CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in ... more CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in patients with chronic lymphocytic leukaemia (CLL). Important functional properties are associated with CD5 expression in B cells, including STAT3 activation, IL-10 production and the promotion of B lymphocyte survival and transformation. However, the pathway(s) through which CD5 influences the biology of B cells and its dependence on B cell receptor (BCR) cosignaling remain unknown. In this study we show that CD5 expression activates a number of important signaling pathways including Erk1/2 leading to IL-10 production through a novel pathway independent of BCR engagement. This pathway is dependent on extracellular calcium (Ca 2+) entry facilitated by upregulation of the transient receptor potential channel 1 (TRPC1) protein. We also show that Erk1/2 activation in a subgroup of CLL patients is associated with TRPC1 overexpression. In this subgroup of CLL patients, small inhibitory RNA (siRNA) for CD5 reduces TRPC1 expression. Furthermore, siRNAs for CD5 or for TRPC1 inhibit IL-10 production. The findings provide new insights into the role of CD5 in B cell biology in health and disease and could pave the way for new treatment strategies for treating patients with B-CLL.
The human cd5 gene has two alternative exons 1: exon 1A (E1A) which encodes the full-length (FL) ... more The human cd5 gene has two alternative exons 1: exon 1A (E1A) which encodes the full-length (FL) CD5 protein and exon 1B (E1B) which encodes a truncated (TR) isoform. The FL variant of CD5 protein is translocated to the plasma membrane, while its TR variant is retained in the cytoplasm. Because there is an inverse relationship between the levels of FL-CD5 and TR-CD5 in B cells, we have addressed the issue of how the selection of exon 1 is determined. In leukemic B cells, DNA methyltransferase (DNMT)1-induced methylation of E1B prevents its transcription. Furthermore, the level of mRNA for DNMT1 correlates inversely with that of mRNA for CD5-E1B. However, suppression of E1B transcription is incomplete, and some molecules of TR-CD5 continue to be synthesized. Bortezomid-induced inhibition of the proteasome establishes that these TR-CD5 molecules are cleared through the ubiquitin-proteasome pathway. Transfection of CD5 mutants into COS-1 cells locates the ubiquitin-binding site at the second destruction box of the extracellular region of CD5. Activation of the B cells by anti-IgM, Staphylococcus aureus Cowan I (SAC), or PMA up-regulates DNMT1, and thereby CD5-E1A mRNA at the expense of CD5-E1B mRNA. Aberrant synthesis of TR-CD5 is thus offset by balanced degradation of excessive protein. Dysregulation of these mechanisms reduces the expression level of membrane CD5, and thereby diminishes the threshold of the response by cells expressing CD5.
Objective. There is evidence to support a dominant role for B cells in the pathophysiology of pri... more Objective. There is evidence to support a dominant role for B cells in the pathophysiology of primary Sjö gren's syndrome (SS). Therefore, we evaluated the safety and efficacy of anti-CD20 monoclonal antibody. Methods. Sixteen patients who met the new American-European Consensus Group criteria for primary SS and scored >50 on at least 2 of 4 visual analog scales (VAS; 100 mm) evaluating global disease, pain, fatigue, and global dryness received infusions of low-dose rituximab (375 mg/m 2) at weeks 0 and 1 without steroid premedication. Results. Slow rituximab infusions (100 mg/hour) were well tolerated, with only 1 patient experiencing serum sicknesslike disease. There was a dramatic reduction in B cells of the blood and salivary gland (SG). At week 12, VAS scores with respect to fatigue and dryness (P < 0.05), tender point count (P < 0.035), and quality of life as evaluated by the Short Form 36 questionnaire (SF-36; P < 0.001) were significantly improved. At week 36, significant improvements were noted in the 4 VAS scores (P < 0.05), tender joint count (P ؍ 0.017), tender point count (P ؍ 0.027), and SF-36 (P < 0.03). Pulmonary manifestations were ameliorated in 1 patient. Patients with improvements on at least 3 of the 4 VAS scores at any visit (n ؍ 11) had a shorter disease duration than the other patients (n ؍ 5; mean ؎ SD duration 3.8 ؎ 5.4 versus 30.1 ؎ 29.5 years; P ؍ 0.02). Conclusion. Low-dose rituximab infusions were well tolerated without the benefit of steroids. Infusions induced a rapid depletion of B cells in the blood and SG and could improve primary SS. Controlled studies are needed.
B lymphocytes from chronic lymphocytic leukemia (CLL) display some CD5 transcripts for CD5 contai... more B lymphocytes from chronic lymphocytic leukemia (CLL) display some CD5 transcripts for CD5 containing the known exon 1 (E1A) and other CD5 transcripts containing the new exon 1 (E1B). These malignant B cells, as well as B cell lines transfected with cDNA for E1A-cd5 or with cDNA for E1B-cd5 produce IL-10, raising the possibility that CD5 participates in the secretion of IL-10. We identified transcription factors involved in this production in CD5 + B lymphocytes from CLL patients and in E1A-cd5transfected or E1B-cd5-transfected Jok cells. STAT3 is activated via phosphorylation of serine 727 but also NFAT2 through its translocation into the nucleus. Chromatin immunoprecipitation experiments confirmed the role of STAT3 and allowed the discovery of a role for NFAT2 in IL-10 production. Both transcription factors bind not only to the enhancer of the Il-10 gene but also to the promoter of the Il-5 and Il-13 genes. Furthermore, transfection of B cell lines with E1A-cd5 or E1B-cd5 established that activation of STAT3 and NFAT2 is regulated by CD5. The same holds true for the production of IL-10, IL-5, and IL-13 and the expression of the receptors for these cytokines. This interpretation was confirmed by two experiments. In the first, downregulation of CD5 by small interfering RNAs lowered the production of IL-10. In the second experiment, transfection of the GFP-NFAT2 gene into B lymphocytes induced nuclear translocation of NFAT2 in CD5 + but not in CD5 2 B cells. Thus, CD5 expression is associated with NFAT2 activity (and mildly STAT3 activity), indicating that CD5 controls IL-10 secretion.
B lymphocytes from patients with systemic lupus erythematosus (SLE) are characterized by reduced ... more B lymphocytes from patients with systemic lupus erythematosus (SLE) are characterized by reduced expression levels of membrane CD5. Recent studies from our laboratory have revealed that the level of membrane CD5 is determined by the relative level of two alternative CD5 isoforms; CD5-E1A, which is expressed on the membrane, and CD5-E1B, which is retained in the cytoplasm. Using bisulfite sequencing and methylation-sensitive endonuclease assays we show that the promoter for the alternative CD5-E1B isoform is demethylated in B cells from patients with SLE but not in healthy controls. We go on to show that differential methylation is more pronounced following BCR engagement. As a result of this demethylation, CD5-E1B mRNA is transcribed at the expense of CD5-E1A mRNA transcription. We provide further evidence that production of high IL-6
We describe a patient with primary Sjögren&#39;s syndrome who developed myositis. The results... more We describe a patient with primary Sjögren&#39;s syndrome who developed myositis. The results of muscle pathologic analysis before and after treatment with monthly pulses of cyclophosphamide (intravenously), are presented.
ABSTRACT Les lymphocytes B régulateurs (Bregs) semblent agir plus tôt que les T régulateurs (Treg... more ABSTRACT Les lymphocytes B régulateurs (Bregs) semblent agir plus tôt que les T régulateurs (Tregs) et pourraient jouer un rôle aussi important que les Tregs dans les maladies auto-immunes et les allergies. L’étude des Bregs se heurte aux mêmes difficultés que celles rencontrées pour les Tregs : fonction régulatrice parfois seulement transitoire ; absence de phénotype consensuel (l’expression de CD5 n’étant ni indispensable ni suffisante) ; différences entre les espèces (homme et souris) ; diverses modalités de suppression (IL-10, TGF-bêta, expression de molécules membranaires proapoptotiques), variant selon les sous-types de Bregs, lesquels semblent les homologues des sous-types de Tregs (Br1 secrétant de l’IL-10, Br3 du TGF-bêta, et B Foxp3), mais avec une prééminence probable des Br1. Des différences semblent toutefois exister d’avec les Tregs : activation des Bregs sans doute plus par les récepteurs Toll-like que par le récepteur à l’antigène ; intervention plus précoce des Bregs, qui facilitent le recrutement des Tregs, mais disparaissent quand les Tregs deviennent opérationnels. Les Bregs contribuent beaucoup à l’auto-immunité associée à certains déficits immuns et à l’absence de rejet de greffe en cas de forte réponse B. Les défauts des Bregs notés dans les lupus pourraient aussi expliquer les résultats décevants des traitements visant à freiner la réponse B, lesquels fragilisent peut-être encore plus cette sous-population défaillante. La stimulation des Bregs dans divers modèles animaux a permis la correction de maladies auto-immunes variées, en particulier celles à point de départ muqueux. Les interactions entre le microbiote intestinal et les Bregs sont un sujet d’étude ayant un grand avenir.
Biochemical and Biophysical Research Communications, 1998
In an effort to contribute to the construction of a tran-As part of an effort to identify genes p... more In an effort to contribute to the construction of a tran-As part of an effort to identify genes potentially inscriptional map of the region between ETS2 and HMG14 volved in the Down Syndrome pathogenesis, in this on chromosome 21, we have recently cloned a new gene, paper we report the identification and characterizacalled SH3BGR (SH3 binding glutamic-rich protein), tion of a new human gene (named SH3BGRL), which which is differentially expressed in heart and skeletal shows a high homology to the SH3BGR gene, premuscle and encodes for a protein characterized by the viously mapped to the Down Syndrome region of chropresence of a leucine-rich NH2-terminal region, a glumosome 21. The SH3BGRL gene encodes for a small tamic acid-rich COOH-terminal region and a prolineprotein of 114 amino acids, sharing 60% identity and rich middle region containing an SH3 binding motif (6).
We have examined serum antibodies to Epstein-Barr virus Nuclear Antigen (EBNA)-1, -2A and -2B, in... more We have examined serum antibodies to Epstein-Barr virus Nuclear Antigen (EBNA)-1, -2A and -2B, in addition to antibodies to viral capsid antigen and early antigen in 100 rheumatoid arthritis patients and 50 of their relatives. Using indirect immunofluorescence on transfected cells and Western-blot technique, we have found increased frequency and titres of antibodies to EBNA-2B in patients and, to a lesser degree, in their family members, whereas other anti-Epstein-Barr virus antibodies appeared to be similar to controls. Cross-inhibition experiments were carried out and show that antibodies to EBNA-2A are distinct from those to -2B, and vice versa.
To determine if the FMS-like tyrosine kinase 3 ligand (FL), a cytokine implicated not only in B c... more To determine if the FMS-like tyrosine kinase 3 ligand (FL), a cytokine implicated not only in B cell ontogenesis and proliferation, but also in haematological malignancies, contributes to increases in the blood Bm2 and Bm2' B cell subsets and heralds lymphoma in patients with primary Sjögren's syndrome (pSS). Patients and methods Serum levels of FL were measured in 64 pSS patients and 20 matched healthy controls (HCs). The densities of FL and its receptor Flt3 were determined in blood B cells and salivary gland (SG) samples by immunofl uorescence. The effect of FL on B lymphocytes was then investigated by coculture with human SG (HSG) cell line cells. Finally, FL serum levels were measured in 334 patients from the French cohort of primary SS patients ('Assessment of Systemic Signs and Evolution of Sjögren's Syndrome', ASSESS). We evaluated the association between FL levels and lymphoma development (past or present), and disease activity according to the EULAR SS Disease Activity Index (ESSDAI). Results Serum levels of FL were increased in patients with pSS, compared to HCs (135.8 ± 5.5 vs 64.4 ± 4.5 pg/ml, p<0.001). These levels of FL correlated with the numbers of Bm2 and Bm2' (r=0.459, p<0.0006) in pSS patients, and Flt3 was selectively expressed in Bm2 and Bm2' cells. B cell culture experiments showed that FL potentiates the proliferative effect of anti-IgM stimulation. SGs-infi ltrating B cells expressed Flt3, and epithelial cells produced FL. Thus, excesses FL appeared to be associated with high ESSDAI (p<0.05) and lymphoma (p<0.0001) in the 334 patients of the ASSESS cohort. ROC analysis showed that 175 pg/ml was the ideal cut-off to detect the association with lymphoma with the sensitivity 44% and the specifi city 97.5%. Conclusions Serum levels of FL are elevated in pSS, accompanied by abnormal B cell distribution, and associated with history of lymphoma. Flt3 is mainly express by Bm2 and Bm2' cells. Serum levels of FL might explain the clinical evolution of pSS to B cell lymphoma, thus opening new avenues for therapy.
Glomerulonephritis is the most serious complication of systemic lupus erythematosus (SLE). Indeed... more Glomerulonephritis is the most serious complication of systemic lupus erythematosus (SLE). Indeed, lupus nephritis evolves by flares that must be addressed as soon as possible, or better be prevented. As a consequence, the immunological diagnosis of this autoimmune disease is essential in conjunction with the monitoring of the renal function. Although hundreds of antibodies have been identified in SLE, some of them seem to accompany or announce the renal disease: anti-dsDNA, anti-nucleosome, anti-α-actinin, and anti-C1q antibodies. This issue aims to communicate the reasons for the tropism of such autoantibodies to the kidneys, and present the interest of these autoantibodies for the diagnosis and the monitoring of lupus nephritis.La glomérulonéphrite est la complication la plus grave du lupus érythémateux disséminé. Cette néphrite lupique peut évoluer par poussées qu’il faut traiter le plus tôt possible, voire prévenir. Son diagnostic est donc essentiel, ainsi que la surveillance du rein. Il s’agit d’une maladie auto-immune où plus d’une centaine d’auto-anticorps (Ac) ont été répertoriés ! Mais, certains d’entre eux, tels que les Ac anti-ADNnatif, les Ac antinucléosomes, les Ac anti-α-actinine et les Ac anti-C1q, semblent accompagner ou annoncer une atteinte rénale. Cette mise au point vise à communiquer les raisons du tropisme de ces auto-Ac pour les reins et, partant, d’en mesurer l’intérêt de chacun d’entre eux pour le diagnostic et la veille au long cours de la néphropathie lupique.
To compare the diagnostic values of antiperinuclear factor (APF), antikeratin antibody (AKA), and... more To compare the diagnostic values of antiperinuclear factor (APF), antikeratin antibody (AKA), and anti-cyclic citrullinated peptides (anti-CCP) to discriminate between patients with and without rheumatoid arthritis (RA) and to determine the diagnostic value of anti-CCP used alone or with other tests. Two hundred and seventy patients with early arthritis underwent standardized investigations in 1995-1997. The clinical utility of APF, AKA, and anti-CCP in first-visit sera was evaluated using receiver-operating characteristic curves. Combinations of anti-CCP with other laboratory tests were assessed by multiple logistic regression. Anti-CCP, APF, and AKA were not perfectly correlated with one another. Anti-CCP with 53 UI as the cutoff was 47% sensitive and 93% specific, versus 52% and 79%, and 47% and 94%, for APF and AKA, respectively. Multiple logistic regression selected anti-CCP, AKA, IgM-rheumatoid factor (RF) ELISA, and the latex test. Rheumatologists can routinely use 2 or 3 tests for diagnosing RA (latex and/or IgM RF ELISA, and either AKA or anti-CCP ELISA) and can add a third or fourth test when the diagnosis remains in doubt.
CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in ... more CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in patients with chronic lymphocytic leukaemia (CLL). Important functional properties are associated with CD5 expression in B cells, including STAT3 activation, IL-10 production and the promotion of B lymphocyte survival and transformation. However, the pathway(s) through which CD5 influences the biology of B cells and its dependence on B cell receptor (BCR) cosignaling remain unknown. In this study we show that CD5 expression activates a number of important signaling pathways including Erk1/2 leading to IL-10 production through a novel pathway independent of BCR engagement. This pathway is dependent on extracellular calcium (Ca 2+) entry facilitated by upregulation of the transient receptor potential channel 1 (TRPC1) protein. We also show that Erk1/2 activation in a subgroup of CLL patients is associated with TRPC1 overexpression. In this subgroup of CLL patients, small inhibitory RNA (siRNA) for CD5 reduces TRPC1 expression. Furthermore, siRNAs for CD5 or for TRPC1 inhibit IL-10 production. The findings provide new insights into the role of CD5 in B cell biology in health and disease and could pave the way for new treatment strategies for treating patients with B-CLL.
The human cd5 gene has two alternative exons 1: exon 1A (E1A) which encodes the full-length (FL) ... more The human cd5 gene has two alternative exons 1: exon 1A (E1A) which encodes the full-length (FL) CD5 protein and exon 1B (E1B) which encodes a truncated (TR) isoform. The FL variant of CD5 protein is translocated to the plasma membrane, while its TR variant is retained in the cytoplasm. Because there is an inverse relationship between the levels of FL-CD5 and TR-CD5 in B cells, we have addressed the issue of how the selection of exon 1 is determined. In leukemic B cells, DNA methyltransferase (DNMT)1-induced methylation of E1B prevents its transcription. Furthermore, the level of mRNA for DNMT1 correlates inversely with that of mRNA for CD5-E1B. However, suppression of E1B transcription is incomplete, and some molecules of TR-CD5 continue to be synthesized. Bortezomid-induced inhibition of the proteasome establishes that these TR-CD5 molecules are cleared through the ubiquitin-proteasome pathway. Transfection of CD5 mutants into COS-1 cells locates the ubiquitin-binding site at the second destruction box of the extracellular region of CD5. Activation of the B cells by anti-IgM, Staphylococcus aureus Cowan I (SAC), or PMA up-regulates DNMT1, and thereby CD5-E1A mRNA at the expense of CD5-E1B mRNA. Aberrant synthesis of TR-CD5 is thus offset by balanced degradation of excessive protein. Dysregulation of these mechanisms reduces the expression level of membrane CD5, and thereby diminishes the threshold of the response by cells expressing CD5.
Objective. There is evidence to support a dominant role for B cells in the pathophysiology of pri... more Objective. There is evidence to support a dominant role for B cells in the pathophysiology of primary Sjö gren's syndrome (SS). Therefore, we evaluated the safety and efficacy of anti-CD20 monoclonal antibody. Methods. Sixteen patients who met the new American-European Consensus Group criteria for primary SS and scored >50 on at least 2 of 4 visual analog scales (VAS; 100 mm) evaluating global disease, pain, fatigue, and global dryness received infusions of low-dose rituximab (375 mg/m 2) at weeks 0 and 1 without steroid premedication. Results. Slow rituximab infusions (100 mg/hour) were well tolerated, with only 1 patient experiencing serum sicknesslike disease. There was a dramatic reduction in B cells of the blood and salivary gland (SG). At week 12, VAS scores with respect to fatigue and dryness (P < 0.05), tender point count (P < 0.035), and quality of life as evaluated by the Short Form 36 questionnaire (SF-36; P < 0.001) were significantly improved. At week 36, significant improvements were noted in the 4 VAS scores (P < 0.05), tender joint count (P ؍ 0.017), tender point count (P ؍ 0.027), and SF-36 (P < 0.03). Pulmonary manifestations were ameliorated in 1 patient. Patients with improvements on at least 3 of the 4 VAS scores at any visit (n ؍ 11) had a shorter disease duration than the other patients (n ؍ 5; mean ؎ SD duration 3.8 ؎ 5.4 versus 30.1 ؎ 29.5 years; P ؍ 0.02). Conclusion. Low-dose rituximab infusions were well tolerated without the benefit of steroids. Infusions induced a rapid depletion of B cells in the blood and SG and could improve primary SS. Controlled studies are needed.
B lymphocytes from chronic lymphocytic leukemia (CLL) display some CD5 transcripts for CD5 contai... more B lymphocytes from chronic lymphocytic leukemia (CLL) display some CD5 transcripts for CD5 containing the known exon 1 (E1A) and other CD5 transcripts containing the new exon 1 (E1B). These malignant B cells, as well as B cell lines transfected with cDNA for E1A-cd5 or with cDNA for E1B-cd5 produce IL-10, raising the possibility that CD5 participates in the secretion of IL-10. We identified transcription factors involved in this production in CD5 + B lymphocytes from CLL patients and in E1A-cd5transfected or E1B-cd5-transfected Jok cells. STAT3 is activated via phosphorylation of serine 727 but also NFAT2 through its translocation into the nucleus. Chromatin immunoprecipitation experiments confirmed the role of STAT3 and allowed the discovery of a role for NFAT2 in IL-10 production. Both transcription factors bind not only to the enhancer of the Il-10 gene but also to the promoter of the Il-5 and Il-13 genes. Furthermore, transfection of B cell lines with E1A-cd5 or E1B-cd5 established that activation of STAT3 and NFAT2 is regulated by CD5. The same holds true for the production of IL-10, IL-5, and IL-13 and the expression of the receptors for these cytokines. This interpretation was confirmed by two experiments. In the first, downregulation of CD5 by small interfering RNAs lowered the production of IL-10. In the second experiment, transfection of the GFP-NFAT2 gene into B lymphocytes induced nuclear translocation of NFAT2 in CD5 + but not in CD5 2 B cells. Thus, CD5 expression is associated with NFAT2 activity (and mildly STAT3 activity), indicating that CD5 controls IL-10 secretion.
B lymphocytes from patients with systemic lupus erythematosus (SLE) are characterized by reduced ... more B lymphocytes from patients with systemic lupus erythematosus (SLE) are characterized by reduced expression levels of membrane CD5. Recent studies from our laboratory have revealed that the level of membrane CD5 is determined by the relative level of two alternative CD5 isoforms; CD5-E1A, which is expressed on the membrane, and CD5-E1B, which is retained in the cytoplasm. Using bisulfite sequencing and methylation-sensitive endonuclease assays we show that the promoter for the alternative CD5-E1B isoform is demethylated in B cells from patients with SLE but not in healthy controls. We go on to show that differential methylation is more pronounced following BCR engagement. As a result of this demethylation, CD5-E1B mRNA is transcribed at the expense of CD5-E1A mRNA transcription. We provide further evidence that production of high IL-6
We describe a patient with primary Sjögren&#39;s syndrome who developed myositis. The results... more We describe a patient with primary Sjögren&#39;s syndrome who developed myositis. The results of muscle pathologic analysis before and after treatment with monthly pulses of cyclophosphamide (intravenously), are presented.
ABSTRACT Les lymphocytes B régulateurs (Bregs) semblent agir plus tôt que les T régulateurs (Treg... more ABSTRACT Les lymphocytes B régulateurs (Bregs) semblent agir plus tôt que les T régulateurs (Tregs) et pourraient jouer un rôle aussi important que les Tregs dans les maladies auto-immunes et les allergies. L’étude des Bregs se heurte aux mêmes difficultés que celles rencontrées pour les Tregs : fonction régulatrice parfois seulement transitoire ; absence de phénotype consensuel (l’expression de CD5 n’étant ni indispensable ni suffisante) ; différences entre les espèces (homme et souris) ; diverses modalités de suppression (IL-10, TGF-bêta, expression de molécules membranaires proapoptotiques), variant selon les sous-types de Bregs, lesquels semblent les homologues des sous-types de Tregs (Br1 secrétant de l’IL-10, Br3 du TGF-bêta, et B Foxp3), mais avec une prééminence probable des Br1. Des différences semblent toutefois exister d’avec les Tregs : activation des Bregs sans doute plus par les récepteurs Toll-like que par le récepteur à l’antigène ; intervention plus précoce des Bregs, qui facilitent le recrutement des Tregs, mais disparaissent quand les Tregs deviennent opérationnels. Les Bregs contribuent beaucoup à l’auto-immunité associée à certains déficits immuns et à l’absence de rejet de greffe en cas de forte réponse B. Les défauts des Bregs notés dans les lupus pourraient aussi expliquer les résultats décevants des traitements visant à freiner la réponse B, lesquels fragilisent peut-être encore plus cette sous-population défaillante. La stimulation des Bregs dans divers modèles animaux a permis la correction de maladies auto-immunes variées, en particulier celles à point de départ muqueux. Les interactions entre le microbiote intestinal et les Bregs sont un sujet d’étude ayant un grand avenir.
Biochemical and Biophysical Research Communications, 1998
In an effort to contribute to the construction of a tran-As part of an effort to identify genes p... more In an effort to contribute to the construction of a tran-As part of an effort to identify genes potentially inscriptional map of the region between ETS2 and HMG14 volved in the Down Syndrome pathogenesis, in this on chromosome 21, we have recently cloned a new gene, paper we report the identification and characterizacalled SH3BGR (SH3 binding glutamic-rich protein), tion of a new human gene (named SH3BGRL), which which is differentially expressed in heart and skeletal shows a high homology to the SH3BGR gene, premuscle and encodes for a protein characterized by the viously mapped to the Down Syndrome region of chropresence of a leucine-rich NH2-terminal region, a glumosome 21. The SH3BGRL gene encodes for a small tamic acid-rich COOH-terminal region and a prolineprotein of 114 amino acids, sharing 60% identity and rich middle region containing an SH3 binding motif (6).
We have examined serum antibodies to Epstein-Barr virus Nuclear Antigen (EBNA)-1, -2A and -2B, in... more We have examined serum antibodies to Epstein-Barr virus Nuclear Antigen (EBNA)-1, -2A and -2B, in addition to antibodies to viral capsid antigen and early antigen in 100 rheumatoid arthritis patients and 50 of their relatives. Using indirect immunofluorescence on transfected cells and Western-blot technique, we have found increased frequency and titres of antibodies to EBNA-2B in patients and, to a lesser degree, in their family members, whereas other anti-Epstein-Barr virus antibodies appeared to be similar to controls. Cross-inhibition experiments were carried out and show that antibodies to EBNA-2A are distinct from those to -2B, and vice versa.
To determine if the FMS-like tyrosine kinase 3 ligand (FL), a cytokine implicated not only in B c... more To determine if the FMS-like tyrosine kinase 3 ligand (FL), a cytokine implicated not only in B cell ontogenesis and proliferation, but also in haematological malignancies, contributes to increases in the blood Bm2 and Bm2' B cell subsets and heralds lymphoma in patients with primary Sjögren's syndrome (pSS). Patients and methods Serum levels of FL were measured in 64 pSS patients and 20 matched healthy controls (HCs). The densities of FL and its receptor Flt3 were determined in blood B cells and salivary gland (SG) samples by immunofl uorescence. The effect of FL on B lymphocytes was then investigated by coculture with human SG (HSG) cell line cells. Finally, FL serum levels were measured in 334 patients from the French cohort of primary SS patients ('Assessment of Systemic Signs and Evolution of Sjögren's Syndrome', ASSESS). We evaluated the association between FL levels and lymphoma development (past or present), and disease activity according to the EULAR SS Disease Activity Index (ESSDAI). Results Serum levels of FL were increased in patients with pSS, compared to HCs (135.8 ± 5.5 vs 64.4 ± 4.5 pg/ml, p<0.001). These levels of FL correlated with the numbers of Bm2 and Bm2' (r=0.459, p<0.0006) in pSS patients, and Flt3 was selectively expressed in Bm2 and Bm2' cells. B cell culture experiments showed that FL potentiates the proliferative effect of anti-IgM stimulation. SGs-infi ltrating B cells expressed Flt3, and epithelial cells produced FL. Thus, excesses FL appeared to be associated with high ESSDAI (p<0.05) and lymphoma (p<0.0001) in the 334 patients of the ASSESS cohort. ROC analysis showed that 175 pg/ml was the ideal cut-off to detect the association with lymphoma with the sensitivity 44% and the specifi city 97.5%. Conclusions Serum levels of FL are elevated in pSS, accompanied by abnormal B cell distribution, and associated with history of lymphoma. Flt3 is mainly express by Bm2 and Bm2' cells. Serum levels of FL might explain the clinical evolution of pSS to B cell lymphoma, thus opening new avenues for therapy.
Glomerulonephritis is the most serious complication of systemic lupus erythematosus (SLE). Indeed... more Glomerulonephritis is the most serious complication of systemic lupus erythematosus (SLE). Indeed, lupus nephritis evolves by flares that must be addressed as soon as possible, or better be prevented. As a consequence, the immunological diagnosis of this autoimmune disease is essential in conjunction with the monitoring of the renal function. Although hundreds of antibodies have been identified in SLE, some of them seem to accompany or announce the renal disease: anti-dsDNA, anti-nucleosome, anti-α-actinin, and anti-C1q antibodies. This issue aims to communicate the reasons for the tropism of such autoantibodies to the kidneys, and present the interest of these autoantibodies for the diagnosis and the monitoring of lupus nephritis.La glomérulonéphrite est la complication la plus grave du lupus érythémateux disséminé. Cette néphrite lupique peut évoluer par poussées qu’il faut traiter le plus tôt possible, voire prévenir. Son diagnostic est donc essentiel, ainsi que la surveillance du rein. Il s’agit d’une maladie auto-immune où plus d’une centaine d’auto-anticorps (Ac) ont été répertoriés ! Mais, certains d’entre eux, tels que les Ac anti-ADNnatif, les Ac antinucléosomes, les Ac anti-α-actinine et les Ac anti-C1q, semblent accompagner ou annoncer une atteinte rénale. Cette mise au point vise à communiquer les raisons du tropisme de ces auto-Ac pour les reins et, partant, d’en mesurer l’intérêt de chacun d’entre eux pour le diagnostic et la veille au long cours de la néphropathie lupique.
To compare the diagnostic values of antiperinuclear factor (APF), antikeratin antibody (AKA), and... more To compare the diagnostic values of antiperinuclear factor (APF), antikeratin antibody (AKA), and anti-cyclic citrullinated peptides (anti-CCP) to discriminate between patients with and without rheumatoid arthritis (RA) and to determine the diagnostic value of anti-CCP used alone or with other tests. Two hundred and seventy patients with early arthritis underwent standardized investigations in 1995-1997. The clinical utility of APF, AKA, and anti-CCP in first-visit sera was evaluated using receiver-operating characteristic curves. Combinations of anti-CCP with other laboratory tests were assessed by multiple logistic regression. Anti-CCP, APF, and AKA were not perfectly correlated with one another. Anti-CCP with 53 UI as the cutoff was 47% sensitive and 93% specific, versus 52% and 79%, and 47% and 94%, for APF and AKA, respectively. Multiple logistic regression selected anti-CCP, AKA, IgM-rheumatoid factor (RF) ELISA, and the latex test. Rheumatologists can routinely use 2 or 3 tests for diagnosing RA (latex and/or IgM RF ELISA, and either AKA or anti-CCP ELISA) and can add a third or fourth test when the diagnosis remains in doubt.
Uploads
Papers by Pierre Youinou