Soluble Interleukin-2 Receptor Research Articles

Improving Prognosis of Aggressive Natural Killer Cell Leukemia in Japan

Introduction Aggressive natural killer cell leukemia (ANKL) is a rare leukemic form of mature NK cell neoplasm that is closely associated with the Epstein-Barr virus (EBV). Patients with ANKL show a fulminant clinical course and poor prognosis with a median overall survival (OS) of a few months after diagnosis. L-asparaginase (L-asp)-containing chemotherapies and allogeneic hematopoietic stem cell transplantation (HSCT) are considered as effective therapeutic strategies. However, owing to the rarity of this disease, the characteristics and outcomes of ANKL remain unclear. Methods Data of 103 patients diagnosed with ANKL between 2002 and 2021 from 64 hospitals were retrospectively analyzed. Diagnosis was based on the World Health Organization classification and was verified by two co-authors (AF and RS). Patients registered in our previous ANKL studies were excluded. Results Patient's median age was 50 years (range, 17-90 years), and males accounted for 58%. Twelve patients (12%) had a medical history of chronic active EBV infection (9%), severe mosquito bite allergy (5%), and chronic lymphoproliferative disorder of NK cells (1%). B symptoms were commonly observed at the time of diagnosis (89%). Performance status (PS) was poor (2-4) in more than half of patients (53%). The median percentage of ANKL cells was 20.0% (range, 0-93.4) in bone marrow (BM) and 10.3% (range, 0-89) in peripheral blood (PB). ANKL cells express CD2 (95%), CD7 (53%), CD16 (41%), CD56 (95%), and EBER (86%). Fifty-two patients analyzed (58%) had chromosomal abnormalities by G-banding method, including chromosome 17 abnormalities in 19, deletion of 6q in 11, and isochromosome 7 in 5. Blood tests at diagnosis typically showed pancytopenia with a median white blood cell count of 2,900/μl, hemoglobin level of 10.3g/dl, and platelets 4.3×104/μl. High serum lactate dehydrogenase and soluble interleukin-2 receptor level were also observed (median, 882U/l and 8,475U/dl, respectively). The most common extra-nodal site of involvement was the BM (100%), followed by the spleen (84%), liver (70%), and PB (59%). Median OS of the present cohort was 5.3 months, and 1-year OS was 25.7%. Prognosis was significantly better in patients who underwent HSCT than in those who did not undergo HSCT (P < 0.001). The median OS and 1-year OS were 12.0 months and 52.3% in the former group and 1.7 months and 3.8% in the latter. Eighty-three patients received multi-agents-containing chemotherapy, while the others received single agent or did not receive any anti-lymphoma chemotherapy owing to poor general condition. The most common first-line chemotherapy was the SMILE regimen (39%), followed by anthracycline-based regimens, mainly CHOP (24%), DeVIC (15%) and other L-asp-containing regimens (8%). The response rate was highest in patients treated with SMILE (66%), followed by those who received other L-asp-containing regimens (57%), DeVIC (36%) and anthracycline-based regimens (32%). OS was significantly better in patients who received SMILE than in those who did not receive SMILE (1-year OS 39.3% vs. 12.1%, P < 0.001, Figure). Furthermore, the HSCT rate was significantly higher in patients who received SMILE (68% vs. 26%, P < 0.001). Multivariate analysis using the Cox proportional hazards model showed good PS (0-1) (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.23-0.91, P = 0.03), administration of SMILE (HR 0.43, 95% CI 0.23-0.80, P = 0.009), and HSCT (HR 0.26, 95% CI 0.12-0.58, P = 0.001) were independent factors associated with favorable OS. Conclusion The present study showed better OS as compared with our previous study. The SMILE chemotherapy and HSCT were suggested to be key components of the therapeutic strategy for ANKL. Further studies are warranted to validate these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Opportunities for correction of immunosuppression in patients with COVID-19

Here, we review thematic publications in available literature sources of the databases PubMed, Scopus, Web of Science, eLibrary, 49 of which were dated of the years 19972022. Analysis of such reports is aimed at assessing features of cytokine storm-induced hyperinflammatory reaction with signs of immunosuppression accompanied by pronounced lymphopenia and lowered count of CD4+T helpers during severe COVID-19. The prognostic factor for unfavorable prognosis was based on the marker of systemic inflammatory reaction correlating with the disease severity the soluble IL-2 receptor as well as the neutrophil-to-lymphocyte ratio and the lymphocyte subset imbalance. An immunosuppressive therapy of severe forms of COVID-19, aimed at weakening the inflammatory response, exacerbates immune dysfunction by suppressing the T cell function, mainly due to Th1 lymphocytes involved in recognizing and eliminating intracellular pathogens particularly viruses. Upon that, cell-mediated immunity becomes compromised that relies on cytotoxic T-lymphocytes, natural killer cells and macrophages. Timely and targeted immunocorrection is required to prevent or reduce the immunosuppression that accompanies a severe disease course and leads to serious and prolonged complications, as well as to association of secondary infections. In fight against the cytokine storm, it is important not to miss a time point of developing immunosuppressive condition that transitions into immunoparalysis as follows from recent publications covering the tactics of treating immune-mediated complications of coronavirus infection. The review discusses opportunities for immunosuppressive therapy along with glucocorticosteroids and monoclonal antibodies blocking IL-6 or cognate receptors. Studies using mesenchymal stem cells (MSCs) to reduce systemic inflammatory response at COVID-19 are outlined in the review. The use of antigen-specific Treg and their combinations with antagonists of tumor necrosis factor- (TNF), interferon- (IFN) as well as low-dose IL-2 in patients with SARS-CoV-2 infection were analyzed. The prognostic perspectives for CAR-T cells and CAR-NK cells technology have been considered as novel therapeutic approaches aimed at training effector cells to recognize the surface SARS-CoV-2 virus spike-like (S) protein. The feasibility of a therapeutic approach is also emphasized by comparatively analyzed of efficacy of using IL-7 or IL-15 during lymphopenia in patients with COVID-19. Here, side effects complicating immunocorrection come to the fore. Critical evaluation of corrected immunosuppressive conditions in patients with COVID-19 in the post-COVID-19 period by using low-dose IL-2 therapy revealed its ability to repair cellular immune response. As a result, a low-dose IL-2 therapy is recommended as a cytokine replacement therapy in such patients with COVID-19 during hyper-to-hypo-inflammatory phase transition in immune response.

NCMP-21. PEMBROLIZUMAB-ASSOCIATED MYOSITIS, MYASTHENIC CRISIS, AND MYOCARDITIS IN A PATIENT WITH METASTATIC UROTHELIAL CARCINOMA

Abstract Although immune checkpoint inhibitors (ICIs) have improved systemic cancer care, in rare cases, patients develop neuromuscular immune related adverse events (irAEs), which carry high morbidity and mortality. This case study describes an 85-year-old male who developed the triad of myositis, myasthenic crisis, and myocarditis in association with ICI treatment for metastatic urothelial carcinoma (T3N0M1). The patient developed progressive weakness and gait impairment five weeks after initiating treatment with pembrolizumab. Later, he developed reduced ambulation, fatigue, shortness of breath, and orthopnea with concomitant ECG changes. Clinical exam demonstrated dysphagia, ptosis, proximal muscle weakness, fatigable weakness, and areflexia, ultimately resulting in respiratory failure, intubation, and inability to stand. Lab workup revealed elevated creatinine kinase, myoglobin, lactate dehydrogenase, and aldolase, but was notably negative for acetylcholine receptor and muscle specific kinase antibodies. Labs, clinical timeline, and clinical features supported his diagnoses. Interestingly, the cytokine panel demonstrated a high-normal soluble IL-2 receptor alpha which supports autoimmune pathology and elevated IL-10. The patient was treated with pyridostigmine, prednisone, and plasma exchange (PLEX) for 10 exchanges. EMG 10 days into treatment supported evidence of inflammatory myositis. After methylprednisone and PLEX treatment, the patient’s symptoms improved to ambulation with a walker and occasional BiPap support. His metastatic disease remained stable for several weeks while holding pembrolizumab due to toxicity. This case illustrates how early intervention and aggressive treatment for neuromuscular ICI-induced triad can stabilize patients and improve neurologic recovery. Due to the high morbidity and mortality for these irAEs, the authors support increased clinical scrutiny when evaluating these rare conditions and consideration of investigating the acute inflammatory processes. With improved pathophysiologic understanding of these rare conditions, the community can improve outcomes and refine treatments.

Clinical significance of serum and vitreous soluble interleukin-2 receptor in patients with intraocular lymphoma

BackgroundIntraocular lymphoma (IOL) is a masquerade syndrome that mimics uveitis, making diagnosis difficult. The serum soluble interleukin-2 receptor (sIL-2R), which is cleaved by matrix metalloproteinase (MMP) -2 and MMP-9, has been recognized as a tumor-related biomarker of malignant lymphomas. The aim of this study was to review the reliability of serum and vitreous sIL-2R for distinguishing IOL from uveitis.MethodsPatients who underwent diagnostic vitrectomy for marked vitreous haze at Hokkaido University Hospital between April 2014 and June 2019 were enrolled. The patients were divided into an IOL group and a uveitis group, according to the pathology of their vitreous samples. The IOL group was further divided at the time of vitrectomy into patients who already had extraocular involvement (IOL with extraocular involvement group) and patients with no evidence of having extraocular involvement (IOL without extraocular involvement group). Serum sIL-2R, and intravitreal sIL-2R, MMP-2, and MMP-9 levels were assessed.ResultsTwenty-five eyes of 25 patients, and 15 eyes of 15 patients were included in the IOL group and uveitis group, respectively. The serum sIL-2R levels were significantly lower in the IOL group than in the uveitis group (P < 0.05), and 20.0% and 66.7% in the IOL and the uveitis group showed high sIL-2R value above the normal range. Vitreous sIL-2R tended to be higher in the IOL group than in the uveitis group (P = 0.80). Serum sIL-2R was significantly lower in the IOL without extraocular involvement group than in the IOL with extraocular involvement group (P < 0.05); 5.9% in the IOL without extraocular involvement group and 50.0% in the IOL with extraocular involvement group showed high sIL-2R value above the normal range. Vitreous sIL-2R, MMP-2, and MMP-9 tended to be higher in the IOL with extraocular involvement group than in the IOL without extraocular involvement group (P = 0.30, < 0.05, 0.16).ConclusionsSerum sIL-2R is often within the normal range in IOL patients. Even if it is within the normal range, the possibility of IOL should be considered. Serum sIL-2R is not a reliable biomarker for IOL, whereas vitreous sIL-2R may be useful for the diagnosis of IOL.

Hemophagocytic Lymphohistiocytosis Associated with Diffuse Large B-Cell Lymphoma: A Case Report

Abstract Introduction/Objective Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome of immune hyperactivation and dysregulation that has been observed in some malignancies. In HLH, natural killer (NK) cells and cytotoxic T-cells fail to control activated macrophages, leading to cytokine-mediated tissue injury and multiorgan failure. Persistent tumor antigenic stimulation and cytokine hypersecretion can trigger HLH. Diffuse large B- cell lymphoma (DLBCL) is uncommonly associated with HLH. Methods/Case Report A 50-year-old woman presented with daily fevers and malaise of one-month duration. Imaging showed marked hepatosplenomegaly with no lymphadenopathy. Laboratory studies were significant for pancytopenia (WBC: 3.8 K/µL, Hb: 6.8 g/dL, Plt: 74 K/µL), hypertriglyceridemia (330 mg/dL), hyperferritinemia (1460 ng/mL), and elevated soluble interleukin-2 receptor (CD25) (42351.5 pg/mL). These findings, along with NK cell activity level (not obtained in this case), fever, splenomegaly and hemophagocytosis (bone marrow, spleen or lymph nodes) represent the eight diagnostic criteria by Histiocyte Society HLH-2004. A splenic biopsy showed a nodular proliferation of medium-to-large neoplastic lymphocytes with CD20, PAX5, BCL6, MUM1, BCL2, CD5 (dim) and CD10 (dim) expression and negative for cyclin D1 and p53. CD21 did not highlight any dendritic cell meshwork. The bone marrow biopsy provided similar results. Overall, these findings were consistent with a DLBCL, germinal center subtype. Rearrangements of MYC, BCL2 or BCL6 genes were not detected. Although hemophagocytosis was not noted in the bone marrow or spleen, the patient met six of the eight HLH-2004 criteria (minimum five are required). The H-score was 174 reflecting up to 70% probability of HLH. Treatment with daily intravenous dexamethasone 10 mg/m2 was initiated as a temporizing measure prior to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy which resulted in complete remission. Results (if a Case Study enter NA) NA Conclusion Physicians should be cognizant of secondary HLH as a rare complication of DLBCL. Prompt initiation of the appropriate therapy could result in rapid and complete resolution.

Rilonacept and Anakinra in Recurrent Pericarditis: A Systematic Review and Meta-Analysis.

Interleukin 1 (IL-1) has been indicated as a mediator of recurrent pericarditis. Rilonacept, a soluble IL-1 receptor chimeric fusion protein neutralizing interleukin 1 alpha (IL-1α) and interleukin 1 beta (IL-1β), has demonstrated promising results in a phase II study in recurrent or refractory pericarditis. Anakinra is a recombinant inhibitor of the IL-1 receptor with a demonstrated reduction in the incidence of recurrent pericarditis. Definite pharmacological management of pericarditis is key to preventing recurrences, mostly treatment options for recurrent pericarditis refractory to conventional drugs. Here we critically discuss the existing therapy options for recurrent pericarditis, with a focus on new pharmacological approaches: rilonacept and anakinra. A systematic search was conducted across online databases such as PubMed, Cochrane, Google Scholar, ScienceDirect, CINAHL, Scopus, and Embase to obtain clinical trials that assess the effectiveness of anti-interleukin 1 therapy such as anakinra and rilonacept in the management of recurrent pericarditis. Our study concluded that anti-interleukin 1 therapy significantly improved both the quality of life and the clinical outcomes of the study population. These outcomes were most prominent with the use of rilonacept and anakinra in the trial treatment. Rilonacept and anakinra are valuable options in case of recurrent pericarditis refractory to conventional drugs.

Increased CRP, anti-CCP antibody, IL-2R, COMP levels in prognosis of post-chikungunya chronic arthritis and protective role of their specific genotypes against arthritic manifestation

Chikungunya infection leads to acute/chronic polyarthritis/polyarthralgia causing long-term morbidity among patients. Prognosis of post-chikungunya chronic arthritis (PCA) is of utmost necessity for proper disease management. Arthritic and hepatic biomarkers were evaluated among chikungunya patients without arthritis, with acute arthritis and with post-chikungunya chronic arthritis in the study. Serum levels of arthritic [CRP (C-reactive protein), anti cyclic-citrullinated-peptide (anti-CCP) antibody, soluble interleukin-2 receptor (sIL-2R), cartilage oligomeric matrix protein (COMP)] and hepatic [ALT (alanine aminotransferase), AST (aspartate aminotransferase), ALP (alkaline phosphatase), albumin and bilirubin] biomarkers of 167 chikungunya positive patients were determined by sandwich-ELISA/immunoturbidimetry/auto-analyser. 167 chikungunya-patients and 102 healthy controls were genotyped to understand role of CRP-rs3093059/rs3091244, IL-2R-rs743777 and COMP-rs144778694 polymorphisms towards chikungunya virus (CHIKV) infectivity and arthralgic manifestation. CRP, anti-CCP antibody, IL-2R and COMP levels significantly increased among PCA patients. Concentrations of AST, ALT, AST/ALT-ratio, bilirubin and ALP increased among arthritic chikungunya patients. Principal component analysis differentiated PCA groups from acute (AA) and non-arthritic groups. Patients with IL-2R-rs743777-GA, G-allele and COMP-rs144778694-GA genotypes were susceptible to chikungunya infection. Moreover, patients with CRP-rs3093059-CT, rs3091244-TT, IL-2R-rs743777-GA and COMP-rs144778694-AA genotypes were significantly protected from arthralgia, whereas, COMP-rs144778694-GA genotype was susceptible towards it. Patients with certain genotypes of CRP, IL-2R and COMP demonstrated significantly higher biomarker serum-levels among patients suffering from AA with/without PCA. Thus, both serum biomarker levels and polymorphic genotypes of infected patients play decisive role in development of PCA.

Oxidative Stress and Inflammatory Biomarkers for Populations with Occupational Exposure to Nanomaterials: A Systematic Review and Meta-Analysis.

Exposure to nanomaterials (NMs) is suggested to have the potential to cause harmful health effects. Activations of oxidative stress and inflammation are assumed as main contributors to NM-induced toxicity. Thus, oxidative stress- and inflammation-related indicators may serve as biomarkers for occupational risk assessment. However, the correlation between NM exposure and these biomarkers remains controversial. This study aimed to perform a meta-analysis to systematically investigate the alterations of various biomarkers after NM exposure. Twenty-eight studies were found eligible by searching PubMed, EMBASE and Cochrane Library databases. The pooled results showed NM exposure was significantly associated with increases in the levels of malonaldehyde (MDA) [standardized mean difference (SMD) = 2.18; 95% confidence interval (CI), 1.50-2.87], 4-hydroxy-2-nonhenal (HNE) (SMD = 2.05; 95% CI, 1.13-2.96), aldehydes C6-12 (SMD = 3.45; 95% CI, 2.80-4.10), 8-hydroxyguanine (8-OHG) (SMD = 2.98; 95% CI, 2.22-3.74), 5-hydroxymethyl uracil (5-OHMeU) (SMD = 1.90; 95% CI, 1.23-2.58), o-tyrosine (o-Tyr) (SMD = 1.81; 95% CI, 1.22-2.41), 3-nitrotyrosine (3-NOTyr) (SMD = 2.63; 95% CI, 1.74-3.52), interleukin (IL)-1β (SMD = 1.76; 95% CI, 0.87-2.66), tumor necrosis factor (TNF)-α (SMD = 1.52; 95% CI, 1.03-2.01), myeloperoxidase (MPO) (SMD = 0.25; 95% CI, 0.16-0.34) and fibrinogen (SMD = 0.11; 95% CI, 0.02-0.21), and decreases in the levels of glutathione peroxidase (GPx) (SMD = -0.31; 95% CI, -0.52--0.11) and IL-6 soluble receptor (IL-6sR) (SMD = -0.18; 95% CI, -0.28--0.09). Subgroup analysis indicated oxidative stress biomarkers (MDA, HNE, aldehydes C6-12, 8-OHG, 5-OHMeU, o-Tyr, 3-NOTyr and GPx) in exhaled breath condensate (EBC) and blood samples were strongly changed by NM exposure; inflammatory biomarkers (IL-1β, TNF-α, MPO, fibrinogen and IL-6sR) were all significant in EBC, blood, sputum and nasal lavage samples. In conclusion, our findings suggest that these oxidative stress and inflammatory indicators may be promising biomarkers for the biological monitoring of occupationally NM-exposed workers.

Variation of Diagnostic Approaches and Treatment Practices for Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome Among Pediatric Subspecialists

To assess the diagnostic and treatment practices among a variety of subspecialists at pediatric institutions in the US. Using a web-based survey, we assessed the consultation, diagnostic, and treatment preferences of providers from the different pediatric subspecialties who care for pediatric patients with hemophagocytic lymphohistiocytosis (HLH)/macrophage activating syndrome (MAS). Domains included demographics, provider training level and specialty, experience and comfort level with the diagnosis and treatment of HLH/MAS, and institutional approaches toward the diagnosis and management of HLH/MAS. Participants also were given 2 case scenarios: one describing Epstein-Barr virus-associated HLH and another describing an underlying rheumatologic condition with MAS. Of 263 respondents, 23%, 29%, 39%, and 7% identified as hematology/oncology, rheumatology, general pediatrics/critical care/hospitalist, and allergy/immunology, respectively. For Epstein-Barr virus/HLH, hematology/oncology was the preferred first consultant by most respondents other than rheumatologists, of whom only 47% agreed. For MAS, 92% of respondents from all specialties favored a rheumatology consultation. Preferred diagnostic tests varied by subspecialty, with hematology/oncology more likely than rheumatology to order an infectious workup, natural killercell function, soluble interleukin-2receptor, bone marrow biopsy, and genetic testing. First-line therapy also varied, with hematology/oncology preferring dexamethasone and etoposide and rheumatology more often preferring methylprednisolone and anakinra. One-half of respondents were unaware of institutional algorithms for diagnosis and treatment of HLH/MAS. Most (85.6%) favored the development of treatment algorithms for HLH/MAS, and 90% supported a multidisciplinary approach. Current consulting patterns, diagnostic workup, and treatment approaches of HLH/MAS vary by specialty, highlighting the need for standardized management algorithms and institutional multidisciplinary HLH/MAS teams.

Association of Soluble IL-1 Receptor Type 2 with Recovery of Left Ventricular Function and Clinical Outcomes in Acute Myocardial Infarction.

The role of soluble interleukin-1 receptor type 2 (sIL-1R2) in acute myocardial infarction (AMI) remains undocumented. In the present study, we aimed to evaluate the possible associations of sIL-1R2 with left ventricular (LV) function, remodeling and future clinical events in the setting of AMI. Circulating sIL-1R2 levels were quantified after percutaneous coronary intervention (PCI) on day 1 of hospital admission for 204 AMI patients, and upon enrollment of 204 healthy controls. Echocardiography was conducted in the acute phase and at 12-month follow-up. Adverse clinical events were registered after 12 months. Circulating sIL-1R2 levels were significantly higher in AMI patients than in healthy controls (medians respectively 6652.81 pg/mL, 3799.13 pg/mL, p 0.0001). AMI patients with sIL-1R2 levels less than the median had a larger proportion of worsened LV ejection fraction [a decrease in LV ejection fraction (LVEF) of more than 10% units] and reduced LVEF (a final LVEF 50%). After multivariate adjustment, sIL-1R2 levels less than the median were associated with an increased risk of worsened LVEF [odds ratio (OR): 3.7, 95% confidence interval (CI): 1.6-8.5, p = 0.002] and reduced LVEF at 12 months (OR: 2.1, 95% CI: 1.1-4.3, p = 0.035). Moreover, low sIL-1R2 levels were associated with an increased risk of having an adverse clinical event during the first 12 months after AMI [hazard ratio (HR): 2.5, 95% CI: 1.0-6.1, p = 0.039]. Low levels of circulating sIL-1R2 were associated with impaired recovery of LV function and adverse clinical outcomes in AMI patients. These findings might contribute to understanding the important role of sIL-1R2 in postinfarction inflammation.

Correlation between serum levels of PTX-3, SIL-2R, inflammatory markers, and APACHE II scores in patients with severe acute pancreatitis.

To investigate the correlation of serum pentraxin 3 (PTX-3), soluble interleukin-2 receptor (SIL-2R), C-reactive protein (CRP), procalcitonin (PCT) levels, and acute physiology and chronic health evaluation II (APACHE II) scores in patients with severe acute pancreatitis (SAP). A total of 30 patients with SAP from October 2020 to October 2021 were selected as the SAP group, and 42 patients with mild acute pancreatitis (MAP) or moderate-severe acute pancreatitis (MSAP) was selected as the control group. The serum levels of PTX-3, SIL-2R, CRP, PCT, and APACHE II scores were evaluated. The serum levels of PTX-3, SIL-2R, CRP, PCT, and APACHE II scores at admission in the SAP group were significantly higher than those in the control group (all P < .05). Spearman analysis showed that serum PTX-3, SIL-2R, CRP, and PCT levels were positively correlated with APACHE II scores (all P < .05). The mortality rate within 28 days was 26.7% in the SAP group; moreover, the serum PTX-3, SIL-2R, CRP, and PCT levels and APACHE II scores at admission in the death group were significantly higher than those in the survival group (all P < .05). The receiver operating curve showed that the combined prediction value of all indicators (PTX-3 + SIL-2R + CRP + PCT + APACHE II) was superior to the single indicators, and the diagnostic sensitivity and specificity were 90.9% and 84.2%, respectively. Serum PTX-3, SIL-2R, CRP, and PCT levels and APACHE II scores have high guiding significance in early diagnosis and prognostic evaluation of SAP patients.

Interleukin 6 receptor is not directly involved in regulation of body weight in diet-induced obesity with and without physical exercise.

High level of interleukin 6 (IL-6), released by adipocytes in an obesity-induced, low grade inflammation state, is a regulator of insulin resistance and glucose tolerance. IL-6 has also regenerative, anti-inflammatory and anti-diabetogenic functions, when secreted as myokine by skeletal muscles during physical exercise. IL-6 mainly activates cells via two different receptor constellations: classic and trans-signalling, in which IL-6 initially binds to membrane-bound receptor (IL-6R) or soluble IL-6 receptor (sIL-6R) before activating signal transducing gp130 receptor. Previously, we generated transgenic soluble IL-6 receptor +/+ (sIL-6R+/+) mice with a strategy that mimics ADAM10/17 hyperactivation, reflecting a situation in which only IL-6 trans-signalling is active, whereas classic signalling is completely abrogated. In this study, we metabolically phenotyped IL-6R deficient mice (IL-6R-KO), sIL-6R+/+ mice and wild-type littermates fed either a standard chow (SD) or a high-fat diet (HFD) in combination with a 6-weeks treadmill exercise protocol. All mice were subjected to analyses of body weight and body composition, determination of blood glucose and insulin level under fasting conditions, as well as determination of substrate preference by indirect calorimetry. Neither classic IL-6 nor trans-signalling do influence the outcome of diet-induced obesity, insulin sensitivity and glycaemic control. Furthermore, IL-6R deficiency is not impairing the beneficial effect of physical exercise. We conclude that the IL-6R does not play a requisite role in regulation of body weight and glucose metabolism in diet-induced obese mice.

A longitudinal study of the association between pro-inflammatory cytokines and mood symptoms in bipolar disorder.

Because of a relative dearth of longitudinal studies, the directionality of the relationship between mood and inflammation among patients with bipolar disorder (BD) is still unclear. We aimed to investigate the longitudinal associations of pro-inflammatory markers with mood symptom severity in BD. Hundred and thirty-two adult patients with BD were enrolled. At the baseline and 1-year follow-up visit, all participants received mood assessment with Montgomery Åsberg depression rating scale (MADRS) and Young mania rating scale, and underwent blood draws to quantify metabolic profile and serum levels of the pro-inflammatory markers, including soluble interleukin-6 receptor, soluble tumor necrosis factor-α receptor type 1 (sTNF-αR1), monocyte chemoattractant protein-1, and C-reactive protein. A four-factor model of MADRS, consisting of sadness, negative thoughts, detachment, and neurovegetative symptoms, were applied. At baseline, 65 patients with BD were in depressed state, and 67 patients with BD were in euthymic state. Among patients in depressed state, baseline MADRS total score positively correlated with sTNF-αR1 level at follow-up. While baseline sTNF-αR1 level positively predicted sadness symptom in euthymic patients with BD who later developed depression (n=22), sadness in patients with bipolar depression predicted later increase in serum sTNF-αR1 level even after remission (n=17). Moreover, lithium had a stronger effect of lowering peripheral sTNF-αR1 level as compared with other mood stabilizers. Our results indicate the bidirectional inflammation-depression relationship in BD.

Interleukin-6 trans-signalling in hippocampal CA1 neurones mediates perioperative neurocognitive disorders in mice

BackgroundInterleukin-6 (IL-6), a pleiotropic cytokine with both degenerative and regenerative properties, is necessary and sufficient to provoke perioperative neurocognitive disorders after aseptic trauma in mice. IL-6 initiates its actions after binding to either membrane-bound IL-6 receptor α (mIL-6Rα) through classical signalling, or soluble IL-6 receptor (IL-6R) through trans-signalling; both signalling pathways require the transducer gp130. We investigated the site and type of IL-6 signalling that pertains in a tibial fracture aseptic trauma model of perioperative neurocognitive disorder. MethodsWild-type or genetically altered adult mice that lacked molecules unique to either classical or trans-IL-6 signalling underwent tibial fracture under isoflurane anaesthesia. In separate cohorts, we assessed postoperative memory using a trace fear conditioning paradigm (72 h postoperatively), and post-receptor IL-6 signalling (24 h postoperatively) using phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) in CA1 hippocampal neurones. Fracture healing was assessed at postoperative day 15 after inhibiting either both forms of IL-6 signalling with BE0047 or only trans-signalling with sgp130Fc. ResultsThe surgical phenotype of memory decline (decrease in freezing in trace fear conditioning) and upregulated IL-6 signalling (pSTAT3) did not occur after pretreatment before surgery with either BE0047 or sgp130Fc, or after depleting gp130 from CA1 neurones. The surgical phenotype still occurred when IL-6Rα was depleted in either CA1 hippocampal neurones (freezing time, 38.9% [11.5%] vs 58.4% [12.3%]; pSTAT+ CA1 neurones, 31.7 [4.9] vs 7.0 [3.1]) or microglia (freezing time, 40.1% [13.9%] vs 65.2% [12.6%]; pSTAT+ CA1 neurones, 30.1 [5.5] vs 7.9 [3.2]). In global IL-6Rα–/– mice, hyper-IL-6, the trans-signalling agonist, produced the surgical phenotype when administered i.c.v. (freezing time, 42.4% [8.8%] vs 59.7% [10.4%]; pSTAT+ cells, 29.3 [4.3] vs 10.0 [4.4]). Bone-fracture healing (% of fracture callus comprised of new collagen) was significantly greater with sgp130Fc than with BE0047 (52.2% [8.3%] vs 39.7% [7.9%]). ConclusionsAfter orthopaedic trauma, IL-6 produces perioperative neurocognitive disorders through IL-6 trans-signalling in mouse CA1 neurones. Druggable targets of the trans-signalling pathway should be sought to reduce perioperative neurocognitive disorders while allowing the healing properties of classical IL-6 signalling.

Expression and regulation of recently discovered hyaluronidases, HYBID and TMEM2, in chondrocytes from knee osteoarthritic cartilage

Destruction of articular cartilage in osteoarthritis (OA) is initiated by depletion of the hyaluronan (HA)-aggrecan network, followed by degradation of the collagen fibrils. Previously, we reported the implications of HA-binding protein involved in HA depolymerization (HYBID), alias cell migration-inducing protein (CEMIP) and KIAA1199, for HA degradation. However, transmembrane protein 2 (TMEM2), which is ~ 50% homologous to HYBID, was discovered as another hyaluronidase, but their expression and regulation by OA chondrocytes remain elusive. Here we report that the absolute mRNA copy numbers of HYBID are significantly (7.1-fold) higher in OA cartilage than normal cartilage, whereas TMEM2 levels are not different between the groups. HA-degrading activity of cultured OA chondrocytes disappeared by siRNA-mediated knockdown of HYBID, but not TMEM2. HYBID expression was significantly up-regulated by treatment with interleukin-6 (IL-6) or tumor necrosis factor-α (TNF-α) and additively increased by the combined treatment. No significant changes in the TMEM2 expression were seen by the factors examined. IL-1α remarkably enhanced IL-6 production and increased HYBID expression when soluble IL-6 receptor was supplemented. These results demonstrate that in stark contrast to the constitutive expression of TMEM2 and its negligible HA-degrading activity, HYBID is overexpressed in OA cartilage and up-regulated by IL-6 and TNF-α in OA chondrocytes.

Predictive Value Analysis of Serum Ig A, Ig G, and TNF-α in Recurrence of Multiple Myeloma.

Objective The study is aimed at analyzing the predictive value of serum Ig A, Ig G, and TNF-α in the recurrence of multiple myeloma (MM). Methods 136 patients with MM treated in our hospital from January 2010 to January 2017 were followed up for 5 years. Finally, 100 patients who met the inclusion and exclusion criteria and had the complete follow-up visit were selected as the study subjects, with the recurrence of MM as endpoint event, and the observation was taken until the occurrence of endpoint event in patients or the termination of this study. They were divided into the recurrence group (RG) and the nonrecurrence group (NRG) according to whether the endpoint event occurred. The venous blood of patients was collected at the first diagnosis and subsequent visit (at the time of recurrence or termination of the study) to measure the Ig A and Ig G using a full automatic special protein analyzer and the TNF-α level by enzyme-linked immunosorbent assay. The data obtained in this study were analyzed by univariate analysis to choose the factors with difference in statistical significance to draw the ROC curve, and the areas under the curve (AUC) were recorded to analyze the potential mechanism of Ig A, Ig G, and TNF-α in predicting the recurrence of MM. Results After follow-up visit, there were 62 patients with recurrence (62.0%) and 38 patients without recurrence (38.0%), with no obvious difference in gender, age, body weight, and immune classification between the two groups (P > 0.05). Compared with the NRG, the levels of soluble interleukin-2 receptor (sIL-2R) and β2-microglobulin (β2-MG) in the RG at the first diagnosis were distinctly higher (P < 0.001); the levels of Ig A, Ig G, and TNF-α in the RG at the first diagnosis were visibly higher (P < 0.05); and the levels of Ig A, Ig G, and TNF-α in the RG at the subsequent visit were clearly higher (P < 0.05). There was a correlation between Ig G, Ig A, and TNF-α and β2-MG at the first diagnosis and the subsequent visit (P < 0.05); there was a correlation between Ig G and TNF-α, and sIL-2R at the first diagnosis and the subsequent visit (P < 0.05); and there was a correlation between Ig A and sIL-2R at the subsequent visit (P < 0.05). The AUC of Ig G, Ig A, and TNF-α in predicting the MM at the first diagnosis were 0.772, 0.776, and 0.778, respectively. Conclusion The serum Ig A, Ig G, and TNF-α had a predictive value in the recurrence of MM, and TNF-α was correlated with sIL-2R and β2-MG, with the highest AUC and the best predictive value.

The multilobated morphology is still a better prognosis factor of diffuse large B-cell lymphoma in the R-CHOP era.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of B-cell lymphoma. Although the multilobated subtype of DLBCL has been observed since the 1970s, little is known about the clinical significance of this unique variant in the era of rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone/prednisolone (R-CHOP) therapy. In this study, the retrospective clinicopathological analysis of 312 patients diagnosed with DLBCL showed that the multilobated DLBCL group comprised 11% of the cases and was predominantly male (p = 0.027), achieved complete remission in the first therapy (p = 0.023), and exhibited germinal center B-cell phenotypes in the Hans algorithm (p = 0.025). The multilobated DLBCL groups had a better prognosis in overall survival (OS) and progression-free survival (PFS) than the non-multilobated DLBCL group (OS, p = 0.006; PFS, p = 0.010). In the multivariate Cox regression analyses for OS, independent prognosis factors were high soluble IL-2 receptor (p = 0.025), high risk of International Prognostic Index, and multilobated morphology (p = 0.031). The most characteristic copy number gains found in more than 50% of the cases were located at 1q, 3p, 10q, 12q, and 14q. Overall, the multilobated morphology in DLBCL exhibits a good outcome in the R-CHOP era.

Serum Soluble Interleukin 2 Receptor Alpha vs. Urinary Parameter and Serum Immunological Markers as a Monitoring Tool of Treatment Response of Lupus Nephritis and their Relation to Lupus Nephritis Class on Renal Biopsy

Background: Lupus Nephritis (LN) is one of the most common and serious manifestations in SLE patients that causes significant morbidity and mortality. Current conventional biomarkers for LN are sometimes unable to predict treatment response of lupus nephritis. Recently serum soluble interleukin-2 receptor alpha (sIL-2 R alpha) is shown to be a good marker to predict treatment response of LN. Objective: To compare serum sIL-2R alpha with other commonly used markers as a marker of treatment response of LN and their relation to the LN class in renal biopsy. Methods: This prospective observational study was conducted in the Department of Nephrology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2018 to August 2019. Twenty seven patients who were diagnosed with lupus nephritis after kidney biopsy were included in this study. Serum soluble interleukin-2 receptor alpha, 24 hrs UTP, anti-dsDNA, complements level (C3 &amp; C4) were measured in all patient at baseline, 3-months and 6- months after treatment. Serum soluble interleukin-2 receptor alpha level was measured by ELISA and is expressed as pg/mg. Serum sIL-2R alpha as well as conventional biomarker value were compared before and after treatment and in between treatment response and non-response group. Results: Serum sIL-2R alpha levels were significantly higher in patients of proliferative lupus nephritis (Class III &amp; Class IV) than non-proliferative lupus nephritis (Class V) at baseline (3934.3 ± 1095.2, 3934.3 ± 1095.2 &amp; 1801.98 ± 205.8 pg/L respectively) and levels were decreased significantly 6 months after treatment (p &lt;0.001). Serum sIL-2R alpha levels were also significantly higher in non-remission proliferative group then remission proliferative group (4071.60 ± 769.91 vs 5169.20 ± 394.76) with p value 0.008 at baseline. In contrast no significant difference were observed for 24 hrs UTP levels at baseline between this group which suggest that serum sIL-2R alpha are more sensitive marker than 24 hrs UTP in predicting treatment response of lupus nephritis. Conclusions: Serum sIL-2R alpha might be a valuable serological biomarker to diagnose and to predict and monitor the treatment response of lupus nephritis.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS SECONDARY TO DISSEMINATED HISTOPLASMOSIS PRESENTING AS DIFFUSE ALVEOLAR HEMORRHAGE IN A 32-YEAR-OLD WOMAN

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS SECONDARY TO DISSEMINATED HISTOPLASMOSIS PRESENTING AS DIFFUSE ALVEOLAR HEMORRHAGE IN A 32-YEAR-OLD WOMAN

Hemophagocytic Lymphohistiocytosis.

Hemophagocytic Lymphohistiocytosis.