Eduardo Martinez-Soria
University of Geneva
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Featured researches published by Eduardo Martinez-Soria.
Journal of Immunology | 2002
Nathalie Busso; Alexander So; Veronique Chobaz-Péclat; Carole Morard; Eduardo Martinez-Soria; Dominique Talabot-Ayer; Cem Gabay
Leptin is produced almost exclusively by adipocytes and regulates body weight at the hypothalamic level. In addition, recent studies showed that leptin plays an important role in T lymphocyte responses. To examine the role of leptin in Ag-induced arthritis, the development of joint inflammation was assessed in immunized leptin-deficient mice (ob/ob), +/?, and wild-type mice (+/+) following the administration of methylated BSA into the knees. The results showed that ob/ob mice developed less severe arthritis compared with control mice. The levels of IL-1β and TNF-α mRNA in the synovium of arthritic knees were lower in ob/ob than in +/? mice. In vitro Ag-specific T cell proliferative responses were significantly decreased in ob/ob mice with lower IFN-γ and higher IL-10 production, suggesting a shift toward a Th2-type response in ob/ob mice. The serum levels of anti-methylated BSA Abs of any isotype were significantly decreased in arthritic ob/ob mice compared with controls. Essentially identical results were obtained in db/db mice, which lack the expression of the long isoform of leptin receptor. By RT-PCR, we observed that B lymphocytes express leptin receptor mRNA, indicating that in addition to its effect on the cellular response, leptin may exert a direct effect on B cell function. In conclusion, leptin contributes to the mechanisms of joint inflammation in Ag-induced arthritis by regulating both humoral and cell-mediated immune responses.
American Journal of Pathology | 2005
Maria L. Olleros; Reto Guler; Dominique Vesin; Roumen Parapanov; Gilles Marchal; Eduardo Martinez-Soria; Nadia Corazza; Jean-Claude Pache; Christoph Mueller; Irene Garcia
To study the specific role of transmembrane tumor necrosis factor (TmTNF) in host defense mechanisms against bacillus Calmette-Guerin (BCG) and Mycobacterium tuberculosis infections, we compared the immune responses of TNF/lymphotoxin (LT)-alpha(-/-) mice expressing a noncleavable transgenic TmTNF (TmTNF tg) to those of TNF/LT-alpha(-/-) and wild-type mice. Susceptibility of TNF/LT-alpha(-/-) mice to BCG infection was associated with impaired induction of systemic RANTES but not of monocyte chemoattractant protein 1 (MCP-1), the development of excessive local and systemic Th1-type immune responses, and a substantially reduced inducible nitric oxide synthase (iNOS) activity. Resistance of TmTNF tg mice to BCG infection was associated with efficient activation of iNOS in granulomas and with the regulated release of local and systemic chemokines and Th1-type cytokines. However, M. tuberculosis infection of TmTNF tg mice resulted in longer survival and enhanced resistance compared to TNF/LT-alpha(-/-) mice but higher sensitivity than wild-type mice. TmTNF tg mice exhibited reduced pulmonary iNOS expression and showed an exacerbated cellular infiltration in the lungs despite a modest bacillary content. Our data thus indicate a role for TmTNF in host defense against mycobacteria by contributing to induction and regulation of Th1-type cytokine and chemokine expression leading to development of bactericidal granulomas expressing iNOS, which critically determines susceptibility versus resistance of the host to mycobacterial infections.
Journal of Immunology | 2003
Hirofumi Amano; Eri Amano; Thomas Moll; Dragan Marinkovic; Nabila Ibnou-Zekri; Eduardo Martinez-Soria; Isabelle Semac; Thomas Wirth; Lars Nitschke; Shozo Izui
The accelerated development of systemic lupus erythematosus (SLE) in BXSB male mice is associated with the presence of an as yet unidentified mutant gene, Yaa (Y-linked autoimmune acceleration). In view of a possible role of marginal zone (MZ) B cells in murine SLE, we have explored whether the expression of the Yaa mutation affects the differentiation of MZ and follicular B cells, thereby implicating the acceleration of the disease. In this study, we show that both BXSB and C57BL/6 Yaa mice, including two different substrains of BXSB Yaa males that are protected from SLE, displayed an impaired development of MZ B cells early in life. Studies in bone marrow chimeras revealed that the loss of MZ B cells resulted from a defect intrinsic to B cells expressing the Yaa mutation. The lack of selective expansion of MZ B cells in diseased BXSB Yaa males strongly argues against a major role of MZ B cells in the generation of pathogenic autoantibodies in the BXSB model of SLE. Furthermore, a comparative analysis with mice deficient in CD22 or expressing an IgM anti-trinitrophenyl/DNA transgene suggests that the hyperreactive phenotype of Yaa B cells, as judged by a markedly increased spontaneous IgM secretion, is likely to contribute to the enhanced maturation toward follicular B cells and the block in the MZ B cell generation.
Journal of Clinical Investigation | 2008
Anne Angelillo-Scherrer; Laurent Burnier; Diether Lambrechts; Richard J. Fish; Marc Tjwa; Stephane Plaisance; Rocco Sugamele; M Demol; Eduardo Martinez-Soria; Patrick H. Maxwell; Greg Lemke; Stephen P. Goff; Glenn K. Matsushima; H. Shelton Earp; Marc Chanson; Desire Collen; Shozo Izui; Marc Schapira; Edward M. Conway; Peter Carmeliet
Many patients with anemia fail to respond to treatment with erythropoietin (Epo), a commonly used hormone that stimulates erythroid progenitor production and maturation by human BM or by murine spleen. The protein product of growth arrest-specific gene 6 (Gas6) is important for cell survival across several cell types, but its precise physiological role remains largely enigmatic. Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. In the absence of Gas6, erythroid progenitors and erythroblasts were hyporesponsive to the survival activity of Epo and failed to restore hematocrit levels in response to anemia. In addition, Gas6 may influence erythropoiesis via paracrine erythroblast-independent mechanisms involving macrophages. When mice with acute anemia were treated with Gas6, the protein normalized hematocrit levels without causing undesired erythrocytosis. In a transgenic mouse model of chronic anemia caused by insufficient Epo production, Gas6 synergized with Epo in restoring hematocrit levels. These findings may have implications for the treatment of patients with anemia who fail to adequately respond to Epo.
Journal of Immunology | 2008
Lucie Clementine Baudino; Falk Nimmerjahn; Samareh Azeredo da Silveira; Eduardo Martinez-Soria; Takashi Saito; Michael C. Carroll; Jeffrey V. Ravetch; J. Sjef Verbeek; Shozo Izui
Murine phagocytes express three different activating IgG FcγR: FcγRI is specific for IgG2a; FcγRIII for IgG1, IgG2a, and IgG2b; and FcγRIV for IgG2a and IgG2b. Although the role of FcγRIII in IgG1 and IgG2a anti-RBC-induced autoimmune hemolytic anemia (AIHA) is well documented, the contribution of FcγRI and FcγRIV to the development of IgG2a- and IgG2b-induced anemia has not yet been defined. In the present study, using mice deficient in FcγRI, FcγRIII, and C3, in combination with an FcγRIV-blocking mAb, we assessed the respective roles of these three FcγR in the development of mild and severe AIHA induced by two different doses (50 and 200 μg) of the IgG2a and IgG2b subclasses of the 34-3C anti-RBC monoclonal autoantibody. We observed that the development of mild anemia induced by a low dose of 34-3C IgG2a autoantibody was highly dependent on FcγRIII, while FcγRI and FcγRIV additionally contributed to the development of severe anemia induced by a high dose of this subclass. In contrast, the development of both mild and severe anemia induced by 34-3C IgG2b was dependent on FcγRIII and FcγRIV. Our results indicate differential roles of the three activating FcγR in IgG2a- and IgG2b-mediated AIHA.
Journal of Immunology | 2008
Lucie Clementine Baudino; Yasuro Shinohara; Falk Nimmerjahn; Jun-ichi Furukawa; Munehiro Nakata; Eduardo Martinez-Soria; Franz Petry; Jeffery V. Ravetch; Shin-Ichiro Nishimura; Shozo Izui
Replacement of aspartic acid by alanine at position 265 (D265A) in mouse IgG1 results in a complete loss of interaction between this isotype and low-affinity IgG Fc receptors (FcγRIIB and FcγRIII). However, it has not yet been defined whether the D265A substitution could exhibit similar effects on the interaction with two other FcγR (FcγRI and FcγRIV) and on the activation of complement. To address this question, 34-3C anti-RBC IgG2a and IgG2b switch variants bearing the D265A mutation were generated, and their effector functions and in vivo pathogenicity were compared with those of the respective wild-type Abs. The introduction of the D265A mutation almost completely abolished the binding of 34-3C IgG2a and IgG2b to all four classes of FcγR and the activation of complement. Consequently, these mutants were hardly pathogenic. Although oligosaccharide side chains of these mutants were found to contain higher levels of sialic acids than those of wild-type Abs, the analysis of enzymatically desialylated D265A variants ruled out the possibility that very poor Fc-associated effector functions of the D265A mutants were due to an increased level of the mutant Fc sialylation. Thus, our results demonstrate that aspartic acid at position 265 is a residue critically implicated in triggering the Fc-associated effector functions of IgG, probably by defining a crucial three-dimensional structure of the Fc region.
Journal of Immunology | 2002
Frédéric Lajaunias; Lars Nitschke; Thomas Moll; Eduardo Martinez-Soria; Isabelle Semac; Yves Chicheportiche; R. Michael E. Parkhouse; Shozo Izui
CD22 is a B cell-restricted transmembrane protein that apparently controls signal transduction thresholds initiated through the B cell Ag receptor (BCR) in response to Ag. However, it is still poorly understood how the expression of CD22 is regulated in B cells after their activation. Here we show that the expression levels of CD22 in conventional B-2 cells are markedly down-regulated after cross-linking of BCR with anti-IgM mAb but are up-regulated after stimulation with LPS, anti-CD40 mAb, or IL-4. In contrast, treatment with anti-IgM mAb barely modulated the expression levels of CD22 in CD5+ B-1 cells, consistent with a weak Ca2+ response in anti-IgM-treated CD5+ B-1 cells. Moreover, in CD22-deficient mice, anti-IgM treatment did not trigger enhanced Ca2+ influx in CD5+ B-1 cells, unlike CD22-deficient splenic B-2 cells, suggesting a relatively limited role of CD22 in BCR signaling in B-1 cells. In contrast, CD22 levels were markedly down-regulated on wild-type B-1 cells in response to LPS or unmethylated CpG-containing oligodeoxynucleotides. These data indicate that the expression and function of CD22 are differentially regulated in B-1 and conventional B-2 cells, which are apparently implicated in innate and adaptive immunity, respectively.
Journal of Immunology | 2005
Thomas Moll; Eduardo Martinez-Soria; Marie-Laure Santiago-Raber; Hirofumi Amano; Maria Pihlgren-Bosch; Dragan Marinkovic; Shozo Izui
An as-yet-unidentified mutation, Y-linked autoimmune acceleration (Yaa), is responsible for the accelerated development of lupus-like autoimmune syndrome in mice. In view of a possible role for Yaa as a positive regulator of BCR signaling, we have explored whether the expression of the Yaa mutation affects the development and activation of transgenic autoreactive B cells expressing either 4C8 IgM anti-RBC or Sp6 IgM anti-DNA. In this study, we show that the expression of the Yaa mutation induced a lethal form of autoimmune hemolytic anemia in 4C8 transgenic C57BL/6 mice, likely as a result of activation of 4C8 anti-RBC autoreactive B cells early in life. This was further supported, although indirectly, by increased T cell-independent IgM production in spleens of nontransgenic C57BL/6 mice bearing the Yaa mutation. In contrast, Yaa failed to induce activation of Sp6 anti-DNA autoreactive B cells, consistent with a lack of increased IgM anti-DNA production in nontransgenic C57BL/6 Yaa mice. Our results suggest that Yaa can activate autoreactive B cells in a BCR-dependent manner, related to differences in the form and nature of autoantigens.
Immunology | 2007
Maria L. Olleros; Dominique Vesin; Eduardo Martinez-Soria; Cindy Allenbach; Fabienne Tacchini-Cottier; Jean-Claude Pache; Gilles Marchal; Jubayer Rahman; Carmen Fernández; Shozo Izui; Irene Garcia
Interleukin (IL)‐12p40, a subunit of IL‐12p70 and IL‐23, has previously been shown to inhibit IL‐12p70 activity and interferon‐γ (IFN‐γ) production. However, recent evidence has suggested that the role of IL‐12p40 is more complex. To study the contribution of IL‐12p40 to immune responses against mycobacterial infections, we have used transgenic (tg) mice overexpressing IL‐12p40 under the control of a major histocompatibility complex‐II promoter. The IL‐12p40 transgene was expressed during steady state at concentrations of 129 ± 25 ng/ml of serum and 75 ± 13 ng per spleen, while endogenous IL‐12p40 was hardly detectable in control littermates. Bacille Calmette–Guérin (BCG) infection strongly induced the expression of IL‐12p40 transgene in infected organs, and IL‐12p40 monomeric and dimeric forms were identified in spleen of IL‐12p40 tg mice. Excessive production of IL‐12p40 resulted in a 14‐fold increase in IL‐12p70 serum levels in tg mice versus non‐transgenic mice. IL‐23 was also strongly elevated in the serum and spleens of IL‐12p40 tg mice through BCG infection. While IFN‐γ and tumour necrosis factor protein levels were similar in IL‐12p40 tg and non‐transgenic mice, Th2 type immune responses were reduced in IL‐12p40 tg mice. The number of BCG granulomas and macrophage expressing inducible nitric oxide synthase were similar in IL‐12p40 tg and non‐transgenic mice. IL‐12p40 tg mice were as resistant as non‐transgenic mice to BCG and Mycobacterium tuberculosis infections as they could efficiently control bacillary growth. These data show that high amounts of IL‐12p40 promotes IL‐12p70 and IL‐23 formation, but that does not affect T helper 1 type immune responses and granuloma function, thus leading to normal mycobacterial clearance in infected organs.
Journal of Immunology | 2004
Eduardo Martinez-Soria; Nabila Ibnou-Zekri; Masahiro Iwamoto; Marie-Laure Santiago-Raber; Shuichi Kikuchi; Marie Kosco-Vilbois; Shozo Izui
A high level expression of the Ead transgene encoding the I-E α-chain is highly effective in the suppression of lupus autoantibody production in mice. To explore the possible modulation of the Ag-presenting capacity of B cells as a result of the transgene expression, we assessed the ability of the transgenic B cells to activate Ag-specific T cells in vitro. By using four different model Ag-MHC class II combinations, this analysis revealed that a high transgene expression in B cells markedly inhibits the activation of T cells in an epitope-dependent manner, without modulation of the I-E expression. The transgene-mediated suppression of T cell responses is likely to be related to the relative affinity of peptides derived from transgenic I-E α-chains (Eα peptides) vs antigenic peptides to individual class II molecules. Our results support a model of autoimmunity prevention based on competition for Ag presentation, in which the generation of large amounts of Eα peptides with high affinity to I-A molecules decreases the use of I-A for presentation of pathogenic self-peptides by B cells, thereby preventing excessive activation of autoreactive T and B cells.