Jacques-olivier Pers - Academia.edu (original) (raw)
Papers by Jacques-olivier Pers
Genetics of Rare Autoimmune Diseases, 2019
Oncotarget, 2018
The anti-CD20-specific monoclonal antibody rituximab (RTX), in combination with chemotherapy, is ... more The anti-CD20-specific monoclonal antibody rituximab (RTX), in combination with chemotherapy, is commonly used for primary treatment in chronic lymphocytic leukemia (CLL). However, relapses remain important and activation of the complement pathway is one of the mechanisms by which RTX generates the destruction of B cells directly by complement-dependent cytotoxicity (CDC), or indirectly by antibodydependent cellular phagocytosis. In this study, the RTX capacity to induce CDC was established in 69 untreated CLL patients, this cohort including 34 patients tested before the initiation of RTX-chemotherapy. In vitro CDC-resistance to RTX predicts lower response rates to RTX-chemotherapy and shorter treatment free survival. Furthermore, the predictive value of CDC-resistance was independent from the clinical, cytogenetic and FcγR3A V158F polymorphism status. In contrast, CLL cell resistance to CDC predominates in IGHV unmutated patients and was related to an important α2-6 sialyl transferase activity, which in turn increases cell surface α2-6 hypersialylation. Suspected factors associated with resistance to CDC (CD20, CD55, CD59, factor H, GM1, and sphingomyelin) were not differentially expressed or recruited between the two CLL groups. Altogether, results provide evidence that testing RTX capacity to induce CDC in vitro represents an independent predictive factor of therapeutic effects of RTX, and that α2-6 hypersialylation in CLL cells controls RTX response through the control of the complement pathway. At a time when CLL therapy is moving towards chemo-free treatments, further experiments are required to determine whether performing an initial in vitro assay to appreciate CLL CDC resistance might be useful to select patients.
Revue du Rhumatisme, 2006
l'activation des lymphocytes B et T et l'expression des molécules HLA sont augmentées et les méca... more l'activation des lymphocytes B et T et l'expression des molécules HLA sont augmentées et les mécanismes de réparation et de fibrose sont diminués : SSB est donc mieux présenté par les cellules épithéliales salivaires, ce qui favorise la diversification de la réponse autoanticorps contre SSB chez les patients HLA-DRB1*03.
Revue du Rhumatisme, 2016
International Journal of Molecular Sciences, 2021
Autoimmune disease development depends on multiple factors, including genetic and environmental. ... more Autoimmune disease development depends on multiple factors, including genetic and environmental. Abnormalities such as sialylation levels and/or quality have been recently highlighted. The adjunction of sialic acid at the terminal end of glycoproteins and glycolipids is essential for distinguishing between self and non-self-antigens and the control of pro- or anti-inflammatory immune reactions. In autoimmunity, hyposialylation is responsible for chronic inflammation, the anarchic activation of the immune system and organ lesions. A detailed characterization of this mechanism is a key element for improving the understanding of these diseases and the development of innovative therapies. This review focuses on the impact of sialylation in autoimmunity in order to determine future treatments based on the regulation of hyposialylation.
Rheumatology, 2018
Biological abnormalities associated with B lymphocytes are a hallmark of patients with primary Sj... more Biological abnormalities associated with B lymphocytes are a hallmark of patients with primary Sjögren’s syndrome. Those patients present abnormal distribution of B lymphocytes in peripheral blood and B cells in exocrine glands. B cells produce auto-antibodies, cytokines and present antigens but can also suppressive functions. In this review, we will summarize current knowledge on B cells in primary Sjögren’s syndrome patients, demonstrate their critical role in the immunopathology of the disease and describe the past and current trials targeting B cells.
PloS one, 2015
The goal of this study was to determine how the choice of the primary endpoint influenced sample ... more The goal of this study was to determine how the choice of the primary endpoint influenced sample size estimates in randomised controlled trials (RCTs) of treatments for primary Sjögren's syndrome (pSS). We reviewed all studies evaluating biotechnological therapies in pSS to identify their inclusion criteria and primary endpoints. Then, in a large cohort (ASSESS), we determined the proportion of patients who would be included in RCTs using various inclusion criteria sets. Finally, we used the population of a large randomised therapeutic trial in pSS (TEARS) to assess the impact of various primary objectives and endpoints on estimated sample sizes. These analyses were performed only for the endpoints indicating greater efficacy of rituximab compared to the placebo. We identified 18 studies. The most common inclusion criteria were short disease duration; systemic involvement; high mean visual analogue scale (VAS) scores for dryness, pain, and fatigue; and biological evidence of act...
Revue du Rhumatisme, 2007
Pathologie-biologie, 2000
The CD5 glycoprotein is detectable on a minute fraction of circulating B cells. The number of CD5... more The CD5 glycoprotein is detectable on a minute fraction of circulating B cells. The number of CD5+ B cells (B1 cells) is increased in patients with autoimmune disorders and these cells, similar to those leading to chronic lymphocytic leukemia (CLL), may be induced to produce multispecific autoantibodies. CD5 is associated with the B cell antigen receptor, and the induction of apoptosis depends on the activation state of the cells. Defective regulation of this phenomenon might result in the production of autoantibodies and/or the development of CD5+ B cell tumors. We have proposed that there may be different B1 populations in man, which depend on the consequence of CD5 ligation on their surface: 'natural' or 'classical' CD5+ B cells, and 'induced' CD5+ B cells.
Oral diseases, 2014
The autoimmune exocrinopathy Sjögren's syndrome (SS) is characterized by mononuclear cell (MN... more The autoimmune exocrinopathy Sjögren's syndrome (SS) is characterized by mononuclear cell (MNC) infiltrates of exocrine glands and overactivity of B lymphocytes. Although T cells have long been perceived as the prime effectors, increasing evidence indicates that the key role is rather served by B cells. Among related abnormalities are rheumatoid factor (RF), anti-SSA/Ro, and anti-SSB/La antibodies (Ab). Also, supporting this view is our finding of an increase in the number of circulating naïve mature B (Bm) cells, with a reciprocal decrease in that of memory B cells. Furthermore, a ratio of Bm2-plus-Bm2' cells to early Bm5-plus-late Bm5 above 5 is diagnostic. This variation partly reflects the migration of active memory B cells into the exocrine glands of the patients, as well as into their skin. More recently, the B-cell-activating factor of the TNF family (BAFF) has been endorsed with a pivotal role in B-cell survival and hence implicated in the pathogenesis of autoimmunit...
La Revue de médecine interne / fondée ... par la Société nationale francaise de médecine interne, 2008
International journal of immunopathology and pharmacology
Interest in B-cells has been revived due to the description of new functions. Supporting a role f... more Interest in B-cells has been revived due to the description of new functions. Supporting a role for B-cells in the genesis of autoimmune diseases is the fact that the B-cell activating factor of the TNF ligand family (BAFF) is essential in their physiology. However, in each disease, this is restricted to a subgroup of patients. Based on experiments in mice, and validated in humans, this new cytokine has been highlighted. Excessive production of BAFF alters immune tolerance by rescuing self-binding B-cells. Overexpression in mice leads to autoimmune manifestation, and BAFF levels are elevated in the serum of autoimmune patients. Similar abnormalities occur in chronic lymphocytic leukemia. Recent works suggest that antagonizing the protein (or competing for its receptors) is relevant to the treatment. Advances in our understanding of the BAFF system offers the opportunity to improve our therapeutic approach.
Autoantibodies, 2014
Abstract Heat shock proteins (HSPs) are a wide family of molecular chaperones. The first members ... more Abstract Heat shock proteins (HSPs) are a wide family of molecular chaperones. The first members of HSPs were observed in cellular stress reactions, especially in thermic changes ascribing their generic names. HSPs can be induced not only following temperature shift but also after other stress pressures such as shear force, cellular injury, and heavy metal intoxication, which all upregulate their expression. In fact, any changes of cellular microenvironment leading to a disturbance of protein integrity will trigger an increased expression of HSPs. Many of them, such as HSP70 and HSP60 subfamilies, are expressed in basal condition as actors of synthesis, protection, and transport of proteins. In all these processes, HSPs will conduct, restore, or maintain the proper folding of proteins to preserve or help to acquire their functions. These purposes make most of them ubiquitously expressed in a similar way to housekeeping proteins. Indeed, knockout animals for HSP60 or GRP75 develop trouble during embryogenesis and are barely viable. Most HSP classifications sort them according to their molecular weights, including subfamilies of HSP90, HSP70, HSP60, HSP40, HSP27, and HSP10. Unfortunately, this classification is not physiologically relevant, especially regarding their implication in autoimmune processes. All HSPs do not derive from the same phylogenic origins. Eukaryotic cells derived from a fusion of eukaryote and mitochondria ancestors. During evolution, both pools of genes mixed with each other to be located either in mitochondria or in the nucleus. Nevertheless, the protein structures of HSPs overall preserve the characteristics of their source. Moreover, HSPs gather proteins from both eukaryotic and bacterial origin, which will later determine their structure and their potential immunogenicity. This feature enlightens the capacity of many HSPs to stimulate pathogen recognition receptors (PRR), which are key elements of innate immunity to detect pathogens during infection.
Arthritis, 2010
CD6 is a 105–130 kDa surface glycoprotein expressed on the majority of T cells and a subset of B ... more CD6 is a 105–130 kDa surface glycoprotein expressed on the majority of T cells and a subset of B cells. The human cd6 gene maps to chromosome 11, and the expression of its protein product is tightly regulated. CD6 mediates cellular adhesion migration across the endothelial and epithelial cells. In addition, it participates in the antigen presentation by B cells and the subsequent proliferation of T cells. CD6 may bind in trans to surface glycoproteins (such as ALCAM and 3A11), or to microbial lipopolysaccharides, and may bind in cis to endogenous ligands (such as CD3 and CD5), and thereby deliver a costimulatory signal. Transinteractions are reinforced during autoimmune diseases (e.g., rheumatoid arthritis (RA), Sjögren's syndrome, and multiple sclerosis) and some cancers. Based on experimental data and on clinical results in RA and psoriasis, we believe that the recent humanized anti-CD6-specific mAb T1h may act as a regulator of the immunological response in addition to its fu...
Sjögren’s Syndrome, 2011
T cells have long dominated the debate on the type of lymphocytes favoring the development of Sjo... more T cells have long dominated the debate on the type of lymphocytes favoring the development of Sjogren’s syndrome (SjS), but in recent years it has become apparent that B cells are also a major contributor to autoimmunity. Beyond the paradigm that T lymphocytes exert control over B lymphocytes, it is now recognized that B cells solicit their own help from T cells, release a flurry of cytokines, and serve as antigen-presenting cells. In SjS, excess of the B-cell activating factor (BAFF) promotes quantitative B-cell anomalies that include an increase in the number of mature B (Bm)2/Bm2’ cells in the circulation and the accumulation of transitional, type 2 marginal zone (MZ) and memory B cells in the target tissues. B cells from SjS patients also display qualitative inconsistencies, such as an abundant local synthesis of BAFF and a default in the mechanism that discards the autoantibody-making B cells within ectopic germinal centers or MZ B-cell aggregates. In short, it is abundantly clear that B cells are involved in the pathogenesis of SjS. Moreover, B-cell-directed treatments have already shown substantial benefits in some SjS subsets.
OncoTargets and Therapy, 2010
The view that B lymphocytes are pathogenic in diverse pathological settings is supported by the e... more The view that B lymphocytes are pathogenic in diverse pathological settings is supported by the efficacy of B-cell-ablative therapy in lymphoproliferative disorders, autoimmune diseases and graft rejection. Anti-B-cell antibodies (Abs) directed against CD20 have therefore been generated, and of these, rituximab was the first anti-CD20 monoclonal Ab (mAb) to be applied. Rituximab-mediated apoptosis, complement-dependent cytotoxicity and Ab-dependent cellular cytotoxicity differ from one disease to another, and, for the same disease, from one patient to another. This knowledge has prompted the development of new anti-CD20 mAbs in the hope of improving B-cell depletion. The inclusion of CD20/anti-CD20 complexes in large lipid rafts (LRs) enhances the results of some, but not all, anti-CD20 mAbs, and it may be possible to include smaller LRs. Lipid contents of membrane may be abnormal in malignant B-cells, and could explain resistance to treatment. The function of these mAbs and the importance of LRs warrant further investigation. A detailed understanding of them will increase results for B-cell depletion in lymphoproliferative diseases.
Journal of Autoimmunity, 2012
Maturation of B cells depends on environmental stimuli. Peripheral immature B cells develop into ... more Maturation of B cells depends on environmental stimuli. Peripheral immature B cells develop into follicular pathway when antigenic stimulation is combined with T cell signals. Here, we wished to identify stimuli contributing to the development into marginal zone B cells known to be involved in autoimmune response. We found that TLR9 stimulation of transitional B cells induces proliferation and specific maturation into CD24 À CD38 þ CD21 high CD23 low IgM high IgD low and Notch2 high B cells characteristics of marginal zone B cells. Terminal differentiation into antibody-secreting cell associated with isotype switch commitment is also triggered which leads to a striking production of autoantibodies. Interestingly, mature B cells do not differentiate into marginal zone pathway following TLR9 stimulation, nor do transitional B cells under antigenic and T cell combined signals. These results suggest that transitional B cells are specifically sensitive to TLR9 stimulation to produce autoreactive marginal zone B cells.
International Journal of Interferon, Cytokine and Mediator Research, 2010
Interleukin (IL)-6 is a pleiotropic cytokine that promotes polyclonal activation of B lymphocytes... more Interleukin (IL)-6 is a pleiotropic cytokine that promotes polyclonal activation of B lymphocytes. This implies that its deregulation favors inflammatory conditions. Through the association of the transducing glycoprotein 130 with the membrane-anchored receptor (R) α, IL-6 can generate functionally distinct signals. Given these particular molecular aspects, numerous activities ascribed to this cytokine are, in fact, due to the insertion into soluble IL-6Rα. The system is instrumental in rheumatoid arthritis (RA), Sjögren's syndrome and systemic lupus erythematosus (SLE). In this respect, it is interesting that the expression of the recombination-activating gene is sustained by IL-6 in B lymphocytes, and repressed by anti-IL-6R antibody (Ab) in RA and SLE. Agents that inhibit IL-6 signaling have now entered clinical trials. As expected, clinical benefits are reported in the treatment of autoimmune disorders with anti-IL-6R Ab, but other perspectives remain open in the forthcoming biotherapies of immune-mediated disorders.
Genetics of Rare Autoimmune Diseases, 2019
Oncotarget, 2018
The anti-CD20-specific monoclonal antibody rituximab (RTX), in combination with chemotherapy, is ... more The anti-CD20-specific monoclonal antibody rituximab (RTX), in combination with chemotherapy, is commonly used for primary treatment in chronic lymphocytic leukemia (CLL). However, relapses remain important and activation of the complement pathway is one of the mechanisms by which RTX generates the destruction of B cells directly by complement-dependent cytotoxicity (CDC), or indirectly by antibodydependent cellular phagocytosis. In this study, the RTX capacity to induce CDC was established in 69 untreated CLL patients, this cohort including 34 patients tested before the initiation of RTX-chemotherapy. In vitro CDC-resistance to RTX predicts lower response rates to RTX-chemotherapy and shorter treatment free survival. Furthermore, the predictive value of CDC-resistance was independent from the clinical, cytogenetic and FcγR3A V158F polymorphism status. In contrast, CLL cell resistance to CDC predominates in IGHV unmutated patients and was related to an important α2-6 sialyl transferase activity, which in turn increases cell surface α2-6 hypersialylation. Suspected factors associated with resistance to CDC (CD20, CD55, CD59, factor H, GM1, and sphingomyelin) were not differentially expressed or recruited between the two CLL groups. Altogether, results provide evidence that testing RTX capacity to induce CDC in vitro represents an independent predictive factor of therapeutic effects of RTX, and that α2-6 hypersialylation in CLL cells controls RTX response through the control of the complement pathway. At a time when CLL therapy is moving towards chemo-free treatments, further experiments are required to determine whether performing an initial in vitro assay to appreciate CLL CDC resistance might be useful to select patients.
Revue du Rhumatisme, 2006
l'activation des lymphocytes B et T et l'expression des molécules HLA sont augmentées et les méca... more l'activation des lymphocytes B et T et l'expression des molécules HLA sont augmentées et les mécanismes de réparation et de fibrose sont diminués : SSB est donc mieux présenté par les cellules épithéliales salivaires, ce qui favorise la diversification de la réponse autoanticorps contre SSB chez les patients HLA-DRB1*03.
Revue du Rhumatisme, 2016
International Journal of Molecular Sciences, 2021
Autoimmune disease development depends on multiple factors, including genetic and environmental. ... more Autoimmune disease development depends on multiple factors, including genetic and environmental. Abnormalities such as sialylation levels and/or quality have been recently highlighted. The adjunction of sialic acid at the terminal end of glycoproteins and glycolipids is essential for distinguishing between self and non-self-antigens and the control of pro- or anti-inflammatory immune reactions. In autoimmunity, hyposialylation is responsible for chronic inflammation, the anarchic activation of the immune system and organ lesions. A detailed characterization of this mechanism is a key element for improving the understanding of these diseases and the development of innovative therapies. This review focuses on the impact of sialylation in autoimmunity in order to determine future treatments based on the regulation of hyposialylation.
Rheumatology, 2018
Biological abnormalities associated with B lymphocytes are a hallmark of patients with primary Sj... more Biological abnormalities associated with B lymphocytes are a hallmark of patients with primary Sjögren’s syndrome. Those patients present abnormal distribution of B lymphocytes in peripheral blood and B cells in exocrine glands. B cells produce auto-antibodies, cytokines and present antigens but can also suppressive functions. In this review, we will summarize current knowledge on B cells in primary Sjögren’s syndrome patients, demonstrate their critical role in the immunopathology of the disease and describe the past and current trials targeting B cells.
PloS one, 2015
The goal of this study was to determine how the choice of the primary endpoint influenced sample ... more The goal of this study was to determine how the choice of the primary endpoint influenced sample size estimates in randomised controlled trials (RCTs) of treatments for primary Sjögren's syndrome (pSS). We reviewed all studies evaluating biotechnological therapies in pSS to identify their inclusion criteria and primary endpoints. Then, in a large cohort (ASSESS), we determined the proportion of patients who would be included in RCTs using various inclusion criteria sets. Finally, we used the population of a large randomised therapeutic trial in pSS (TEARS) to assess the impact of various primary objectives and endpoints on estimated sample sizes. These analyses were performed only for the endpoints indicating greater efficacy of rituximab compared to the placebo. We identified 18 studies. The most common inclusion criteria were short disease duration; systemic involvement; high mean visual analogue scale (VAS) scores for dryness, pain, and fatigue; and biological evidence of act...
Revue du Rhumatisme, 2007
Pathologie-biologie, 2000
The CD5 glycoprotein is detectable on a minute fraction of circulating B cells. The number of CD5... more The CD5 glycoprotein is detectable on a minute fraction of circulating B cells. The number of CD5+ B cells (B1 cells) is increased in patients with autoimmune disorders and these cells, similar to those leading to chronic lymphocytic leukemia (CLL), may be induced to produce multispecific autoantibodies. CD5 is associated with the B cell antigen receptor, and the induction of apoptosis depends on the activation state of the cells. Defective regulation of this phenomenon might result in the production of autoantibodies and/or the development of CD5+ B cell tumors. We have proposed that there may be different B1 populations in man, which depend on the consequence of CD5 ligation on their surface: 'natural' or 'classical' CD5+ B cells, and 'induced' CD5+ B cells.
Oral diseases, 2014
The autoimmune exocrinopathy Sjögren's syndrome (SS) is characterized by mononuclear cell (MN... more The autoimmune exocrinopathy Sjögren's syndrome (SS) is characterized by mononuclear cell (MNC) infiltrates of exocrine glands and overactivity of B lymphocytes. Although T cells have long been perceived as the prime effectors, increasing evidence indicates that the key role is rather served by B cells. Among related abnormalities are rheumatoid factor (RF), anti-SSA/Ro, and anti-SSB/La antibodies (Ab). Also, supporting this view is our finding of an increase in the number of circulating naïve mature B (Bm) cells, with a reciprocal decrease in that of memory B cells. Furthermore, a ratio of Bm2-plus-Bm2' cells to early Bm5-plus-late Bm5 above 5 is diagnostic. This variation partly reflects the migration of active memory B cells into the exocrine glands of the patients, as well as into their skin. More recently, the B-cell-activating factor of the TNF family (BAFF) has been endorsed with a pivotal role in B-cell survival and hence implicated in the pathogenesis of autoimmunit...
La Revue de médecine interne / fondée ... par la Société nationale francaise de médecine interne, 2008
International journal of immunopathology and pharmacology
Interest in B-cells has been revived due to the description of new functions. Supporting a role f... more Interest in B-cells has been revived due to the description of new functions. Supporting a role for B-cells in the genesis of autoimmune diseases is the fact that the B-cell activating factor of the TNF ligand family (BAFF) is essential in their physiology. However, in each disease, this is restricted to a subgroup of patients. Based on experiments in mice, and validated in humans, this new cytokine has been highlighted. Excessive production of BAFF alters immune tolerance by rescuing self-binding B-cells. Overexpression in mice leads to autoimmune manifestation, and BAFF levels are elevated in the serum of autoimmune patients. Similar abnormalities occur in chronic lymphocytic leukemia. Recent works suggest that antagonizing the protein (or competing for its receptors) is relevant to the treatment. Advances in our understanding of the BAFF system offers the opportunity to improve our therapeutic approach.
Autoantibodies, 2014
Abstract Heat shock proteins (HSPs) are a wide family of molecular chaperones. The first members ... more Abstract Heat shock proteins (HSPs) are a wide family of molecular chaperones. The first members of HSPs were observed in cellular stress reactions, especially in thermic changes ascribing their generic names. HSPs can be induced not only following temperature shift but also after other stress pressures such as shear force, cellular injury, and heavy metal intoxication, which all upregulate their expression. In fact, any changes of cellular microenvironment leading to a disturbance of protein integrity will trigger an increased expression of HSPs. Many of them, such as HSP70 and HSP60 subfamilies, are expressed in basal condition as actors of synthesis, protection, and transport of proteins. In all these processes, HSPs will conduct, restore, or maintain the proper folding of proteins to preserve or help to acquire their functions. These purposes make most of them ubiquitously expressed in a similar way to housekeeping proteins. Indeed, knockout animals for HSP60 or GRP75 develop trouble during embryogenesis and are barely viable. Most HSP classifications sort them according to their molecular weights, including subfamilies of HSP90, HSP70, HSP60, HSP40, HSP27, and HSP10. Unfortunately, this classification is not physiologically relevant, especially regarding their implication in autoimmune processes. All HSPs do not derive from the same phylogenic origins. Eukaryotic cells derived from a fusion of eukaryote and mitochondria ancestors. During evolution, both pools of genes mixed with each other to be located either in mitochondria or in the nucleus. Nevertheless, the protein structures of HSPs overall preserve the characteristics of their source. Moreover, HSPs gather proteins from both eukaryotic and bacterial origin, which will later determine their structure and their potential immunogenicity. This feature enlightens the capacity of many HSPs to stimulate pathogen recognition receptors (PRR), which are key elements of innate immunity to detect pathogens during infection.
Arthritis, 2010
CD6 is a 105–130 kDa surface glycoprotein expressed on the majority of T cells and a subset of B ... more CD6 is a 105–130 kDa surface glycoprotein expressed on the majority of T cells and a subset of B cells. The human cd6 gene maps to chromosome 11, and the expression of its protein product is tightly regulated. CD6 mediates cellular adhesion migration across the endothelial and epithelial cells. In addition, it participates in the antigen presentation by B cells and the subsequent proliferation of T cells. CD6 may bind in trans to surface glycoproteins (such as ALCAM and 3A11), or to microbial lipopolysaccharides, and may bind in cis to endogenous ligands (such as CD3 and CD5), and thereby deliver a costimulatory signal. Transinteractions are reinforced during autoimmune diseases (e.g., rheumatoid arthritis (RA), Sjögren's syndrome, and multiple sclerosis) and some cancers. Based on experimental data and on clinical results in RA and psoriasis, we believe that the recent humanized anti-CD6-specific mAb T1h may act as a regulator of the immunological response in addition to its fu...
Sjögren’s Syndrome, 2011
T cells have long dominated the debate on the type of lymphocytes favoring the development of Sjo... more T cells have long dominated the debate on the type of lymphocytes favoring the development of Sjogren’s syndrome (SjS), but in recent years it has become apparent that B cells are also a major contributor to autoimmunity. Beyond the paradigm that T lymphocytes exert control over B lymphocytes, it is now recognized that B cells solicit their own help from T cells, release a flurry of cytokines, and serve as antigen-presenting cells. In SjS, excess of the B-cell activating factor (BAFF) promotes quantitative B-cell anomalies that include an increase in the number of mature B (Bm)2/Bm2’ cells in the circulation and the accumulation of transitional, type 2 marginal zone (MZ) and memory B cells in the target tissues. B cells from SjS patients also display qualitative inconsistencies, such as an abundant local synthesis of BAFF and a default in the mechanism that discards the autoantibody-making B cells within ectopic germinal centers or MZ B-cell aggregates. In short, it is abundantly clear that B cells are involved in the pathogenesis of SjS. Moreover, B-cell-directed treatments have already shown substantial benefits in some SjS subsets.
OncoTargets and Therapy, 2010
The view that B lymphocytes are pathogenic in diverse pathological settings is supported by the e... more The view that B lymphocytes are pathogenic in diverse pathological settings is supported by the efficacy of B-cell-ablative therapy in lymphoproliferative disorders, autoimmune diseases and graft rejection. Anti-B-cell antibodies (Abs) directed against CD20 have therefore been generated, and of these, rituximab was the first anti-CD20 monoclonal Ab (mAb) to be applied. Rituximab-mediated apoptosis, complement-dependent cytotoxicity and Ab-dependent cellular cytotoxicity differ from one disease to another, and, for the same disease, from one patient to another. This knowledge has prompted the development of new anti-CD20 mAbs in the hope of improving B-cell depletion. The inclusion of CD20/anti-CD20 complexes in large lipid rafts (LRs) enhances the results of some, but not all, anti-CD20 mAbs, and it may be possible to include smaller LRs. Lipid contents of membrane may be abnormal in malignant B-cells, and could explain resistance to treatment. The function of these mAbs and the importance of LRs warrant further investigation. A detailed understanding of them will increase results for B-cell depletion in lymphoproliferative diseases.
Journal of Autoimmunity, 2012
Maturation of B cells depends on environmental stimuli. Peripheral immature B cells develop into ... more Maturation of B cells depends on environmental stimuli. Peripheral immature B cells develop into follicular pathway when antigenic stimulation is combined with T cell signals. Here, we wished to identify stimuli contributing to the development into marginal zone B cells known to be involved in autoimmune response. We found that TLR9 stimulation of transitional B cells induces proliferation and specific maturation into CD24 À CD38 þ CD21 high CD23 low IgM high IgD low and Notch2 high B cells characteristics of marginal zone B cells. Terminal differentiation into antibody-secreting cell associated with isotype switch commitment is also triggered which leads to a striking production of autoantibodies. Interestingly, mature B cells do not differentiate into marginal zone pathway following TLR9 stimulation, nor do transitional B cells under antigenic and T cell combined signals. These results suggest that transitional B cells are specifically sensitive to TLR9 stimulation to produce autoreactive marginal zone B cells.
International Journal of Interferon, Cytokine and Mediator Research, 2010
Interleukin (IL)-6 is a pleiotropic cytokine that promotes polyclonal activation of B lymphocytes... more Interleukin (IL)-6 is a pleiotropic cytokine that promotes polyclonal activation of B lymphocytes. This implies that its deregulation favors inflammatory conditions. Through the association of the transducing glycoprotein 130 with the membrane-anchored receptor (R) α, IL-6 can generate functionally distinct signals. Given these particular molecular aspects, numerous activities ascribed to this cytokine are, in fact, due to the insertion into soluble IL-6Rα. The system is instrumental in rheumatoid arthritis (RA), Sjögren's syndrome and systemic lupus erythematosus (SLE). In this respect, it is interesting that the expression of the recombination-activating gene is sustained by IL-6 in B lymphocytes, and repressed by anti-IL-6R antibody (Ab) in RA and SLE. Agents that inhibit IL-6 signaling have now entered clinical trials. As expected, clinical benefits are reported in the treatment of autoimmune disorders with anti-IL-6R Ab, but other perspectives remain open in the forthcoming biotherapies of immune-mediated disorders.