Rituximab in rheumatic diseases.
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Animals↗
Biomedical subjects
Pierre Youinou
Publications and source records attributed to Pierre Youinou.
Double reactivity against actin and alpha-actinin defines a severe form of autoimmune hepatitis type 1.
Anti-filamentous actin antibodies characterize autoimmune hepatitis type 1 (AIH-1). Recently, the binding domain of alpha-actinin on actin was shown to be a predominant epitope. To test this reactivity, an anti-alpha-actinin enzyme-linked immunosorbent assay was developed, and positivity confirmed by Western blot. Anti-alpha-actinin antibody was found in 21/50 (42%) of AIH-1 patients, compared with 52/401 (12.9%) of liver disease control patients, and with 6/200 (6%) of blood donors. Anti-filamentous and anti-alpha-actinin activities were found specifically together in 66% of anti-filamentous-positive AIH-1 patients. This combination of specificities reflected clinical and histological disease activity, short duration and absence of treatment. Finally, using an actin-alpha-actinin complex assay, the binding of anti-filamentous actin to alpha-actinin-binding domain on actin was demonstrated, as well as that of anti-alpha-actinin on the actin-binding domain of alpha-actinin. Thus, the frequent combination of anti-filamentous and anti-alpha-actinin antibodies seems to be the hallmark of activity in AIH-1.
Actinin↗
BAFF-induced changes in B cell antigen receptor-containing lipid rafts in Sjögren's syndrome.
OBJECTIVE: To determine the effect of excessive production of BAFF on the distribution and function of B cell subsets in patients with primary Sjögren's syndrome (SS). METHODS: The phenotype of B lymphocytes was analyzed by flow cytometry. Differences in the expression level of membrane IgD and CD38 were used to identify B lymphocyte subsets evolving from naive Bm1 through memory Bm5 cells. Based on our finding of a low expression of CD45RA, we sorted Bm2/Bm2' cells to determine the time course of translocation of the CD19 molecule and the B cell receptor into lipid rafts, by confocal microscopy. Serum levels of BAFF were measured by an enzyme-linked immunosorbent assay developed in-house. RESULTS: "Circulating" Bm2/Bm2' cells were expanded in patients with primary SS compared with rheumatic disease controls and with normal controls. In addition, these B cell subsets were functionally abnormal. Prolonged residency of the B cell receptor in lipid rafts in these cells was associated with elevated CD19 expression in B cells, most notably, Bm2 and Bm2' cells, obtained from the patients with primary SS. BAFF levels were higher in the patients than in the normal controls and correlated with the percentage of Bm2/Bm2' cells and their expression of CD19 in primary SS patients. These correlations were confirmed by placing sorted Bm1 or Bm2 cells from normal controls in culture in the presence or absence of BAFF. CONCLUSION: Bm2/Bm2' cells express more CD19 molecules in primary SS patients than in normal controls. BAFF might participate in this elevated expression of CD19. These patients might be suitable candidates for treatment with BAFF antagonists.
B-Cell Activating Factor↗
Identification of transitional type II B cells in the salivary glands of patients with Sjögren's syndrome.
OBJECTIVE: To identify B cell subpopulations participating in the lymphocyte infiltrate of salivary glands from patients with primary Sjögren's syndrome. A special emphasis was placed on those B lymphocytes included in the ectopic germinal centers (GCs). METHODS: The presence of B cells in salivary glands and their polyclonality were ascertained by phenotyping and reverse transcription-polymerase chain reaction in salivary gland samples from 18 patients. Their phenotype was thoroughly analyzed using a number of double-staining combinations. The results obtained in tissue sections were confirmed by fluorescence-activated cell sorting analysis of B cells eluted from salivary glands, and these findings were compared with those in tonsils. RESULTS: Memory-type B cells were defined as CD20+, CD27+ and were seen in all specimens, whereas GCs were found in only 7 specimens. Furthermore, B cells found in these GCs lacked certain characteristics of centroblasts and centrocytes. Instead, they fulfilled the criteria for transitional type II (TII) B cells and resembled marginal-zone B cells. BAFF (the assistance of which is required for proper transformation of transitional TI B cells into transitional TII B cells) accumulated adjacent to transitional and marginal-zone-like B lymphocytes. Further evidence for the involvement of BAFF came from the expression of its receptors on infiltrating B cells. CONCLUSION: These transitional TII and marginal-zone-like B cells are probably instrumental in the local production of autoantibodies and possibly influential in the ensuing destruction of epithelial cells.
Adult↗
Association of alpha-actinin-binding anti-double-stranded DNA antibodies with lupus nephritis.
OBJECTIVE: Anti-double-stranded DNA (anti-dsDNA) antibodies may contribute to the pathogenesis of glomerulonephritis (GN) by cross-reacting with alpha-actinin in murine models and in some patients with systemic lupus erythematosus (SLE). We therefore sought to determine possible disease associations with serologic and clinical features and to characterize this new autoantibody specificity. METHODS: One hundred patients with SLE were recruited into this multicenter study, as well as 100 rheumatic disease controls and 2,100 healthy blood donors. Clinical disease was evaluated by the SLE Disease Activity Index (SLEDAI; excluding the anti-DNA component). Anti-dsDNA antibodies were detected by conventional enzyme-linked immunosorbent assay (ELISA) and by a commercial enzyme immunoassay (EIA). Anti-alpha-actinin antibodies were detected by ELISA, and their specificity was confirmed by Western blotting and by indirect immunofluorescence using rat kidney sections and mesangial cells as substrates. Highly positive sera were selected for absorption experiments and were affinity-purified for cross-reactivity studies and measurement of antibody avidity. RESULTS: Sera from 62 of the SLE patients had anti-dsDNA antibodies; 21 of these sera also had anti-alpha-actinin antibodies, as compared with 1 of the 38 sera without anti-dsDNA antibodies. Of the 22 patients with anti-alpha-actinin antibodies, 10 had GN, as compared with 14 of the 78 without anti-alpha-actinin antibodies (P < 0.01). In patients with GN, anti-alpha-actinin, but not anti-dsDNA, antibodies correlated with the SLEDAI score (minus the anti-DNA component) and with treatment. The fraction of serum anti-dsDNA antibodies that cross-reacted with alpha-actinin exhibited high avidity for dsDNA, as determined using a commercial EIA for high-avidity anti-dsDNA antibodies and an in-house conventional ELISA. CONCLUSION: The alpha-actinin-binding antibodies are significantly associated with GN in SLE. Whether such autoantibodies may anticipate the development of this complication of SLE remains to be verified.
Actins↗
Epratuzumab (humanised anti-CD22 antibody) in autoimmune diseases.
B cells play an important role in the pathogenesis of many autoimmune diseases. Different approaches targeting the B cell compartment are under investigation. Selective modulation of B cells has been recently achieved using a humanised monoclonal antibody against the B cell surface marker CD22. This antibody (epratuzumab) was originally developed for the treatment of non-Hodgkin's lymphoma and was found to be effective, with a very good safety profile. Recent studies have demonstrated the efficacy and safety of epratuzumab in several autoimmune diseases, including systemic lupus erythematosus and primary Sjögren's syndrome.
Animals↗
Performance of hand radiographs in predicting the diagnosis in patients with early arthritis.
OBJECTIVE: To evaluate the ability of baseline hand radiographs to predict the diagnosis 2 years later in a cohort of patients with early arthritis. METHODS: A total of 258 patients with arthritis onset within the previous year were evaluated. At baseline, all patients underwent a standardized evaluation including laboratory tests and radiographs. Hand radiographs were read by a blinded observer who used a standardized procedure for detecting features of crystal deposition diseases and rheumatoid arthritis (RA). After 30 +/- 11.3 months, the final diagnosis was established by a panel of rheumatologists. All radiographs were evaluated. RESULTS: Significant associations were found between radiographic features and a clinical diagnosis of RA, calcium pyrophosphate dihydrate (CPPD) arthritis, and hydroxyapatite arthritis. No radiographic abnormalities suggesting psoriatic arthritis or gout were seen. The sensitivities of hand radiographs for diagnosing CPPD or hydroxyapatite arthritis ranged from 80% to 100%. Baseline hand radiographs suggested the final diagnosis in 31/258 patients, including 21 (22.5%) of the 93 patients with RA, 10 of the 11 (91%) patients with CPPD or hydroxyapatite deposition disease, and none of the patients with other disorders. Sensitivity was 29%, specificity 86.5%, positive predictive value 61%, and negative predictive value 63%. CONCLUSION: In our cohort of patients with recent arthritis, the overall performance of hand radiographs in predicting a diagnosis 2 years later was modest. However, they had an excellent diagnostic value for calcium deposition diseases.
Arthritis, Rheumatoid↗
New target antigens for anti-endothelial cell antibodies.
Numerous connective tissue diseases, such as systemic lupus erythematosus (SLE), and infectious states, such as leprosy, are characterized by early vascular endothelial cell (EC) damage. There is substantial interest in the role of anti-EC antibodies (AECA) in such an injury. Due to the diversity of AECA-associated conditions, these autoantibodies are likely to be heterogeneous, and, therefore, identification of their antigens (Ag) to be difficult. They may be classified into three groups: membrane components, ligand-receptor complexes and Ag derived from the blood and attached to the cell surface. New technologies have been developed to sort it out, such as expression libraries and two-dimensional electrophoresis. A handful of Ag have hitherto been recognized viz. heat-shock protein 60 in SLE and leprosy, or plasminogen activator inhibitor-1 in SLE and Wegener granulomatosis. In reality, most of the target Ag for AECA remain to be identified.
Autoantibodies↗
Endothelium, a target for immune-mediated assault in connective tissue disease.
Evidence is lacking that antibodies (Ab) to endothelial cells (AECA) are pathogenic. They are frequently associated with antiphospholipid Ab (aPL), binding to complexes of phosphatidylserine (PS) with beta2GPI. Recent studies have, however, kindled a new debate on their pathogenicity of AECA. A group is responsible for PS reaching the surface of a cell, a feature of commitment to apoptosis. Defective clearance by macrophages of AECA-induced apoptotic cells might display beta2GPI on their surface, and challenge T cell tolerance, until aPL production. Some AECA are thus induced by cell membrane structures, while others recognize "planted" antigens and possibly ligand-receptor complexes. A second group promotes procoagulant factor, and a third has the capacity to trigger apoptosis. Clearly, the most direct demonstration of the pathogenicity of AECA is the autoAb-induced murine model of vasculiltis.
Antibodies, Antiphospholipid↗
B lymphocytes on the front line of autoimmunity.
The paradigm that B cell response to self antigens (Ag) is promoted by antibodies (Ab) has become unsatisfactory. Studies over the last decade have indeed revealed that B cells serve extraordinarily diverse functions within the immune system other than Ab production. They normally play a role in the development in the regulation, as well as the activation of lymphoid architecture, regulating dentritic cells and T cell subsets function through cytokine production. Receptor editing is also essential in B cells and aids in preventing autoimmunity. Both abnormalities in the distribution of B cells subsets and clinical benefit response to B cell depletion in autoimmune states illustrate their importance. Transgenic animal models have demonstrated that sensitivity of B cells to Ag receptor cross-linking correlates to autoimmunity: negative signaling by CD5 and CD22 in maintaining tolerance through recruitment of phosphatase has thus been documented. In short, a new area has been reached, whereby B lymphocytes return as a significant contributor to autoimmune disorders.
Autoimmunity↗
An alternative exon 1 of the CD5 gene regulates CD5 expression in human B lymphocytes.
T lymphocytes and a subpopulation of B lymphocytes express the CD5 coreceptor. Its functional importance is evident from the multiple levels and developmental stages of the regulation of its expression. We here report the discovery of a novel regulatory exon upstream of the noncoding region of the CD5 gene in humans. This alternate exon 1 is designated E1B (with the conventional exon 1 renamed E1A) and was shown to regulate the expression of CD5. E1B-containing transcripts existed exclusively in B lymphocytes and encoded a protein that was truncated and retained intracellularly. As a consequence, the amount of E1A-containing transcripts was down-regulated and the membrane CD5 expression was diminished in the presence of E1B-containing transcripts. High levels of E1A transcripts were found in chronic lymphocytic leukemia, and there were no E1A transcripts in 697 pre-B cells, which have no membrane CD5. Introduction of E1B into Jurkat cells reduced their membrane expression of CD5, and sequence analysis revealed that the E1B motif is a defective human endogenous retrovirus. A balance between the 2 alternative exons 1 might be central to the regulation of membrane CD5 in human B cells, and, through CD5-associated SH2-containing phosphatase 1, to the modulation of B-cell antigen receptor-transduced signals.
Alternative Splicing↗
Expression of RAGs in peripheral B cells outside germinal centers is associated with the expression of CD5.
Previous studies have indicated that mature B cells reactivate secondary V(D)J recombination inside and outside the germinal center (GC) of peripheral lymphoid organs. The nature of the B cells undergoing Ig rearrangement before they enter GC is unknown. In this study, we present evidence that activated mature CD5-positive human tonsil B cells coexpress both RAG1 and RAG2 mRNA and protein, and display DNA cleavage resulting from their recombinase activity. Furthermore, in vitro activation of CD5-negative naive mature B cells by IgR and CD40 cross-linking induces expression of CD5 on a subset of cells, and leads to the up-regulation of RAG1 and RAG2 only in cells turned positive for CD5. Thus, RAG gene expression is closely related to CD5 expression outside GCs. These data suggest that CD5 is associated with receptor revision in activated mature B cells and likely to promote expression of suitable IgR capable of initiating the GC reaction.
Adolescent↗
B cell response to surface IgM cross-linking identifies different prognostic groups of B-chronic lymphocytic leukemia patients.
On the basis of responses to surface IgM (sIgM) cross-linking, B cells from 41 patients with B-chronic lymphocytic leukemia were categorized as 15 nonresponders (group I) and 26 responders (group II). The latter cases were subclassified as those seven where proliferation was induced (subgroup IIa) and the remaining 19 in whom apoptosis occurred (subgroup IIa). Signal disruption in group I was confirmed by the absence of Ca2+ mobilization. Activation of PI3K was constitutive in subgroup IIa, but not in subgroup IIb, and that of Akt induced by anti-mu in subgroup IIa, but not in subgroup IIb. Among the MAPK, ERK was more highly activated relative to p38 in subgroup IIa, whereas activation of p38 predominated over that of ERK in subgroup IIb. For subgroup IIb cells, based on tyrosine phosphorylation and translocation into lipid rafts, sIgM signaling was shown to be enhanced by Zap70. The different consequences of signaling through sIgM were associated with biological prognosis indicators. These included high levels of CD38, lack of mutations in the IgVH chain genes, preferential usage of full-length CD79b, and severe clinical stage. Thus, modification of sIgM-induced signaling could be a therapeutic approach.
Adult↗
Is periodontal disease mediated by salivary BAFF in Sjögren's syndrome?
OBJECTIVE: To correlate the periodontal status of 15 patients with primary Sjögren's syndrome (SS) with their salivary levels of BAFF. METHODS: The periodontal status of 15 patients who fulfilled the criteria for primary SS was compared with that of 15 controls with xerostomia who did not fulfill the criteria for primary SS but had similar symptoms of dry mouth. The level of BAFF was measured in paired samples of saliva and serum using in-house enzyme-linked immunosorbent assays. Periodontitis was assessed by the plaque index, the modified gingival index, the papillary bleeding index, and the periodontal pocket depth. RESULTS: Notwithstanding the better oral hygiene practices of the patients with primary SS compared with those of the xerostomia controls and the subsequent reduction of their plaque index scores, complications of periodontitis, such as bleeding, gingival hypertrophy, and periodontal pockets, were not improved. This failure to ameliorate the complications of periodontitis in patients with primary SS was associated with high levels of BAFF in their saliva compared with the levels in xerostomia controls (7.4 +/- 2.1 versus 1.0 +/- 0.4 ng/ml [P < 0.002]). The levels of BAFF in saliva did not correlate with the levels in sera but did correlate with the periodontal pocket depth (P < 0.002). CONCLUSION: These findings are similar to the bone resorption observed in patients with rheumatoid arthritis. They suggest that the known effect of B cells in periodontitis would be partly mediated by salivary BAFF in patients with primary SS.
Aged↗
Induction of endothelial cell apoptosis by the binding of anti-endothelial cell antibodies to Hsp60 in vasculitis-associated systemic autoimmune diseases.
OBJECTIVE: Anti-endothelial cell antibodies (AECAs), which recognize a number of endothelial antigens, are seen in patients with systemic autoimmune diseases, more often in the presence of vasculitis than in its absence. Some AECAs induce apoptosis of endothelial cells (ECs), but their target antigens remain unknown. The aim of this study was to determine whether Hsp60 is a target antigen and whether AECAs induce apoptosis in ECs. METHODS: Two-dimensional electrophoresis and conventional Western blotting techniques were used to characterize AECA targets. Hsp60 reactivity was determined by enzyme-linked immunosorbent assay. RESULTS: Hsp60 was shown to be targeted by a proportion of AECAs. The level of reactivity was higher in patients with systemic autoimmune disease and vasculitis than in those without vasculitis and in patients with systemic lupus erythematosus than in patients with other systemic autoimmune diseases. Hsp60 was expressed on the plasma membrane of heat-stressed ECs, and this followed Hsp60 messenger RNA transcription, confinement of the protein to the cytoplasm, and translocation of the protein to the surface. Shedding of Hsp60 from ECs was induced by stress and resulted in the binding of soluble Hsp60 to the surface of ECs, particularly stressed ECs. Apoptosis of ECs was triggered by anti-Hsp60-containing AECA-positive sera and was inhibited by preincubation of the ECs with recombinant Hsp60. CONCLUSION: Our data support the notion that Hsp60 is an important target for AECAs and that such an interaction contributes to pathogenic effects, especially in vasculitis-associated systemic autoimmune disease.
Adult↗
Establishment of a novel human B-CLL-like xenograft model in nude mouse.
We have developed a novel murine model for B-CLL by engrafting human prolymphocytic leukemia (PLL) or B-CLL cell line cells (JVM-3 and MEC-2 cell lines, respectively) into nude mice. Not only treatment of the mice was a prerequisite for the success of the graft, but also for the first time, females appeared to accept the cells more easily than males. Surprisingly, tumoral murine models for B-CLL could be established with PLL cells but not with B-CLL cells. JVM-3 cells were efficiently transplanted into nude mice through subcutaneous or intravenous routes. Irradiated female mice appeared to be the optimal recipients for tumor growth. Such murine models for human B-CLL may help the development of therapeutic agents.
Animals↗
Rheumatoid factor on a daily basis.
Rheumatoid factors (RF), which are antibodies (Ab) with specificity directed against gamma (?) globulins, are the commonest auto-Ab ever described in man. Some of them are referred to as agglutinating RF, others designated non-agglutinating RF. Not only do these characterize rheumatoid arthritis (RA), but they are also encountered in a variety of disease conditions, as well as a proportion of healthy controls. Although non-specific for RA, the measurement of agglutinating IgM-RF remains the most useful serological test for the diagnosis of this disease. Demonstration of abnormal amount of serum RF by any method for which the result has been positive in less than 5% of normal subjects has indeed become one of the seven revised criteria, listed by the American College of Rheumatology (Arnett, FC, Edworthy, SM, Bloch, DA, McShane, DJ, Fries, JF, Cooper, NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum, 1988: 31: 315-24), for the classification of RA. Over the course of years, the relative importance of genetic (Carson, DA, Chen, PP, Kipps, TJ, Radoux, V, Jirik, FR, Goldfien, RD, et al. Idiotypic and genetic studies of human rheumatoid factors. Arthritis Rheum, 1987: 30: 1321-1325) and environmental (Nemazee, DA, Sato, VL. Enhancing antibody, a novel component of the immune response. Proc Natl Acad Sci USA, 1982: 79: 3828-3832) factors in the production of such intriguing auto-Ab has been delineated.
Animals↗
Expression and reexpression of recombination activating genes: relevance to the development of autoimmune states.
Like all antibodies, autoreactive antibodies are generated in developing B cells in the bone marrow by variable (V), diversity (D), and joining (J) recombination under the regulation of recombination activating gene (RAG) 1 and RAG2 proteins. Deletion, anergy, and receptor edition prevent the emergence of autoreactive B cells. In the periphery, somatic hypermutation during the course of germinal center responses can lead to the emergence of autoreactive and low-affinity antibody-producing B cells. Deletion and receptor revision regulate autoreactive and inappropriate B cells. Defects in central or peripheral tolerance mechanisms associated with RAG expression could contribute to the appearance of autoreactive B cells. We demonstrate the presence of RAG(+) B cells in CD5-expressing cells outside germinal centers. Our data suggest that receptor revision in the periphery also may occur in unusual sites when B cells are induced to express CD5. This revision may correspond to a novel regulation checkpoint in which impaired control of RAG expression could generate autoreactive B cells and lead to autoimmune states.
Animals↗