Comparability of nonlinear measures of heart rate variability between long- and short-term electrocardiographic recordings.
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Adult↗
Biomedical subjects
J Couderc
Publications and source records attributed to J Couderc.
Production of stromal cell-derived factor 1 by mesothelial cells and effects of this chemokine on peritoneal B lymphocytes.
B1a lymphocytes accumulate and proliferate in the peritoneal cavity. Stromal cell-derived factor 1 (SDF-1) is a chemotactic and growth promoting factor for B cell precursors. It is required for fetal liver B cell lymphopoiesis, which generates mostly B1a lymphocytes. Using immunohistochemistry with an anti-SDF-1 monoclonal antibody, we found that SDF-1 was produced by peritoneal mesothelial cells in adult mice. Peritoneal B1a lymphocytes expressed a functional SDF-1 receptor, as shown by actin polymerization experiments. In vitro, SDF-1 stimulated migration, proliferation of a minority of peritoneal B1a lymphocytes, and prevented apoptosis in a large fraction of cells. B1a cells migrating in response to SDF-1 were largely enriched in the CD5(high)CD43(high)B220(-)CD1d(-) subpopulation. In vivo, neutralization of SDF-1 for 3 weeks significantly decreased the number of peritoneal B1 cells. SDF-1 also acted on peritoneal B2 cells. These findings show that after the cessation of B cell lymphopoiesis in the liver, around birth, the persistence of B1a cells remains SDF-1 dependent, and that SDF-1 production by mesothelial cells plays a role in the peritoneal location of B1a cells. Thus, the role of mesothelial cells for B1a cells in adults may be similar to that of SDF-1-producing biliary ductal plate cells in the fetus, and to that of bone marrow stromal cells for B2 cell precursors.
Animals↗
Prevention of autoimmune attack by targeting specific T-cell receptors in a severe combined immunodeficiency mouse model of myasthenia gravis.
Myasthenia gravis (MG) is an autoimmune disease targeting the skeletal muscle acetylcholine receptor. We have previously demonstrated a selection bias of CD4+ T cells expressing the Vbeta5.1 T-cell receptor gene in the thymus of HLA-DR3 patients with MG. To evaluate the pathogenicity of these cells, severe combined immunodeficiency mice engrafted with MG thymic lymphocytes were treated with anti-Vbeta5.1 antibody. Signs of pathogenicity (eg, acetylcholine receptor loss and complement deposits at the muscle end plates of chimeric mice) were prevented in anti-Vbeta5.1-treated severe combined immunodeficiency chimeras. Pathogenicity was mediated by autoantibodies against acetylcholine receptor. Thymic cells depleted of Vbeta5.1-positive cells in vitro before cell transfer were nonpathogenic, indicating that Vbeta5.1-positive cells are involved in the production of pathogenic autoantibodies. Acetylcholine receptor loss was prevented by Vbeta5.1 targeting in HLA-DR3 patients only, demonstrating specificity for HLA-DR3-peptide complexes. The action of the anti-Vbeta5.1 antibody involved both the in vivo depletion of Vbeta5.1-expressing cells and an increase in the interferon-gamma/interleukin-4 ratio, pointing to an immune deviation-based mechanism. This demonstration that a selective and specific T-helper cell population is involved in controlling pathogenic autoantibodies in MG holds promise for the treatment of MG.
Adolescent↗
Human interleukin-6 is in vivo an autocrine growth factor for human herpesvirus-8-infected malignant B lymphocytes.
Human interleukin-6 (hIL-6) acts as a growth factor in several human B lymphoid cancers. As human herpesvirus-8 (HHV-8) encodes for a viral IL-6 (vIL-6), the viral cytokine may be responsible for several manifestations of HHV-8-related disorders. Using an anti-hIL-6 mAb (B-E8) which does not recognize vIL-6, we investigated the involvement of the human cytokine in the proliferation of HHV-8-positive primary effusion lymphoma (PEL) cells. In vitro, 5/5 PEL cell lines produced hIL-6 (4 to 1,200 pg/ml). The EBV- HHV-8+ cell line (BCBL-1) was adapted to grow in SCID mice. hIL-6 was detected in the serum of mice with grafts, as well as human soluble CD138 (sCD138) and human IL-10 (hIL-10). The serum level of these mediators increased with tumor progression. The effect of treatment with the B-E8 mAb on the tumor progression and survival was evaluated. This treatment significantly slowed down the tumor development: on day 54, there were more mice with low levels of sCD138 and hIL-10 in the treated group than in controls (p = 0.03 and 0.02, respectively); treatment also delayed death (median date of death was day 65 for control mice and day 84 for anti-hIL-6 mAb-treated mice; p < 0.02). Thus, hIL-6 is expressed in addition to vIL-6 in HHV-8-positive malignant B lymphocytes, and the viral cytokine does not totally substitute for human IL-6 in promoting tumor progression.
Animals↗
[Interleukin 10: a key cytokine in disseminated lupus erythematosus].
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Animals↗
Dysregulation of interleukin-10 production in relatives of patients with systemic lupus erythematosus.
OBJECTIVE: To evaluate interleukin-10 (IL-10) production in relatives of patients with systemic lupus erythematosus (SLE). METHODS: Production of IL-10 was evaluated in 13 families in which several members had SLE. The constitutive IL-10 production in SLE patients (n = 16) was compared with that in healthy members of these multiplex families (n = 70), in 30 SLE patients who had no relatives with SLE, and in 46 healthy unrelated controls. RESULTS: The level of IL-10 production did not differ between SLE patients who were members and those who were not members of multiplex families (mean +/- SEM 4,384 +/- 908 pg/ml and 4,709 +/- 560 pg/ml, respectively), but was higher in both groups than in healthy unrelated controls (515 +/- 88 pg/ml). The healthy members of the multiplex families constitutively produced large amounts of IL-10 (3,080 +/- 311 pg/ml; P < 0.001 compared with healthy unrelated controls). This high IL-10 production was independent of age and sex, and was similar in first- and second-degree relatives of SLE patients. The IL-10 was produced both by monocytes and by a subpopulation of B lymphocytes in SLE patients and in their relatives. CONCLUSION: The dysregulation of IL-10 production previously identified in SLE patients is also present in healthy members of families with several cases of SLE, and it may contribute to the immunologic abnormalities affecting relatives of SLE patients.
Age Factors↗
Interactions between H-2 and background genes modulate collagen induced arthritis in high (HI) and low (LI) antibody producer Biozzi mice.
The experimental arthritis (collagen induced arthritis, CIA) induced in mice by heterologous collagen of type II is mainly restricted to the H-2q or H-2r haplotypes. However, data including ours, strongly suggest that CIA is also under non MHC polygenic control. This point has been studied in new sub-strains of high (HI) and low (LI) Biozzi mice made congenic for H-2q and H-2s: the original Biozzi lines HI/H-2q and LI/H-2s and the new HI/H-2s, LI/H-2q congenic mice. 80% of the HI/H-2q mice develop severe chronic inflammatory symptoms with joint deformation and swelling soon after induction of the disease, while 60% of LI/H-2q counterpart develop at a later stage, deformation of joints with no or mild swelling. In the H-2s haplotype, considered to be non or weakly permissive to CIA, 40% of HI/H-2s have strong CIA symptoms; the LI/H-2s being totally refractory. Thus, if MHC products play a crucial role in selecting the arthritogenic epitope of CII; non H-2 genes strongly modulate the severity of experimental arthritis.
Animals↗
Functional differences in the specific B-cell compartment in high or low antibody responder mice.
The role of antigen-presenting cells (APC) in quantitative antibody synthesis regulation was studied in mice genetically selected for high (HI) or low (LI) antibody response. Irradiated spleen cells and enriched specific B cells from HI and LI mice co-isogenic at H-2s locus, were compared for their capacity to present chicken ovalbumin (OVA) to specific T-cell hybridomas. Minor differences were observed between HI and LI mice when three distinct hybridomas were stimulated in the presence of OVA and splenic macrophages APC. These differences were totally abolished when APC were pulsed with OVAxAb complexes. Looking at the B-cell compartment, hybridoma IL-2 responses were similar when TNP primed B cells were pulsed with OVA. However, when OVA was targeted on TNP-specific enriched B cells by pulsing with TNP-OVA, the IL-2 production by the T-cell hybridomas was stronger in the presence of HI B cells than in the presence of LI B cells. These results strongly suggest that an efficient Ag handling/processing by specific B cells is a major component of the high Ab responder status in Biozzi mice.
Animals↗
T helper subset involvement in two high antibody responder lines of mice (Biozzi mice): HI (susceptible) and HII (resistant) to collagen-induced arthritis.
CD4+ T helper cells play a critical role in the chronicity of collagen-induced arthritis (CIA) in mice. The present results focus on the involvement of Th1 and Th2 subsets at the initial stage of the experimental disease in two lines of mice selected for high antibody production: HI that is susceptible, and HII that is resistant to CIA. Both lines are known to be H-2q, display an identical full set of V-beta genes, and mount similar antibody responses to both heterologous and autologous CII. The kinetic analysis of local T cell and anti-bovine CII antibody responses was followed by Elispot assays, the production of interferon-gamma (IFN-gamma) and IgG2a being considered indicative of a Th1 profile, and interleukin-5 (IL-5) as well as IgG1-IgE, of a Th2 profile. The number of IL-5 Elispots is constantly higher in susceptible than in resistant mice. The IFN-gamma production is rather low in HI compared to HII, and besides, preferential help is observed for the Th2-dependent IgG1-IgE isotype-producing B cells in HI, while a switch-over toward IgG2a anti-CII isotype is found in HII. These results suggest that a Th1 preeminence at the onset of the anti-CII response is decisive in the resistance to CIA.
Animals↗
Co-selection of the rare T cell receptor-gamma B haplotype in mouse lines selected for low responsiveness to red blood cell antigens.
T cell receptor (TcR)-gamma haplotype was investigated in seven pairs of murine Biozzi lines selected for low and high antibody (Ab) response to different antigens (Ag). High-responder lines (H) express gamma A or gamma C haplotypes irrespective of the selecting Ag. In contrast, the gamma B haplotype, which is rare in laboratory mouse strains, is found in all low-responder lines (L) to sheep erythrocyte Ag (SE). However, the TcR-gamma B locus might only have a low penetrance in the control of the SE response. Moreover, investigations using LIVA mice, which were selected for low SE response from homozygous gamma A founder parents, indicate that the gamma B haplotype is neither necessary nor sufficient to achieve a low-responder phenotype. The gamma B haplotype might, thus, be co-selected to confer to L mice an improved resistance to bacterial infections mediated by gamma delta T cells compensating the profound and nonspecific immune perturbation associated with the low Ab response.
Animals↗
T-cell compartment involvement in two high antibody responder lines of mice (HI and HII Biozzi mice) respectively susceptible and resistant to collagen-induced arthritis.
The T-cell compartment was investigated in two high antibody responder lines of mice respectively susceptible (HI) and resistant (HII) to chicken collagen (CII)-induced arthritis (CIA). Previous data had shown that both lines were high anti-CII Ab producers, without any TCR V-beta gene defect or membrane expression impairment. The present studies demonstrate that anti-CII proliferation is much lower in HII than in HI. These results are confirmed by the limiting dilution analysis of anti-CII T-precursor frequencies (1/991 in HI and 1/12175 in HII). The percentage of CD8+ T cells is constitutively higher in HII mice, this difference increasing after CII immunization. This finding suggests a suppressive effect accounting for resistance to CIA. However, no restoration of specific response was achieved by in-vivo or in-vitro depletion of CD8+ T cells. T clones specific for Chicken CII could be obtained only from primed HI mice. Four of five clones with CD8+ phenotype proliferated in vitro to native and denatured CII and showed cytotoxic function in an anti-CD3 redirected assay. The CD4+ clone was shown to proliferate on both HI and HII-pulsed APC, which rules out a major CII processing/presentation defect in HII.
Animals↗
Mls-1 and Mls-2 superantigens do not control susceptibility to collagen-induced arthritis in HI and HII mice.
The HI mouse line is sensitive to collagen-induced arthritis (CIA), whereas HII is refractory, although both express the H-2q permissive haplotype. The two lines also share the same T-cell receptor (TcR) gene haplotypes for alpha and beta chains. The distribution of mouse mammary tumour viruses (MMTV), which encode endogenous superantigens (SAg) such as minor leucocyte-stimulating antigens (Mls) known to modulate the available TcR-V beta repertoire, was investigated in the two lines. Mls-1 is present in HI-susceptible mice, while Mls-2 and Mls-2-like SAg are absent in both lines. This suggests that Mls antigens play no significant role in the resistance to CIA. Moreover, HI and HII exhibit close V beta gene usage as assessed by fluorescence staining with 11 V beta-specific monoclonal antibodies (mAb). These results indicate that mechanisms other than clonal deletion based on V beta expression and induced by SAg are involved in the resistance of H-2q-positive mice to experimental arthritis. Yet, a slightly reduced level of V beta 5+ T cells is observed in HII animals which might correlate with the presence of Mtv-6 and Mtv-9 proviruses.
Animals↗
Processing and presentation of ovalbumin in mice genetically selected for antibody response.
Lines of mice selected for high or low antibody production to sheep red blood cells (H-I and L-I) were studied for their ability to process and present ovalbumin to a panel of 12 T-T hybridomas in two different H-2 haplotypes. When H-I and L-I spleen cells were used as antigen-presenting cells, no difference could be observed in the peptide generation by these mice compared to H-2-compatible B.10.Q and B.10.S spleen cells, respectively. Neither normal splenic L-I B-cells nor L-I thioglycolate-induced peritoneal macrophages were defective at presenting native ovalbumin, to six and eight different I-As-restricted T-T hybrids, respectively. Altogether, these results differ from previous findings which had indicated a deficiency in the processing and presentation of antigen by the low line, L-I.
Animals↗
Migration stimulation factor (MStF), from murine B cells, constitutively produced by a T-B hybridoma.
Hybridomas were established between murine spleen B cells and the thymoma cell line BW5147, to purify the migration stimulation factor (MStF), a molecule likely involved in immunosuppression. The parental B cells were from Lo/PHA mice previously shown to produce high levels of MStF after immunization by appropriate (tolerogenic) doses of ovalbumin. Among the positive clones, B9 was selected, since it produced high levels of MStF constitutively, and no immunoglobulin. This clone was shown to contain the genome of the B-cell fusion partner, since one of its L chain genes had undergone a VK-JK rearrangement. Isolation of MStF by size-exclusion chromatography showed 2 major peaks of activity, one of which eluted in a 20-kDa, almost protein-free fraction. This elution is unlikely to correspond to the true molecular mass, since MStF was found not to be a protein. Indeed, MStF was TCA-soluble, thermoresistant, highly hydrophobic and protease-resistant, but activity was abolished by neuraminidase digestion. The possibility of its being a small molecule transported by a protein carrier was also ruled out. These results suggest that MStF is a complex molecule containing both sialic residues and a lipid moiety. Experiments are planned to further investigate the chemical structure of this unusual B-cell factor.
Animals↗
Resistance to collagen-induced arthritis in Biozzi mice is not associated with a defect in autoantibodies to accessible epitopes on cartilage collagen.
In order to understand why most strains of Biozzi mice are unexpectedly either arthritis-resistant, or susceptible, we investigate the autoantibody reactivity against matrix-embedded collagen molecules. We show a close correlation between these tissular and the free collagen antibodies, irrespective of arthritis susceptibility. These results are against an antibody response restricted to hidden non-pathogenic epitopes in the resistant mice.
Animals↗
T-helper functions in lines of mice selected for high or low antibody production (Selection III): modulation by anti-CD4+ monoclonal antibody.
T-helper function was evaluated in mice genetically selected for high (H) or low (L) antibody (Ab) responsiveness to Salmonella flagellar antigen (Ag) (Selection III). In this Selection as opposed to what was demonstrated in Selections I, II and IVA, the interline difference was not proven to be based upon the modification of Ag processing and presentation at macrophage level. CD4+/CD8+ lymph node ratio is similar in HIII and LIII mice, both lines being equally susceptible to in vivo depletion of CD4+ T cells by GK 1-5 monoclonal antibody (mAb) treatment. Nevertheless, the Ab responsiveness of the two lines was differently modulated by GK 1-5 mAb: the inhibition of Ab responses to various Ag required lower mAb doses and was long lasting in LIII as compared to the transient effect of higher mAb doses observed in HIII. LIII mice were also refractory to Salmonella-induced reversion of GK 1-5 mAb inhibition. Moreover, in vitro specific I proliferation was constantly lower in LIII, though its IL-2 production was unexpectedly similar to that of HIII T cells. Results of in vivo and in vitro experiments are thus consistent with a defective response of T-helper cells to immunogenic challenge in LIII mice.
Animals↗
Resistance to collagen-induced arthritis in Biozzi mice is not associated with T cell receptor V beta gene polymorphism.
H-I and H-II high antibody-responder Biozzi mice, which express the H-2q permissive haplotype, were shown to be sensitive and refractory to collagen-induced arthritis, respectively. To assess a possible role of T cell receptor (TcR) V beta gene deletion or polymorphism in the resistance to arthritis in H-II mice, the germinal structure of TcR V beta genes and their expression at the membrane level were compared in both lines. In contrast to H-2q refractory SWR mice, which exhibit a deletion of about 50% of TcR V beta gene segments. H-I and H-II lines have an identical and complete set of V beta genes and exhibit no difference in the average expression of V beta 6, V beta 8 and V beta 11 gene products on T cell surface. These results indicate that mechanisms other than V beta gene deletion or polymorphism can be involved in the resistance of H-2q-positive mice to experimental arthritis.
Animals↗
Differential expression of migration inhibitory and migration stimulatory factors in two lines of mice genetically selected for high or low responsiveness to phytohemagglutinin. 1. Migration stimulatory factor(s) from T and B cells of immune spleen.
Expression of the lymphokine migration inhibition factor in two lines of mice genetically selected for the high (Hi/PHA) or low (Lo/PHA) response of their lymph node cells to phytohemagglutinin was found to be modulated by concomitant expression of migration stimulation factor(s) [MStF(s)]. The expression of both lymphokines was dependent on genetic character and the immunizing dose of antigen. In mice immunized 5 days earlier with 50 micrograms ovalbumin in Freund's complete adjuvant (Ova in FCA immune), migration inhibition factor, assessed with a sensitive photoelectric method, was well expressed by male spleen or lymph node 24-hour culture supernatants of Lo/PHA but Hi/PHA, especially female, expressed marked MStF(s) instead. Immunization with 500 micrograms Ova in FCA markedly enhanced expression of MStF(s) in Lo/PHA but inhibited it in Hi/PHA. MStF(s) of Ova in FCA immune spleens of the two lines were found to derive from both T and B cells, B cell activity being greater. Lo/PHA were by far better expressors of both T- and B-cell-derived MStF(s) as compared to Hi/PHA (p less than 0.01). Spleen cells of mice immunized with FCA alone also expressed MStF(s) but to lesser extent than Ova in FCA immune spleens, expression by Lo/PHA B cells being significantly higher than in Hi/PHA (p less than 0.05). The MStF(s) of Ova in FCA immune spleens was found to be non-immunoglobulin in nature.
Animals↗