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Concept: Cytokines


Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.

Concepts: Immune system, Antibody, Asthma, Infection, Cytokines, Interleukin, Chemokine, Chronic fatigue syndrome


Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous syndrome in which patients often experience severe fatigue and malaise following exertion. Immune and cardiovascular dysfunction have been postulated to play a role in the pathophysiology. We therefore, examined whether cytokine profiling or cardiovascular testing following exercise would differentiate patients with ME/CFS. Twenty-four ME/CFS patients were matched to 24 sedentary controls and underwent cardiovascular and circulating immune profiling. Cardiovascular analysis included echocardiography, cardiopulmonary exercise and endothelial function testing. Cytokine and growth factor profiles were analyzed using a 51-plex Luminex bead kit at baseline and 18 hours following exercise. Cardiac structure and exercise capacity were similar between groups. Sparse partial least square discriminant analyses of cytokine profiles 18 hours post exercise offered the most reliable discrimination between ME/CFS and controls (κ = 0.62(0.34,0.84)). The most discriminatory cytokines post exercise were CD40L, platelet activator inhibitor, interleukin 1-β, interferon-α and CXCL1. In conclusion, cytokine profiling following exercise may help differentiate patients with ME/CFS from sedentary controls.

Concepts: Immune system, Cytokine, Cytokines, Lyme disease, Fibromyalgia, Fatigue, Chronic fatigue syndrome, Malaise


Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.Molecular Psychiatry advance online publication, 24 May 2016; doi:10.1038/mp.2016.77.

Concepts: Immune system, Regression analysis, Cytokines, Autism, Chemokine, Down syndrome, Mental retardation, Developmental disability


Therapy for advanced renal-cell cancer has evolved considerably in the past decade, with new agents greeted like “buried treasure,” although these agents come with substantial costs to both patients and the health system. Before 2005, the widely used systemic agents were cytokines - interferon alfa and interleukin-2, which yielded modest efficacy and substantial toxicity. Nevertheless, underlining the immunogenic nature of renal-cell cancer, durable complete responses occur in some patients who receive interleukin-2; these patients are mostly cured.(1) After 2005, angiogenesis and mammalian target of rapamycin (mTOR) pathway inhibitors displaced cytokine therapy.(2),(3) Although the most effective sequence of therapies is . . .

Concepts: Immune system, Antibody, Medicine, Cytokine, Apoptosis, Cytokines, Interferon, Interleukin


Allergy is inversely related to glioma risk. To determine whether prediagnostic allergy-related serum proteins are associated with glioma, we conducted a nested case-control study of seven cytokines (IL4, IL13, IL5, IL6, IL10, IFNG, TGFB2), two soluble cytokine receptors (sIL4RA, sIL13RA2) and three allergy-related transcription factors (FOXP3, STAT3, STAT6) using serum specimens from the Janus Serum Bank Cohort in Oslo, Norway. Blood donors subsequently diagnosed with glioma (n = 487) were matched to controls (n = 487) on age and date of blood draw and sex. We first estimated individual effects of the 12 serum proteins and then interactions between IL4 and IL13 and their receptors using conditional logistic regression. We next tested equality of case-control inter-correlations among the 12 serum proteins. We found that TGFB2 is inversely related to glioblastoma (Odds Ratio (OR) = 0.87, 95% Confidence Interval (CI)) = 0.76, 0.98). In addition, ≤ 5 years before diagnosis, we observed associations between IL4 (OR = 0.82, 95% CI = 0.66, 1.01), sIL4RA (OR = 0.80, 95% CI = 0.65, 1.00), their interaction (OR = 1.06, 95% CI = 1.01, 1.12) and glioblastoma. This interaction was apparent > 20 years before diagnosis (IL4-sIL4RA OR = 1.20, 95% CI = 1.05, 1.37). Findings for glioma were similar. Case correlations were different from control correlations stratified on time before diagnosis. Five years or less before diagnosis, correlations among case serum proteins were weaker than were those among controls. Our findings suggest that IL4 and sIL4RA reduce glioma risk long before diagnosis and early gliomagenesis affects circulating immune function proteins.

Concepts: Antibody, Experimental design, Epidemiology, Cytokine, Signal transduction, Hormone, Receptor, Cytokines


We report the crystal structure of a 40mer mirror-image RNA oligonucleotide completely built from nucleotides of the non-natural L-chirality in complex with the pro-inflammatory chemokine L-CLL2 (monocyte chemoattractant protein-1), a natural protein composed of regular L-amino acids. The L-oligonucleotide is an L-aptamer (a Spiegelmer) identified to bind L-CCL2 with high affinity, thereby neutralizing the chemokine’s activity. CCL2 plays a key role in attracting and positioning monocytes; its overexpression in several inflammatory diseases makes CCL2 an interesting pharmacological target. The PEGylated form of the L-aptamer, NOX-E36 (emapticap pegol), already showed promising efficacy in clinical Phase II studies conducted in diabetic nephropathy patients. The structure of the L-oligonucleotide·L-protein complex was solved and refined to 2.05 Å. It unveils the L-aptamer’s intramolecular contacts and permits a detailed analysis of its structure-function relationship. Furthermore, the analysis of the intermolecular drug-target interactions reveals insight into the selectivity of the L-aptamer for certain related chemokines.

Concepts: Immune system, Inflammation, Clinical trial, Signal transduction, Chemotaxis, Cytokines, Chemokine, CCL2


OBJECTIVE: The aim of this study was to evaluate possible immunologic relationships between sickle cell anaemia (SCA) and periodontal inflammation and its impact on serum cytokines. DESIGN: Twenty-five Brazilian children of African descent were involved in this study and divided in two groups: SCA (n=10): confirmed diagnosis of homozygous anaemia; and CTR-control (n=15): no sickle anaemia. Clinical examination included comprehensive medical (routine physical evaluation) and periodontal exams: plaque index (PI), bleeding on probing (BoP), and haematological analysis. Serum samples were collected for cytokine evaluation by microarray. Clinical and laboratorial parameters were compared statistically (alpha=5%). RESULTS: The higher values of PI and BoP were similar for both groups (p>0.05) confirming a diagnosis of generalized gingivitis for all individuals. Intergroup analysis showed higher levels of interferon gamma (IFNγ), tumour necrosis alpha (TNFα), interleukin (IL)-4, -5, -8, -10 and 13 only in the SCA group (p<0.05). In addition, PI was negatively correlated with IL-2, IL-4, IL-5, IL-6, IL-8 and IL-13, while BoP was positively correlated with IL-10. CONCLUSION: Within the limits of the present study, it was concluded that SCA increase the levels of serum cytokines regardless of the presence of periodontal inflammation. Therefore, a direct immunological relationship between SCA and periodontal inflammation was not established.

Concepts: Immune system, Cytokine, Red blood cell, Cytokines, Interferon, Gingiva, Interleukin, Sickle-cell disease


OBJECTIVE: The aim of this preliminary study was analyze the possible alterations in some salivary interleukins, usually associated with the inflammatory processes. MATERIAL AND METHODS: The study comprised three groups: group 1, with 26 cases with bisphosphonates-related osteonecrosis of the jaws (BRONJ). Group 2, with 29 patients who had received iBF but without BRONJ. Group 3, with 26 control patients not treated with BF and without oral lesions. We collected unstimulated whole saliva in all groups. A semiquantitative study was performed based on a cytokine array panel. We used the proteome profiler array for the study. We analyzed: Interleukin 1 alpha (IL-1α), interleukin-1 receptor antagonist (IL-1RA), and interleukin 1 beta (IL-1β). RESULTS: We found higher salivary values for all the cytokines studied in group 1 than in group 2 and 3. IL-1β showed the major differences compared with control group. (P < 0.05) CONCLUSIONS: This preliminary study confirms that there are alterations in these interleukins in patients with BRONJ. These results give support to further additional salivary studies on these biomarkers by quantitative measures.

Concepts: Inflammation, Cytokine, Interleukin 1, Cytokines, Sociology, Interleukin 10, Interleukin, Interleukin-1 receptor


Osteoprotegerin (OPG) and receptor activator of nuclear factor κB (RANK) are members of the tumor necrosis factor receptor (TNFR) superfamily that regulate osteoclast formation and function by competing for RANK ligand (RANKL). RANKL promotes osteoclast development through RANK activation, while OPG inhibits this process by sequestering RANKL. For comparison, we solved crystal structures of RANKL with RANK and RANKL with OPG. Complementary biochemical and functional studies reveal that the monomeric cytokine-binding region of OPG binds RANKL with ∼500-fold higher affinity than RANK and inhibits RANKL-stimulated osteoclastogenesis ∼150 times more effectively, in part because the binding cleft of RANKL makes unique contacts with OPG. Several side chains as well as the C-D and D-E loops of RANKL occupy different orientations when bound to OPG versus RANK. High affinity OPG binding requires a 90s loop Phe residue that is mutated in juvenile Paget’s disease. These results suggest cytokine plasticity may help to fine-tune specific tumor necrosis factor (TNF)-family cytokine/receptor pair selectivity.

Concepts: Signal transduction, Cytokines, Osteoclast, Tumor necrosis factor-alpha, RANK, RANKL, Osteoprotegerin, Osteoimmunology


OBJECTIVES: To investigate effects of high-dose ulinastatin on the release of proinflammatory cytokines and lung injury in patients with aortic dissection after cardiopulmonary bypass (CPB) under deep hypothermic circulatory arrest (DHCA). DESIGN: A prospective, randomized and double-blinded study. SETTING: A teaching hospital. PARTICIPANTS: Thirty-six patients with acute type-A aortic dissection undergoing cardiac surgery using CPB under DHCA. INTERVENTIONS: These patients randomly were selected to received total doses of 20,000units/kg of ulinastatin (n = 18) or 0.9% saline (control, n = 18) at 3 time points (after anesthetic induction, before aortic cross-clamp, and after aortic cross-clamp release). MEASUREMENTS AND MAIN RESULTS: Tumor necrosis factor-alpha, interleukin 6, interleukin 8 and polymorphonuclear neutrophil elastase (PMNE) were measured after anesthetic induction (T0), 30 minutes (T1) after aortic cross-clamp, 3 (T2), 6 (T3) and 9 (T4) hours after weaning from CPB. Except for T1, pulmonary data, such as alveolar-arterial oxygen pressure difference, physiologic deadspace, peak inspiratory pressure, plateau pressure, static compliance and dynamic compliance, were obtained at the same time points. Concentrations of cytokines and PMNE were significantly lower in the ulinastatin group than the control group from T1 to T4, and peaked at T2 between the 2 groups. Compared with the pulmonary data of the control group at T2∼T4, postoperative alveolar-arterial oxygen pressure difference, physiologic deadspace, peak inspiratory pressure, and plateau pressure significantly were lower, and static compliance and dynamic compliance higher in the ulinastatin group. Significantly shorter intubation time and intensive care unit stay were found in the ulinastatin group. CONCLUSIONS: High-dose ulinastatin attenuates the elevation of cytokines and PMNE, reduces the pulmonary injury and improves the pulmonary function after CPB under DHCA. Consequently, it shortens the time of intubation and intensive care unit stay.

Concepts: Inflammation, Heart, Cytokines, Interleukin, Aortic dissection, Neutrophil granulocyte, Elastase, Drowning