Behavioral, Hormonal, Inflammatory, and Metabolic Effects Associated with FGF21-Pathway Activation in an ALS Mouse Model.

In amyotrophic lateral sclerosis (ALS), motor neuron degeneration occurs simultaneously with systemic metabolic dysfunction and neuro-inflammation. The fibroblast growth factor 21 (FGF21) plays an important role in the regulation of both phenomena and is a major hormone of energetic homeostasis. In this study, we aimed to determine the relevance of FGF21 pathway stimulation in a male mouse model of ALS (mutated SOD1-G93A mice) by using a pharmacological agonist of FGF21, R1Mab1. Mice (SOD1-WT and mutant SOD1-G93A) were treated with R1Mab1 or vehicle. Longitudinal data about clinical status (motor function, body weight) and biological parameters (including hormonal, immunological, and metabolomics profiles) were collected from the first symptoms to euthanasia at week 20. Multivariate models were performed to identify the main parameters associated with R1Mab1 treatment and to link them with clinical status, and metabolic pathways involving the discriminant metabolites were also determined. A beneficial clinical effect of R1Mab1 was revealed on slow rotarod (p = 0.032), despite a significant decrease in body weight of ALS mice (p < 0.001). We observed a decrease in serum TNF-α, MCP-1, and insulin levels (p = 0.0059, p = 0.003, and p = 0.01, respectively). At 16 weeks, metabolomics analyses revealed a clear discrimination (CV-ANOVA = 0.0086) according to the treatment and the most discriminant pathways, including sphingolipid metabolism, butanoate metabolism, pantothenate and CoA biosynthesis, and the metabolism of amino acids like tyrosine, arginine, proline, glycine, serine, alanine, aspartate, and glutamate. Mice treated with R1Mab1 had mildly higher performance on slow rotarod despite a decrease on body weight and could be linked with the anti-inflammatory effect of R1Mab1. These results indicate that FGF21 pathway is an interesting target in ALS, with a slight improvement in motor function combined with metabolic and anti-inflammatory effects.

Liver fibrosis is associated with cutaneous inflammation in the imiquimod-induced murine model of psoriasiform dermatitis.

BACKGROUND: Psoriasis exhibits several extracutaneous manifestations. Little is known about hepatic parameters specifically associated with psoriasis. OBJECTIVES: To study whether psoriasiform dermatitis is associated with liver injury. METHODS: We studied liver parameters of inflammation and fibrosis in a murine model of psoriasiform dermatitis induced by topical application of imiquimod for 9 weeks. RESULTS: Topical treatment with imiquimod induced a form of psoriasiform dermatitis reminiscent of the human disorder, characterized by thickened and scaly skin, psoriasiform epidermal hyperplasia, altered keratinocyte differentiation and cutaneous overexpression of interleukin-17A. Mice with dermatitis displayed hepatitis, as shown by elevation of plasma transaminase levels, as well as portal and periportal hepatitis, characterized by T-lymphocyte (CD3ε+ ) and polymorphonuclear cell (Gr1+ ) infiltrates. The hepatitis progressed towards liver fibrogenesis, as shown by excessive Sirius red staining, which is consistent with the expression of α-smooth muscle actin by hepatic stellate cells. CONCLUSIONS: These results indicate that liver inflammation and fibrosis are associated with experimental psoriasiform dermatitis. Our results suggest that psoriatic inflammation may be associated with specific liver injury.

Distinct expression of interleukin (IL)-36α, ß and γ, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn's disease.

Interleukin (IL)-36α, IL-36ß and IL-36γ are expressed highly in skin and are involved in the pathogenesis of psoriasis, while the antagonists IL-36Ra or IL-38, another potential IL-36 inhibitor, limit uncontrolled inflammation. The expression and role of IL-36 cytokines in rheumatoid arthritis (RA) and Crohn's disease (CD) is currently debated. Here, we observed that during imiquimod-induced mouse skin inflammation and in human psoriasis, expression of IL-36α, γ and IL-36Ra, but not IL-36ß and IL-38 mRNA, was induced and correlated with IL-1ß and T helper type 17 (Th17) cytokines (IL-17A, IL-22, IL-23, CCL20). In mice with collagen-induced arthritis and in the synovium of patients with RA, IL-36α, ß, γ, IL-36Ra and IL-38 were all elevated and correlated with IL-1ß, CCL3, CCL4 and macrophage colony-stimulating factor (M-CSF), but not with Th17 cytokines. In the colon of mice with dextran sulphate sodium-induced colitis and in patients with CD, only IL-36α, γ and IL-38 were induced at relatively low levels and correlated with IL-1ß and IL-17A. We suggest that only a minor subgroup of patients with RA (17-29%) or CD (25%) had an elevated IL-36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By immunohistochemistry, IL-36 cytokines were produced by various cell types in skin, synovium and colonic mucosa such as keratinocytes, CD68⁺ macrophages, dendritic/Langerhans cells and CD79α⁺ plasma cells. In primary cultures of monocytes or inflammatory macrophages (M1), IL-36ß and IL-36Ra were produced constitutively, but IL-36α, γ and IL-38 were produced after lipopolysaccharide stimulation. These distinct expression profiles may help to explain why only subgroups of RA and CD patients have a potentially elevated IL-36 agonists/antagonists ratio.

Increased immunoglobulin A in alcoholic liver cirrhosis: exploring the response of B cells to Toll-like receptor 9 activation.

Alcoholic liver cirrhosis (ALC) is characterized by increased circulating levels of immunoglobulins (Igs). ALC patients undergo bacterial translocation evidenced by the presence of bacterial DNA in peripheral blood. Bacterial pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS), peptidoglycan (PGN) and unmethylated cytosine-guanine dinucleotide (CpG) DNA are ligands of Toll-like receptor (TLR)-4, TLR-2 and TLR-9, respectively. Although TLR activation results generally in the secretion of proinflammatory cytokines, activation of B cells through TLR-7 or TLR-9 is involved in their maturation and Ig synthesis. The aim of the present study was to assess Ig synthesis by ALC B cells under PAMP activation in order to evaluate the possible involvement of TLR pathways in the increased Ig levels, and especially the hyper-IgA observed in ALC. CpG, in combination with interleukin (IL)-10 or IL-21, enhanced IgA, IgG and IgM synthesis by healthy donor (HD) PBMCs, but had only a weak effect on ALC PBMCs. Relative CpG-induced IgA production by purified ALC B cells was less important when compared to HD B cells, in accordance with the lower TLR-9 expression on ALC B cells compared to HD B cells, but the absolute IgA production by CpG-activated B cells was enhanced significantly for ALC when compared to HD, in agreement with their intrinsic ability to produce spontaneously more IgA than HD. LPS and PGN had no direct activity on B cells, whereas R848 also enhanced Ig synthesis, as reported recently. Taken together, these results suggest that TLR priming of B cells could account for the hyperimmunoglobulinaemia observed in ALC patients.

Rituximab for prevention of delayed hemolytic transfusion reaction in sickle cell disease.

Delayed hemolytic transfusion reaction (DHTR), a life-threatening transfusion complication in sickle cell disease (SCD), is characterized by a marked hemoglobin drop with destruction of both transfused and autologous red blood cells (RBCs) and exacerbation of SCD symptoms. One mechanism of RBCs destruction is auto-antibody production secondary to transfusion. As rituximab specifically targets circulating B cells, we thought that it could be beneficial in preventing this immune-mediated transfusion complication. We report the case of a SCD patient who previously experienced DHTR with auto-antibodies and who needed a new transfusion. DHTR recurrence was successfully prevented by rituximab administration prior transfusion, supporting the safe use of rituximab to prevent DHTR in SCD patients as a second line approach when other measures failed.

A role for T cell-derived interleukin 22 in psoriatic skin inflammation.

Interleukin (IL)-22 is a T cell-derived cytokine that has been reported recently to induce cutaneous inflammation in an experimental murine model of psoriasis, and to induce in vitro an inflammatory-like phenotype. In the present study, we assessed the presence of IL-22 and the IL-22 receptor 1 (IL-22R1) in skin lesions, skin-derived T cells, as well as IL-22 levels in sera from patients with psoriasis. IL-22R1 and IL-10R2 transcripts are expressed at a similar level in psoriatic and healthy skin. In contrast, IL-22 mRNA expression was up-regulated in psoriatic skin lesions compared to normal skin, whereas IL-22 mRNA levels in peripheral blood mononuclear cells from psoriatic patients and normal subjects were similar. Circulating IL-22 levels were significantly higher in psoriatic patients than in normal subjects. T cells isolated from psoriatic skin produced higher levels of IL-22 in comparison to peripheral T cells isolated from the same patients. IL-10 was expressed at similar levels in skin biopsies and peripheral blood mononuclear cells of psoriatic patients and normal subjects. Finally, we show here that supernatants of lesional psoriatic skin-infiltrating T cells induce an inflammatory response by normal human epidermal keratinocytes, resembling that observed in psoriatic lesions. Taken together, the results reported in this study indicate that IL-22 is a cytokine produced by skin-infiltrating lymphocytes that is potentially involved in initiation and/or maintenance of the pathogenesis of psoriasis.

[Value of systematic biological markers of inflammation for the prognosis at 12 months of patients undergoing programmed coronary angioplasty]. / Intérêt du dosage de marqueurs systémiques de l'inflammation dans l'évalualion pronostique à 12 mois de patients traités par angioplastie coronaire programmée.

Value of systematic dosage of biological markers of inflammation for the prognosis at 12 months of patients undergoing programmed coronary angioplasty Systematic dosage of proteins of inflammation has been suggested for assessing the prognosis of athero-thrombotic diseases. The authors undertook a study of plasma C-reactive protein (CRP) and interleukin 6 (IL-6) for evaluating the prognosis of patients undergoing programmed coronary angioplasty. A prospective monocentric study of 117 patients (65 +/- 8 years) was divided into a control group of 28 patients undergoing coronary angiography (Group 1) and 89 patients undergoing programmed coronary angioplasty (Group 2). Serum IL-6 and CRP levels were measured before arterial puncture and at H12 and H24 after coronary catheterisation. The follow-up period was 12 months. The angioplasty did not significantly increase CRP and IL-6 concentrations compared with coronary angiography. Twenty patients (Group 2) (22%) suffered a cardiovascular event in the 12 months' follow-up. These patients had significantly higher CRP levels at H0, H12 and H24 after coronary angioplasty than those who had uncomplicated outcomes. This was not observed for IL-6 concentrations because of the wide dispersion of the results obtained. Increased CRP concentrations between H0 and H24 was also a good predictive factor independently of high basal CRP levels potentially due to other causes than atheroma. Coronary angioplasty is associated with increased CRP at H0, H12 and H24. These values are correlated with the risk of future events at 6 and 12 months. This information is easily obtained and should help management of these patients.

Immunoglobulin D enhances interleukin-6 release from the KU812 human prebasophil cell line.

Despite the role of secreted immunoglobulin D (IgD) remains still largely unknown, previous studies have suggested that secreted IgD could induce basophils degranulation in some allergic asthma patients. In the present study we have searched direct evidence of the action of IgD on KU812 cells, generally classified as an immature basophilic cell line. We analyzed by flow cytometry the capacity of IgD, purified from IgD myeloma sera, to bind KU812 cells. Biotinylated monomeric IgD (mIgD) and biotinylated oligomeric IgD (oIgD) could bind KU812 cells. Blocking experiments with others immunoglobulin isotypes showed that KU812 cells expressed an unspecific receptor for IgD. However, oIgD but not mIgD enhances the release of interleukin-6 (IL-6) from KU812 cells. On the other hand, mIgD and oIgD failed to induce histamine release from KU812 cells or from cord blood derived basophils. Since IL-6 is known to induce basophil differentiation, we proposed that IgD could be implicated in allergic disorders by stimulating IL-6 release by prebasophil cells, then IL-6 could further induce an autocrine maturation of the cells.

Survival prognostic value of serum interleukin-6 level in very old people.

OBJECTIVE: To determine the survival prognostic value of serum interleukin-6 level in very old people. DESIGN: Prospective 12-month clinical survey in a long term ward and in a day care hospital. SETTING: A long-term ward and a day care hospital for very old and dependent people, located in Poitiers (France). PARTICIPANTS: A cohort of 115 old people [Range 64-101], either in a long-term ward (n=71) or in day care hospital (n=44). MEASUREMENTS: Patients were checked for different nutritional parameters and the Interleukin-6 level in the serum at baseline and patients were followed up for one year. RESULTS: A high level of interleukin-6 (Il-6) is associated with increased Prognostic Inflammatory and Nutritional Index (PINI) value, serum CRP thereby demonstrating the inflammatory role of this molecule. It is also associated with an increased risk of death. Using a survival regression model, a high Il-6 serum level observed at the beginning of the study is a bad prognostic indicator, with other biological or nutritional parameters having no significant influence. CONCLUSION: A high level of Interleukin-6 may be a better marker of prognosis than an increased PINI score.

[Systemic markers of inflammation after coronary angioplasty]. / Marqueurs systémiques de l'inflammation après angioplastie coronaire.

UNLABELLED: THE RISK OF RESTENOSIS: Coronary angioplasty is an effective treatment of stable and instable coronary disease and its principle limitation, despite technical progress, remains restenosis. In instable angina, the physiopathologic and prognostic role of inflammation proteins is well documented. THE ROLE OF THE C-REACTIVE PROTEIN (CRP): Is a validated risk factor for patients presenting with heart failure, whether instable or stable angina and in the general population. This risk factor is distinct from tobacco abuse, hypercholesterolemia or diabetes. In all the series studied to date, the frequency of restenosis following coronary angioplasty increases when CRP values are high prior to surgery and continue to rise up to the 48th or 72nd hour. PERSPECTIVES: New therapeutic measures widen the possibilities of mechanical strategies (angioplasty with or without stent) and treatment of inflammatory mechanisms in the atheromatous plaques (statines, brachytherapy or "covered" stents).

Interleukine-6 (IL-6) synthesis and gp130 expression by human pericardium.

Growing evidence shows that cytokines of the IL-6 family play an important regulatory role in heart physiology such as inducing cardiomyocyte hypertrophy. The purpose of this study was to see if IL-6 and its soluble receptors (sIL-6R and sgp130) could be detected in pericardial fluids, and to see if they are produced by the pericardium. We report that human pericardial fluid from patients with coronary pathologies contained IL-6, sIL-6R, and sgp130. However, the levels present in sera and pericardial fluid did not correlate, which suggests local production. This observation was confirmed by in vitro studies demonstrating massive IL-6 production by cultured pericardial samples, which could be strongly inhibited by methylprednisolone. RT-PCR studies revealed that IL-6 was weakly expressed in fresh tissues and strongly induced after culture. In situ hybridisation and immunohistochemical analysis showed that IL-6 and gp130 were mainly present in mesothelial cells. sIL-6R and sgp130 were also produced by pericardium in vitro, and their synthesis was upregulated by methylprednisolone. Taken together, these results demonstrate that IL-6 is present in pericardial fluid and that its presence could be due to synthesis by pericardial tissue. In vitro studies suggest that IL-6 production by this tissue could be strongly induced and regulated. A potential paracrine role of these factors in cardiomyocyte functions in normal or pathological conditions is discussed.

Familial Mediterranean Fever: association of elevated IgD plasma levels with specific MEFV mutations.

Familial Mediterranean Fever (FMF) is a recessively inherited disorder, characterized by episodic fever, abdominal and arthritic pain, as well as other forms of inflammation. Some FMF patients present higher IgD serum levels, and it is not yet known whether such an elevation is related to specific genotypes or correlated with a specific phenotype. In order to evaluate the association between known FMF-related mutations and IgD levels in confirmed patients, as well as the correlation between those levels and the presence of specific clinical signs, genotypic analysis and IgD plasma measurements were performed for 148 Lebanese and Jordanian FMF patients. Most common mutational patterns were M694V heterozygotes (19%) and homozygotes (17%), and V726A heterozygotes (18%) and homozygotes (5%), with an additional 11% combining both mutations. Twenty-one patients had higher IgD levels (superior to 100 microg/ml). The risk for higher IgD levels was significantly associated with M694V homozygote status (OR = 6.25) but not with heterozygotic one (OR = 1). Similarly, the risk for higher IgD was also found with V726A homozygotes (OR = 2.2) but not with heterozygotes (OR = 1.05). The use of colchicine was not statistically associated with IgD levels. Clinically, hyper IgD was also found significantly associated with arthritis (OR = 18). Thus, homozygotic status for M694V, and to a lesser extent V726A, is associated with increased risk for higher IgD plasma levels, regardless of colchicine use. Elevated IgD plasma levels are also correlated with the severity of FMF manifestations, and especially with arthritis.

Correlation between IL-8 induction, cagA status and vacA genotypes in 153 French Helicobacter pylori isolates.

The polymorphism of clinical presentations associated with Helicobacter pylori infection is potentially due to differences in the virulence of individual strains. H. pylori virulence has been associated with the ability to induce secretion of interleukin-8 (IL-8), the vacA genotypes, and the cagA status. The aim of this study was to determine the virulence profiles of 153 French H. pylori isolates on the basis of vacA genotypes, cagA status, and IL-8 induction ability. A total of 153 H. pylori isolates from patients with chronic gastritis (n = 74) or gastro-duodenal ulcers (n = 79) was examined for vacA genotypes and cagA status by polymerase chain reaction (PCR) and dot blot, and for their ability to induce IL-8 secretion by HEp-2 cells. The prevalence of vacA genotypes was: s1/m1 44.3%, s1/m2 24.9%, and s2/m2 23.5%. The cagA gene was present in 64% of the strains. IL-8 secretion was induced by 58.7% of the isolates. The presence of the cagA gene was significantly correlated with the s1/m1 vacA genotype and with the induction of IL-8. Thirty-four strains were atypical (cagA-positive/IL-8 noninducer or cagA-negative/IL-8 inducer). vacA genotypes, cagA status, and IL-8 induction ability are not correlated with the presence or absence of ulcer. The cagA status is not sufficient to predict the proinflammatory ability of H. pylori.

Circulating soluble gp130, soluble IL-6R, and IL-6 in patients undergoing cardiac surgery, with or without extracorporeal circulation.

OBJECTIVE: Soluble forms of interleukin-6 (IL-6) receptors are known to modulate biological activities of IL-6. The purpose of the study was to measure circulating levels of IL-6, sIL-6R and sgp130 in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass (CPB group) or without CPB (non-CPB group). METHODS: The CPB group included 19 patients and the non-CPB group 12 patients. Sera levels of IL-6, sIL-6R and sgp130 were measured by specific ELISA at the beginning of the operation (T0, 15 min before skin incision) and 6 h later (T1). RESULTS: IL-6 sera levels were respectively 9+/-20 pg/ml (mean+/-SD) and 13+/-19 pg/ml at T0 and reached 340+/-250 pg/ml and 965+/-1060 pg/ml at T1 in CPB and non-CPB groups, indicating a significant increase from T0 to T1, but no differences between the two groups. When compared to T0 values, sgp130 levels decreased in both groups (respectively 105+/-37 and 115+/-35 ng/ml at T0 for CPB and non-CPB groups, and 72+/-25 and 84+/-29 ng/ml at T1) while we are not able to detect differences between the groups. Whatever the group or the time, sIL-6R concentrations remained unchanged. CONCLUSIONS: We showed that the increase of IL-6 after artery bypass grafting was similar between patients operated with CPB or without CPB. We conclude that the main inductor of IL-6 release is linked to surgical trauma rather than a reaction to CPB. Since it is known that gp130 inhibits IL-6-biological activities, we suggest that the decrease of sgp130 sera levels could further enhance the inflammatory effects of IL-6 in cardiac surgery.

Structural and functional properties of membrane and secreted IgD.

More than 35 years ago, study of an unknown immunoglobulin (Ig) in the serum from a myeloma patient led to the discovery of IgD. Subsequently, the finding that it also exists as a membrane-bound Ig stimulated a large number of studies during the 70s. Then, the interest on IgD shrank, largely because of the lack of known function of secretory IgD (secIgD) and of a stagnating knowledge of the functions of surface IgD. In the recent years, very significant advances followed the tremendous accumulation of data on the physiology of the B cell receptor, of which IgD is the major component, on the role of secIgD in normal and diseased individuals. This review, which is focused on human IgD but integrates data in the mouse and other species when needed, summarizes present data on the structure, synthesis and functions of both membrane and secIgD, IgD receptors and the involvement of IgD in various diseases, especially the hyperIgD syndrome.

T(h)2 cytokine dependence of IgD production by normal human B cells.

IgD is a minor component of serum Ig and the control of IgD secretion is virtually unknown. We measured concentrations of IgD (and IgE and IgM as controls) in culture supernatants of peripheral blood mononuclear cells (PBMC) from 60 normal donors as well as mononuclear cells from 10 tonsils following culture in the absence or presence of CD40 mAb and cytokines. Low levels of IgD were measured in cultures of PBMC, either unstimulated or stimulated by anti-CD40 antibodies. IL-4 and IL-10 significantly increased IgD production by CD40 mAb-stimulated cells in the majority of normal subjects studied, whereas in a limited number of individuals, spontaneous IgD production was either low or high, but with no increase upon stimulation. Spontaneous IgD production by tonsil-derived mononuclear cells was higher than by PBMC and increased after CD40 stimulation and even more in the presence of IL-10, but not IL-4. IL-2 and IFN-gamma exerted a dose-dependent inhibition on spontaneous as well as CD40- and cytokine-induced IgD production by PBMC, but not by tonsil mononuclear cells. Activation by IL-4 of CD40-stimulated purified B cells from tonsil and PBMC, and by IL-10 of tonsil B cells increased IgD production, whereas IL-2 and IFN-gamma had no detectable inhibitory effect. This suggests that accessory cells indirectly regulate IgD synthesis. IgD production induced in PBMC by IL-4 or IL-10 appeared to result from an active synthesis, and correlated with an increase in the number of IgD-containing plasma cells as demonstrated by immunofluorescence and increased expression of secreted IgD transcripts. These findings suggest that IgD production by normal peripheral blood human B cells is regulated positively by T(h)2 cytokines and negatively by T(h)1 cytokines.