unit (Helena Laboratories, Beaumont, Michigan, USA). BM aspirate, as the mainstay in diagnosis (with or without trephine biopsy), was performed for all patients for confirmation and assessment of the degree of infiltration, and PC phenotyping. The stained smears made from PB, BM aspirate, and/or trephine biopsies were morphologically evaluated by two experienced hematopathologists. Appropriate imaging studies were performed where relevant.
Once diagnosed by BM PC infiltration and confirmation of clonality by immunophenotyping, patients’ EDTA samples used for complete blood count testing at the time of diagnosis were centrifuged and the recovered plasma was stored at −70°C. All plasma samples from patients and controls were assayed at the end of the study. Concentrations of IL-17 and IL-27 were measured by using a solid-phase sandwich enzyme-linked immunosorbent assay using monoclonal human antibodies against IL-17 and IL-27, respectively (Quantikine R&D Systems Inc., Minneapolis, Minnesota, USA). IL-17 and IL-27 in plasma were bound to their respective monoclonal antibodies coating the enzyme-linked immunosorbent assay microplates. After washing, an enzyme-linked polyclonal antibody specific for each IL was added to the wells, which acted afterwards upon an added substrate with a color developing in proportion to the amount of IL bound in the initial step. The intensity of the color was measured at 450 nm on a Stat Fax 2100 microplate reader (Awareness Technology, Palm City, Florida, USA). The assayed ILs were measured in pg/ml. Intra-assay and interassay coefficients of variation were 5.0 and 5.1%, respectively.
Statistical analyses were performed using the MedCalc v.13.2.2 software (MedCalc Software, Ostend, Belgium). Quantitative data were expressed as median and range, whereas qualitative data were expressed as number and percentage. The Mann–Whitney U-test was used to compare medians of continuous variables between the selected groups. Correlations between different parameters were determined using Spearman’s rank test. Multiple regression analysis was conducted to identify the unique contribution of the individual independent variables, while controlling for the effects of other independent variables. The significance levels (P values) were set at 0.05 for all tests.
| Results|| |
Plasma concentrations of IL-17 and IL-27 among patients and controls
Levels of IL-17 and IL-27 were compared between the MM de-novo patients and healthy control volunteers. The median value of IL-17 was nonsignificantly higher in MM patients than in controls [69 (IQR: 60–75) pg/ml vs. 59 (IQR: 53–63.5) pg/ml; P=0.055]. IL-27 showed no significant difference between MM patients and controls [median: 12 (IQR: 9.5–16.5) pg/ml vs. 12.5 (IQR: 10–18) pg/ml, respectively; P=0.08].
Interrelationship between plasma concentrations of IL-17 and IL-27
Bivariate correlations between parameters were assessed by using the Spearman correlation coefficient, where a significant positive correlation between IL-17 and IL-27 was observed (ρ=0.52, P=0.001) ([Figure 1]).
|Figure 1 Significant correlation between IL-17 and IL-27 levels in patients with multiple myeloma. IL, interleukin.|
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Levels of the IL-17 and IL-27 in relation to disease staging and known prognostic determinants
IL-17 was positively correlated with monoclonal Ig (ρ=0.66, P<0.001) and β2-MG (ρ=0.42, P=0.012), and a positive correlation was found between IL-27 and monoclonal Ig (ρ=0.515, P=0.001) ([Figure 2]). Other variables including serum albumin, hemoglobin level, platelet count, and BM PCs were not related to IL-17 or IL-27 (P>0.05).
|Figure 2 Correlations between IL-17 and the studied prognostic factors in patients with multiple myeloma. β2-MG, β2-microglobulin; ALC, absolute lymphocyte count; AMC, absolute monocyte count; ANC, absolute neutrophil count; IL, interleukin.|
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A comparison was conducted of the levels of IL-17 and IL-27 in relation to ISS  and the morphological staging system . Significantly higher levels of IL-17 were found in patients who were categorized as ISS-stage III (P=0.03) and in morphologically group II patients (P=0.012) than those of ISS-stage II and group I patients by morphological classification, respectively. No correlation was detected between levels of IL-27 and either ISS nor morphological staging system ([Table 1]).
|Table 1 IL-17 and IL-27 levels in relation to disease staging and surface expression of prognostic immunophenotypes in multiple myeloma patients|
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Moreover, IL-17 was significantly increased in patients showing CD117− and CD56+ phenotypes (P=0.006 and 0.001, respectively). In contrast, IL-27 showed no significant difference as regards the expression of the prognostically significant phenotypes ([Table 1]).
Relation between IL-17 and IL-27 levels and leukocyte differential counts
IL-17 was positively correlated with AMC (ρ=0.38, P=0.027) and ANC/ALC ratio (ρ=0.39, P=0.022) and negatively correlated with ALC/AMC ratio (ρ=−0.6, P<0.001) ([Figure 2]). IL-27 was negatively correlated with ALC (ρ=−0.638, P<0.001). The multivariate regression analysis was used for ranking of the correlated parameters to IL-17, and out of the correlated prognostic variables, monoclonal Ig concentration and ALC/AMC ratio were the two variables that continued to show significant correlation with IL-17 (P=0.007 and 0.009, respectively) ([Table 2]).
|Table 2 Comparison between the bivariate and partial correlations between IL-17 levels and relevant variables in patients with multiple myeloma|
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Cutoff levels were adapted in previous studies for ALC (1.4×1012/l), AMC (0.49×1012/l), and ALC/AMC (2.9), aiming at more efficient use of leukocyte differentials as prognostic indicators ,. In our study, we evaluated these cutoffs in relation to the levels of IL-17 and IL-27. IL-17 showed significant difference as regards AMC, where higher levels were found in patients with AMC values greater than 0.49×1012/l (P<0.001). Likewise, significantly higher levels of IL-27 were found in patients having ALC lower than 1.4×1012/l (P<0.001) ([Figure 3]).
|Figure 3 IL-17 levels based on AMC cutoff (490 cells/µl), and IL-27 levels based on ALC cutoff among patients with multiple myeloma. ALC, absolute lymphocyte count; AMC, absolute monocyte count; IL, interleukin.|
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The presence or absence of CPCs in PB smear was evaluated in relation to IL-17 and IL-27. CPCs were encountered in 15 patients, ranging from 1 to 4%. The presence of CPCs was associated with higher IL-27 levels (median: 25; IQR: 10–42.5) than those who did not show CPCs (median: 9.5; IQR: 9–11.5) (P=0.009), whereas no significant difference of IL-17 values was found between patients having CPCs (median: 76.5; IQR: 53.8–90) compared with their counterparts (median: 71.5; IQR: 38–75) (P=0.56).
| Discussion|| |
In MM, immune dysfunction is the rule and tumor expansion is regulated by cytokines secreted by myeloma cells and the microenvironment of the BM . In this study, we investigated the plasma levels of IL-17 and IL-27 and how they coexist in MM patients at the time of diagnosis. The acknowledgment of these IL-producing leukocytes and the evidence of the prognostically predictive ability of either the ILs or white blood cells count have aroused the question of whether the easily available leukocyte differentials can indicate plasma levels of the cytokines and, hence, the possibility of using IL-17 and IL-27 in the treatment.
On comparing the assayed plasma levels of IL-17 between de-novo MM patients and healthy control volunteers, the median value of IL-17 was found to be higher in MM patients than in controls; yet, it was not statistically significant. Similar results were reported by Alexandrakis et al. . However, IL-17 was significantly higher in MM patients than in healthy controls in other studies ,.
Our results revealed no significant difference between MM patients and the controls regarding IL-27 levels. In a study by Song et al. , IL-27 was significantly lower in MM patients. Forrester et al.  found the plasma level of IL-27 in normal individuals to be widely variable and the possibility of them being partially affected by genetic heritability, smoking, and exercise. In the present study, the impact of these factors could not be accurately predicted in view of the paucity of the numbers of cases and controls.
IL-27 was identified by some researchers to inhibit Th17 cells generation and suppress the molecules linked to Th17 function. They described the inhibition of IL-17-polarizing cytokines from dendritic cells by IL-27, with the consequent decrease of IL-17 secretion from T cells . Other studies indicated inconsistent or even reciprocal effects between both cytokines ,,. In this study, a positive correlation was observed between IL-17 and IL-27, adding to the greatly divergent results reported in previous studies. In their study, Song et al.  found a negatively significant correlation between both cytokines in MM patients. On the other hand, a recent study, conducted on mice, has identified a novel proinflammatory role for IL-27 in vivo that promotes Th17 differentiation by inducing Th17-supporting cytokines in antigen-presenting cells (APCs) , providing an evidence of a boosting effect of IL-27 on the production of IL-17. Moreover, as the Th17 cell represents the cell type that is most subjected to the suppressive action of IL-27 , production of IL-17 by cells other than the Th17 ,, can hypothetically maintain IL-17 levels despite the inhibitory effect of IL-27.
The correlation between IL-17 and adverse prognostic markers, higher staging, and worse clinical outcome were demonstrated in previous studies ,,. In agreement with this, our findings indicated that the markers that were significantly related to IL-17 were those generally known to indicate poor prognosis. In this context, IL-17 was positively correlated to β2-MG as well as monoclonal Ig concentration. In addition, a direct association was found between higher levels of IL-17 and of ISS-stage III. Another categorization system indicating prognosis is the morphological classification introduced by Bartl and Frisch , which depends on the presence or absence of particular morphological features of BM PCs. They have suggested a classification that divides myeloma into three groups: (i) low grade, in which PCs are mature with minimal dysplasia; (ii) intermediate grade, in which PCs are dysplastic but not blastic; and (iii) high grade, comprising plasmblasts. On the basis of this morphological classification, our results revealed higher IL-17 values in association with the presence of signs of immaturity and dysplasia.
Another poor prognostic aspect of IL-17 found in our study was based on the immunophenotypic expression, where higher levels IL-17 were found among patients who were CD117− and among those who were CD56+ compared with their counterparts. The expression of CD56 and absence of CD117 on PCs in MM patients are known poor prognostic markers ,,.
Although IL-27 has been described as a marker of good prognosis in MM , our results were in contrast to this, as higher levels of IL-27 were associated with the poor prognostic sign of higher monoclonal Ig. We consider this result as another aspect of congruity between IL-17 and IL-27 secretion.
To our knowledge, no previously published study has considered the relation between absolute white blood cells counts and plasma levels of IL-17 or IL-27 in MM, though each parameter was individually linked to MM outcome ,,. Lower ALC, higher AMC, and lower ALC/AMC have been related to worse outcome and were associated with the presence of poor prognostic markers ,, whereas low ANC/ALC was linked to better overall survival and event-free survival . One study had demonstrated that IL-17 was secreted as a result of stimulation of T-lymphocytes with cytokines secreted by APCs ,. Human dendritic cells, which partially belong to monocytes , are efficient APCs for the induction of polyfunctional Th17–Th1 cells, and such cells are the dominant population of IL-17 producers in the tumor bed in human myeloma . In addition, a subset of PB monocytes producing IL-17 was detected in Langerhans cell histiocytosis patients . Thus, a direct relationship can be proposed between the presence of monocytes and the secretion of IL-17, an assumption that was clearly displayed in our study, where IL-17 was positively correlated with AMC and negatively correlated with ALC/AMC ratio. Moreover, on using the determined cutoff values for ALC, AMC, and ALC/AMC , AMC cutoff value of 0.49×1012/l was found efficient to demarcate IL-17 high and low levels, supporting the positive relationship between IL-17 levels and monocytes in PB.
ANC/ALC ratio is another leukocyte parameter that was recently introduced to predict independently overall survival and event-free survival in MM patients by univariate and multivariate analyses . The capacity of Th17 cells to hire and trigger neutrophils is well-established and can lead to the destruction of pathogens, as well as injury to peripheral tissues . In agreement with this, a positive correlation of IL-17 to ANC/ALC ratio was found in our study. Our results have also displayed a link between IL-27 and ALC, where higher levels of IL-27 were associated with low ALC, and ALC cutoff value of 1.4×1012/l was competent to categorize high and low IL-27 levels.
As regards the relation to CPCs, our results showed an association between higher IL-27 levels and the presence of CPCs. A previous study  has shown that IL-27 possesses chemotactic properties on in-vitro generated PC and polyclonal plasmablastic cells (PPC). The authors have proven that IL-27 was able to influence the expression of chemokines/chemokine receptors in PPC and PC, hence providing an additional signal for PC and PPC migration. Still, neither the malignant nature of the CPCs nor the lymphocyte subtype was evaluated in our work, interfering with full compliance with results of the aforementioned study.
| Conclusion|| |
This study demonstrated a direct relationship between IL-17 and IL-27 in MM, and both cytokines were variably related to poor prognostic markers, being more evident with IL-17. The correlation to differential leukocyte counts was strongly validated by our results, offering a simple efficient means of informing about the levels of either cytokine, and such a relationship might introduce an area of investigation so as to assess its potential use in newer modalities of treatment. Larger studies with comprehensive analysis of many determinants are required in the future to determine the actual state of performance of each cytokine, and to understand the pattern of their coexistence in MM.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]