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ABSTRACT: Different studies have shown that some autoantibodies are able to penetrate into living cells and that this phenomenon has functional consequences, including apoptosis. We have explored the effect of anti-DNA antibodies (Ab) on the in vitro activation of peripheral blood mononuclear cells (PBMNC) and found that a human polyclonal anti-DNA, IgG, which efficiently penetrated living cells, was able to induce the expression of different cell activation antigens in vitro such as CD69, CD71 or CD98 by PBMNC from normal individuals. However, the cell activation phenotype induced by anti-DNA Ab was considered anomalous since the expression of some activation antigens was not up-regulated, and others showed aberrant behaviour (such as down-regulation of ICAM-1 expression). Similar results were obtained using different murine anti-DNA monoclonal antibodies (mAb). In addition, mAb that showed an efficient ability to penetrate living cells tended to have a greater effect on PBMNC activation. Anti-DNA Ab were also able to induce a noticeable expression of CD95/Fas. These data indicate that penetrating anti-DNA Ab are able to induce an anomalous activation state in vitro in a significant fraction of PBMNC. We believe this effect may occur in vivoand could have an important function in the pathogenesis of the immune dysregulation seen in SLE.
Journal of Autoimmunity 11/1998; 11(5):563-71. · 7.37 Impact Factor
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ABSTRACT: Several data suggest that immature lymphoid cells are more prone to penetration and therefore are affected more by antibodies than their mature counterparts. In this study, we examined the penetration of monoclonal anti-DNA antibodies in several models of immature cells. Results confirm that most anti-DNA antibodies penetrate larger proportions of immature cells than normal adult cells. It was also proven that anti-DNA antibodies induce larger fractions of immature cells to undergo apoptosis than mature cells; however, there is not a numerical association between penetration and apoptosis. Additionally, the penetration and induction of apoptosis of several anti-DNA monoclonal antibodies into U937 and NIH-3T3 cells followed a rather heterogeneous pattern. When mature and immature cells were stimulated polyclonally, it was shown that polyreactive antibodies might act as an accessory signal to induce apoptosis in immature cells. This process could contribute to the edition of the immune repertoire. We propose that naturally occurring polyreactive antinuclear antibodies, through penetration and deletion of self-reacting cells, could participate, either as a unique or secondary signal, in the mechanism of self tolerance. If these polyreactive antibodies undergo affinity maturation, it is possible they may develop into pathogenic antibodies.
Journal of Autoimmunity 11/1998; 11(5):547-56. · 7.37 Impact Factor
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Pathologie Biologie 11/1998; 46(8):583-5. · 1.53 Impact Factor
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Thrombosis Research 07/1998; 90(5):239-43. · 2.44 Impact Factor
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L Llorente,
Y Richaud-Patin,
J Couderc,
D Alarcon-Segovia,
R Ruiz-Soto,
N Alcocer-Castillejos,
J Alcocer-Varela,
J Granados,
S Bahena,
P Galanaud,
D Emilie
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ABSTRACT: To evaluate interleukin-10 (IL-10) production in relatives of patients with systemic lupus erythematosus (SLE).
Production of IL-10 was evaluated in 13 families in which several members had SLE. The constitutive IL-10 production in SLE patients (n = 16) was compared with that in healthy members of these multiplex families (n = 70), in 30 SLE patients who had no relatives with SLE, and in 46 healthy unrelated controls.
The level of IL-10 production did not differ between SLE patients who were members and those who were not members of multiplex families (mean +/- SEM 4,384 +/- 908 pg/ml and 4,709 +/- 560 pg/ml, respectively), but was higher in both groups than in healthy unrelated controls (515 +/- 88 pg/ml). The healthy members of the multiplex families constitutively produced large amounts of IL-10 (3,080 +/- 311 pg/ml; P < 0.001 compared with healthy unrelated controls). This high IL-10 production was independent of age and sex, and was similar in first- and second-degree relatives of SLE patients. The IL-10 was produced both by monocytes and by a subpopulation of B lymphocytes in SLE patients and in their relatives.
The dysregulation of IL-10 production previously identified in SLE patients is also present in healthy members of families with several cases of SLE, and it may contribute to the immunologic abnormalities affecting relatives of SLE patients.
Arthritis & Rheumatism 08/1997; 40(8):1429-35. · 7.87 Impact Factor
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ABSTRACT: Actinic prurigo (AP) appears to be an immune-mediated disease triggered by exposure to ultraviolet light (UV).
To assess the profile of cytokine production in skin lesions from AP patients.
The cytokine production (IL-1 beta, IL-2, IL-4, IL-6, IL-10, IL-13, TNF-alpha, IFN-tau, and TGF-beta) in skin biopsies from 12 AP lesions was determined by a semiquantitative coupled reverse transcription-polymerase chain reaction.
We found expression of TGF-beta and IL-13 genes in most AP skin lesions; IL-1 beta, IL-6, TNF-alpha, IFN-tau, and IL-10 were detected in some of these specimens. However, the levels of expression of all cytokines studied were not significantly different in AP skin lesions compared to nonlesional skin.
TGF-beta and IL-13 might have a key role in both the inflammatory phenomenon and absence of significant expression of most cytokines in AP skin. The cytokine production in AP skin resembles that observed in rheumatoid synovium, a paucity in cytokine expression despite the presence of infiltrating activated mononuclear cells.
Experimental Dermatology 05/1997; 6(2):91-7. · 3.54 Impact Factor
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ABSTRACT: Healthy elderly people tend to have autoantibodies in their sera. These antibodies, not being associated with any clinical manifestation, have been considered as natural autoantibodies. In systemic lupus erythematosus, as well as in rheumatoid arthritis, the presence of autoantibodies characteristic of these disease (anti-dsDNA and rheumatoid factor, respectively) depends on the endogeneous production of IL-10. The same could hold true for autoantibodies found in healthy elderly individuals. In the present work, the authors analysed whether an increased production of IL-10 contributed to the production of autoantibodies in elderly people. The authors found that there is neither increased in vivo gene expression nor augmented production of IL-10 by peripheral blood mononuclear cells from elderly women even if they do produce autoantibodies. The authors further sought to determine if the production of autoantibodies is inhibited in vitro by adding an anti-IL-10 MoAb to cell cultures and found that it is not. Despite these negative findings of a role for IL-10 in the production of autoantibodies in elderly people, the authors investigated which cells produce IL-10. In so doing they found that intracellular IL-10 expression occurred exclusively in monocytes in young female controls, but in elderly females it involved also CD8+CD3+ large granular cells. These results indicate that autoantibody production in healthy aged individuals is IL-10 independent.
Scandinavian Journal of Immunology 05/1997; 45(4):401-7. · 2.23 Impact Factor
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ABSTRACT: It is generally believed that erythema nodosum is the result of an immunologic attack centered within the subcutaneous fat. This belief, however, is based on indirect evidence. The aim of this study was to analyze whether erythema nodosum could represent an example of a polarized Th1 or Th2 immune response. We have studied herein, by semiquantitative coupled reverse transcription-polymerase chain reaction the Th1 (IL-2, IFN-gamma) and Th2 (IL-4, IL-10) cytokine gene expression in skin biopsies and peripheral blood from eleven patients with erythema nodosum. As controls, we studied skin and peripheral blood from nine healthy subjects. We found expression of Th1 cytokines in most erythema nodosum skin lesions as well as in their peripheral blood. Both Th1 and Th2 cytokine gene expressions were scarcely or not detected in the skin and peripheral blood of control subjects. These results directly demonstrate that a polarized Th1 immune response occurs in the skin lesions of erythema nodosum patients regardless of the wide variety of provoking agents.
European cytokine network 04/1997; 8(1):67-71. · 1.73 Impact Factor
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D Emilie,
W Zou,
R Fior, L Llorente,
A Durandy,
M C Crevon,
M C Maillot,
I Durand-Gasselin,
M Raphael,
M Peuchmaur,
P Galamaud
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ABSTRACT: We analyzed the production and the roles of IL-6, IL-10, and IL-13 in B-lymphoid malignancies and in specific diseases with B-lymphocyte hyperactivity. Both IL-13 and IL-10 genes are expressed in B-cell lymphomas. However, their contribution to tumor progression is unclear. In certain lymphoproliferative disorders that develop in transplanted patients, IL-6 is produced by malignant cells and is a major factor of their proliferation. In other lymphomas, the IL-6 gene is expressed only in malignancies where differentiated malignant cells are present. In these lymphomas, IL-6 is produced by stromal cells, and the malignant cells express the IL-6 receptor. In patients with HIV infection, the level of production of IL-6, IL-10, and IL-13 is not higher than those of other conditions with immune activation. However, IL-6 contributes to increased production of IgG and IgA in vivo. In Castleman's disease, IL-6 is produced in the lymph node germinal centers, partly originating from follicular dendritic cells, which may explain some of the pathogenesis of this disease. In systemic lupus erythematosus, the critical cytokine is IL-10, which is produced in large amounts by B lymphocytes and monocytes and is responsible for autoantibody production. Taken together, these data emphasize the roles of IL-6 and IL-10, usually produced by nonlymphoid cells, on B lymphocytes, either malignant or hyperactivated.
Methods 02/1997; 11(1):133-42. · 4.01 Impact Factor
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ABSTRACT: Connective tissue diseases are generated by different immunoregulatory alterations. Their better knowledge may lead to new treatment modalities. In systemic lupus erythematosus (SLE), increased IL-10 production by non-T cells might exert an inhibitory effect on Thl CD4+ T cells which would explain the decreased T cell functions observed in these patients. In rheumatoid arthritis (RA) patients, there may be a balance within the synovium, where the local production of IFN-gamma may limit the anti-inflammatory properties of IL- 10, thus leading to chronic damage. This article shows that rational approaches to therapy need to be individualized. In SLE, the potential therapeutic use of monoclonal antibodies to IL-10 seems to be gathering strength, whereas in RA exactly the opposite is contemplated: IL-10 is tried for its potential therapeutic use.
International Archives of Allergy and Immunology 01/1997; 111(4):348-54. · 2.40 Impact Factor
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Immunology Today 05/1996; 17(4):163-4.
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ABSTRACT: Autoantibodies to intracellular constituents often occur naturally. This would be difficult to understand were they unable to penetrate live cells, as was once generally accepted; however, they can and in so doing may alter cell functions, cause damage and even kill cells by apoptosis. Different autoantibodies have different effects and in this paper, further to our previous report on the penetration of anti-DNA, the penetration of anti-RNP, which may be a possible cause of apoptosis, is demonstrated. Penetration of lymphocytes by autoantibodies may play a role in the causation of autoimmune disease, influencing immune regulation and causing cell damage either directly or through nucleosomal DNA release as a result of apoptosis. This, in turn, could also further promote antigen-driven production of anti-DNA. In addition, by causing apoptosis of autoreactive cell clones, natural autoantibodies could influence tolerance during development and also later in life, thus, paradoxically, helping prevent autoimmune disease.
Journal of Autoimmunity 05/1996; 9(2):295-300. · 7.37 Impact Factor
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ABSTRACT: Lymphocyte B hyperactivity and cell-mediated immune deficiency are characteristic features of systemic lupus erythematosus. This imbalance is seen in cytokine production. T lymphocyte production of interleukin-2 is defective while proinflammatory cytokines such as IL1 beta, IL6 and TNF alpha increase spontaneously during flare-ups. However, the capacity of the monocytes in these patients to produce cytokines is reduced after stimulation by exterior agents such as LPS. Moreover, production of interleukin 10 is increased in lupus patients. Most likely, it is this increase in interleukin 10 production which causes the disrupted immunity in this disease.
Annales de medecine interne 02/1996; 147(7):480-4.
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ABSTRACT: Primary Sjögren's syndrome (PSS) is an autoimmune inflammatory disorder characterized by lymphocytic infiltration of exocrine glands, B cell hyperactivity and autoantibody production. The aim of this study was to determine the presence of IL-10 and IL-13 in this disease. We studied the IL-10 and IL-13 gene expression in vivo by peripheral blood mononuclear cells and minor salivary glands from PSS patients. We found a high expression of the IL-10 gene and its product by their peripheral blood mononuclear cells (PBMC) as well as by their salivary glands. Peripheral blood B cells and monocytes were responsible for 89% of total IL-10 secretion. IL-13 gene expression was not observed in PBMNC from either PSS patients or healthy controls, and was confined to PSS salivary glands. Our results suggest that IL-10 and IL-13 contribute to the pathogenesis of PSS and might explain the B cell abnormalities and the development of lymphoma observed in this autoimmune disease.
Immunology Letters 02/1996; 49(1-2):105-9. · 2.53 Impact Factor
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M F Herrera,
C M López-Graniel,
J Saldaña,
A Gamboa-Domínguez,
Y Richaud-Patín,
F Vargas-Vorackova,
A Angeles-Angeles, L Llorente,
C Castillo,
B Pérez,
R Rivera,
O González,
J Rull
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ABSTRACT: The present study characterizes papillary thyroid carcinoma (PTC) in a Mexican patient sample and evaluates potential prognostic factors for recurrence. Clinical records of 229 patients with PTC were analyzed. Surgical specimens were rereviewed and DNA ploidy determined. Cox logistic regression was used to explore prognostic factors. Mean age +/- SD of the patients was 42 +/- 16 years, with a male/female ratio of 24:205. A thyroid mass was the initial manifestation in 99%. Extrathyroid invasion occurred in 45% and nodal metastases in 38%. Mean size +/- SD of the tumors was 3 +/- 2 cm. By flow cytometry 88% of the tumors were DNA euploid and 12% aneuploid. Complete tumor resection was achieved in 83% with an operative mortality of 0.4%. Postoperative hormone suppression was administered in 65% and remnant 131I thyroid ablation in 84%. The 10-year recurrence-free survival was 85%. In the group of patients with tumors totally removed and without distant metastases, none of the 14 evaluated variables demonstrated statistical significance as an independent prognostic factor for recurrence. However, the group of patients in whom a combination of the following factors was present--age > or = 40 years, tumor size > or = 3 cm, local invasion, and lymph node metastases--showed a higher incidence of tumor recurrence.
World Journal of Surgery 01/1996; 20(1):94-9; discussion 99-100. · 2.36 Impact Factor
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ABSTRACT: The authors evaluated the outcome and potential prognostic factors of 60 patients with surgically resected periampullary tumors.
Periampullary carcinomas exhibit different clinical behaviors according to their site of origin. There are no prognostic factors for deciding the type of surgery to be used or for choosing patients with tumors that have a poor prognosis for adjuvant treatment.
A retrospective review was performed of 15 clinical and pathologic variables encountered among 60 patients with periampullary tumors. Tumors were divided into four groups according to their site of origin. Kaplan-Meier survival curves of the four groups were plotted and differences were evaluated with the log-rank test. Cox's proportional hazards model was used to test for separate and combined independent predictors of disease-free survival.
Twenty-nine ampullary carcinomas, 20 ductal pancreatic carcinomas, 7 distal common bile duct carcinomas, and 4 carcinomas of the periampullary duodenum were found. Five-year disease-free survival was 43%, 0%, 0%, and 75%, respectively. According to the Cox analysis, absence of neural invasion and use of adjuvant chemotherapy were significant factors for longer survival of patients with ampullary tumors. Lymphatic invasion was related to a shorter survival in patients with pancreatic carcinoma.
Five-year disease-free survival of patients with periampullary tumors is related to tumor type. Prognosis was better for ampullary tumors if neural invasion was absent and if adjuvant chemotherapy was used. Lymphatic invasion was associated with a shorter recurrence-free survival among patients with pancreatic carcinoma.
Annals of Surgery 12/1995; 222(5):632-7. · 7.49 Impact Factor
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Revue du rhumatisme (English ed.) 05/1995; 62(4):229-32.
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L Llorente,
W Zou,
Y Levy,
Y Richaud-Patin,
J Wijdenes,
J Alcocer-Varela,
B Morel-Fourrier,
J C Brouet,
D Alarcon-Segovia,
P Galanaud,
D Emilie
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ABSTRACT: Interleukin-10 (IL-10) is produced at a high level by B lymphocytes and monocytes of patients with systemic lupus erythematosus (SLE). In the present work, we analyzed whether this increased production of IL-10 contributed to the abnormal production of immunoglobulins (Ig) and of autoantibodies in SLE. The role of IL-10 was compared with that of IL-6, another cytokine suspected to play a role in these abnormalities. The spontaneous in vitro production of IgM, IgG, and IgA by peripheral blood mononuclear cells from SLE patients was weakly increased by recombinant IL (rIL)-6, but strongly by rIL-10. This production was not significantly affected by an anti-IL-6 mAb but was decreased by an anti-IL-10 mAb. We then tested the in vivo effect of these antibodies in severe combined immunodeficiency mice injected with PBMC from SLE patients. The anti-IL-6 mAb did not significantly affect the serum concentration of total human IgG and of anti-double-stranded DNA IgG in the mice. In contrast, the anti-IL-10 mAb strongly inhibited the production of autoantibodies, and, to a lesser extent, that of total human IgG. These results indicate that the Ig production by SLE B lymphocytes is largely IL-10 dependent, and that the increased production of IL-10 by SLE B lymphocytes and monocytes may represent a critical mechanism in the emergence of the autoimmune manifestations of the disease.
Journal of Experimental Medicine 04/1995; 181(3):839-44. · 13.85 Impact Factor
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L Llorente,
W Zou,
Y Levy,
Y Richaud-Patin,
J Wijdenes,
J Alcocer-Varela,
B Morel-Fourrier,
J C Brouet,
D Alarcon-Segovia,
P Galanaud,
D Emilie
[show abstract]
[hide abstract]
ABSTRACT: Interleukin-10 (IL-10) is produced at a high level by B lymphocytes and monocytes of patients with systemic lupus erythematosus
(SLE). In the present work, we analyzed whether this increased production of IL-10 contributed to the abnormal production
of immunoglobulins (Ig) and of autoantibodies in SLE. The role of IL-10 was compared with that of IL-6, another cytokine suspected
to play a role in these abnormalities. The spontaneous in vitro production of IgM, IgG, and IgA by peripheral blood mononuclear
cells from SLE patients was weakly increased by recombinant IL (rIL)-6, but strongly by rIL-10. This production was not significantly
affected by an anti-IL-6 mAb but was decreased by an anti-IL-10 mAb. We then tested the in vivo effect of these antibodies
in severe combined immunodeficiency mice injected with PBMC from SLE patients. The anti-IL-6 mAb did not significantly affect
the serum concentration of total human IgG and of anti-double-stranded DNA IgG in the mice. In contrast, the anti-IL-10 mAb
strongly inhibited the production of autoantibodies, and, to a lesser extent, that of total human IgG. These results indicate
that the Ig production by SLE B lymphocytes is largely IL-10 dependent, and that the increased production of IL-10 by SLE
B lymphocytes and monocytes may represent a critical mechanism in the emergence of the autoimmune manifestations of the disease.
Journal of Experimental Medicine 02/1995; 181(3):839-844. · 13.85 Impact Factor
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ABSTRACT: We studied mononuclear cell subsets in 17 patients with primary Sjögren's syndrome (PSS) and in 11 normal controls by flow cytometry. We found a decreased percentage of CD4+ cells (p = 0.027) and a higher percentage of CD8+ cells in patients as compared to controls. In both, CD4+ cells and CD8+ cells, CD25 antigen was overexpressed (p = 0.005 and p = 0.025, respectively as compared to controls). We then measured spontaneous mRNA cytokine expression by T cells from 7 PSS patients and 5 normal controls by coupled reverse transcription-polymerase chain reaction. We found spontaneous mRNA expression for IFN-gamma, IL-10, IL-13 as well as for CD25. Our results suggest an overall T cell activation in PSS patients and provides evidence of a T cell cytokine regulatory imbalance which may play a role in the pathogenesis of this disease.
Autoimmunity 02/1995; 20(4):223-9. · 2.47 Impact Factor
