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J F Subra

Publications and source records attributed to J F Subra.

At least 19 recordsLinked to original sources
PubMed2001

The balance between CD45RChigh and CD45RClow CD4 T cells in rats is intrinsic to bone marrow-derived cells and is genetically controlled.

The level of CD45RC expression differentiates rat CD4 T cells in two subpopulations, CD45RC(high) and CD45RC(low), that have different cytokine profiles and functions. Interestingly, Lewis (LEW) and Brown Norway (BN) rats, two strains that differ in their ability to mount type 1 and type 2 immune responses and in their susceptibility to autoimmune diseases, exhibit distinct CD45RC(high)/CD45RC(low) CD4 T cell ratios. The CD45RC(high) subpopulation predominates in LEW rats, and the CD45RC(low) subpopulation in BN rats. In this study, we found that the antiinflammatory cytokines, IL-4, IL-10, and IL-13, are exclusively produced by the CD45RC(low) CD4 T cells. Using bone marrow chimeras, we showed that the difference in the CD45RC(high)/CD45RC(low) CD4 T cell ratio between naive LEW and BN rats is intrinsic to hemopoietic cells. Furthermore, a genome-wide search for loci controlling the balance between T cell subpopulations was conducted in a (LEW x BN) F(2) intercross. Genome scanning identified one quantitative trait locus on chromosome 9 (approximately 17 centiMorgan (cM); log of the odds ratio (LOD) score 3.9). In addition, two regions on chromosomes 10 (approximately 28 cM; LOD score 3.1) and 20 (approximately 40 cM; LOD ratio score 3) that contain, respectively, a cytokine gene cluster and the MHC region were suggestive for linkage. Interestingly, overlapping regions on these chromosomes have been implicated in the susceptibility to various immune-mediated disorders. The identification and functional characterization of genes in these regions controlling the CD45RC(high)/CD45RC(low) Th cell subpopulations may shed light on key regulatory mechanisms of pathogenic immune responses.

Aging↗
PubMed2001

Gold is a T cell polyclonal activator in BN and LEW rats but favors IL-4 expression only in autoimmune prone BN rats.

Gold salts are beneficial in the treatment of rheumatoid arthritis but may induce immune-mediated disorders in predisposed patients. Gold salts induce Th2-dependent autoimmunity in Brown-Norway (BN) rats but not in Lewis (LEW) rats. The aim of this study was to define molecular targets of gold salts and to approach why LEW rats are resistant. Gold salts act on early steps of transduction in T cells from BN and LEW rats since they trigger tyrosine phosphorylation of numerous proteins including p56(lck) and a calcium signal which results in IL-4 and IFN-gamma expression by BN and LEW T cells. However, the IL-4 response was favored in BN spleen cells in vitro and in vivo. IFN-gamma, produced in part by CD8(+) cells, contributes to the resistance of LEW rats since gold salt-injected LEW rats receiving anti-CD8 or anti-IFN-gamma mAb displayed the parameters characteristics of gold salt-induced Th2 autoimmunity although to a lesser extent than in BN rats. Gold salts transduce a signal in BN and LEW spleen cells resulting in IL-4 and IFN-gamma gene transcription with a preferential IL-4 response in BN rats, a Th2-prone strain, while IFN-gamma contributes to the resistance of LEW rats.

Animals↗
PubMed2001

Induction of autoimmunity through bystander effects. Lessons from immunological disorders induced by heavy metals.

Autoreactive T cells exist in healthy individuals and represent a potential reservoir of pathogenic effectors which, when stimulated by microbial adjuvants, could trigger an autoimmune disease. Experimental studies have indicated that xenobiotics, well defined from a chemical point of view, could promote the differentiation of autoreactive T cells towards a pathogenic pathway. It is therefore theoretically possible that compounds present in vaccines such as thiomersal or aluminium hydroxyde can trigger autoimmune reactions through bystander effects. Mercury and gold in rodents can induce immunological disorders with autoimmune reactions. In vitro, both activate signal transduction pathways that result in the expression of cytokines, particularly of IL-4 and IFNgamma. In a suitable microenvironment heavy metals could therefore favour the activation of autoreactive T cells. In that respect, genetic background is of major importance. Genome-wide searches in the rat have shown that overlapping chromosomal regions control the immunological disorders induced by gold salt treatment, the development of experimental autoimmune encephalomyelitis and the CD45RC(high)/CD45RC(low)CD4(+)T cells balance. The identification and functional characterization of genes controlling these phenotypes may shed light on key regulatory mechanisms of immune responses. This should help to improve efficacy and safety of vaccines.

Adjuvants, Immunologic↗
PubMed2001

Cellular and genetic factors involved in the difference between Brown Norway and Lewis rats to develop respectively type-2 and type-1 immune-mediated diseases.

The understanding of the mechanisms of immune tolerance and the unravelling of the pathophysiology of autoimmune diseases rely on animal models. In this respect, BN and LEW rats represent models of choice to study immune-mediated diseases from the cellular and genetic points of view. Indeed, BN and LEW rats are extremes with respect to their polarisation of the immune response as well as their susceptibility to autoimmune diseases. LEW rats are susceptible to Th1-mediated autoimmune diseases while BN rats are highly susceptible to Th2-mediated autoimmune disease. Comparison of the T cell compartment between LEW and BN rats revealed several important differences. 1) A MHC-dependent quantitative difference that is due to a defect in the CD8 T cell compartment in BN rats. 2) A qualitative MHC-independent difference that is related to a high frequency of CD45RClow CD4 and CD8 T cell subsets, producing IL-4, IL-13, IL-10 and TGF-beta in BN rats as compared to LEW rats. 3) Interestingly, the genetic studies showed that susceptibility to Th1-mediated experimental autoimmune encephalomyelitis, and to Th2-mediated disorders triggered by gold salts as well as the difference in the CD4SRChigh/CD45RClow ratio between LEW and BN rats are genetically determined by regions on chromosomes 9, 10 and 20.

Animals↗
PubMed2001

Lymphopenia in occupational pulmonary silicosis with or without autoimmune disease.

An increased prevalence of autoimmune diseases such as rheumatoid arthritis has been demonstrated in silica-exposed patients. The aim of this study was to determine the peripheral blood lymphocyte phenotype in a population of silicotic workers employed in the slate mines of the district. Silicosis was assessed in 58 patients according to the International Labor Office's criteria. Clinical and biological data including flow cytometric evaluation of the lymphocyte subsets were compared with those from 41 healthy volunteers. The silicotic patients had a higher prevalence of autoimmune diseases (6/58 versus 0/41: P < 0.05) and of elevated antinuclear antibody titres compared to the control group. A very significant decrease of total lymphocyte count (P < 0.001) involving B, T and Natural Killer cells was found in silicotic patients as compared with matched healthy volunteers. A significant increase in the percentage of activated T cells (12.3%) was observed in the silicotic group as compared to 6.5% in the control group (P = 5 x 10(-5)). Our results show that in silicotic patients, the absolute number of circulating lymphocytes is diminished with an increased proportion of activated T cells. Whether these findings could predispose to the development of autoimmune disorders is discussed.

Adult↗
PubMed2001

Antigen inhalation as a triggering factor in systemic small-sized-vessel vasculitis. Four cases.

In order to identify small-sized-vessel vasculitis occurring immediately after massive inhalation of particles which could be considered antigenic, we performed a retrospective review of patients who consulted our Department of Internal Medicine between 1980 and 1998 and were diagnosed as having small-vessel vasculitis that developed immediately after massive exposure to inhaled particles. Four patients, 27 to 55 years old, presented with small-sized-vessel vasculitis (one with Wegener's granulomatosis and three with Churg-Strauss syndrome) which developed after massive inhalation of particles. Clinical manifestations occurred from a few hours to 10 days after inhalation of diesel fumes, cereal dust, flour or cereal dust and/or pigeon droppings. Three patients remain disease-free 8, 9 and 18 years after discontinuing treatment. One patient remains well after 3 years on low-dose corticosteroids and cyclophosphamide therapy. Our data suggest that primary antigens can cause small-sized-vessel vasculitides. Identifying such etiological factors could improve our understanding of the pathogenesis of systemic vasculitides and prevent relapses due to similar antigenic exposure.

Adult↗
PubMed2000

Rat chromosome 9 bears a major susceptibility locus for IgE response.

Injection of Brown Norway (BN) rats with gold salts provides a model to analyze the genetic control of the IgE response. A cohort of F2 progeny of susceptible BN and resistant LEW strains has been studied to carry out a genome-wide search for loci controlling the IgE response. Genome scanning identified two previously described loci, Atps1 and Atps2, and a new locus, Atps3. Atps1 linked to the MHC and Atps2 linked to the cytokine gene cluster that included the IL-4 region have been previously associated with serum IgE concentrations and with other Th2-dependent immune manifestations triggered by gold salts. The new interval, Atps3, identified on chromosome 9 (Lod score = 16), appears to play a major role in the control of the IgE response since it accounts for 31% of the genetic variance. Moreover, Atps3 is linked to anti-laminin antibody response and to glomerular immunoglobulin deposits. The identification and functional characterization of genes involved in these regions, particularly in Atps3, may shed light on the pathogenesis of atopic diseases in man.

Animals↗
PubMed1999

Effect of protein A immunoadsorption in nephrotic syndrome of various etiologies.

Protein A immunoadsorption (IA) has proved effective in reducing proteinuria in patients with nephrotic syndrome after recurrence of focal and segmental glomerulosclerosis (FSGS) in kidney transplants. The effect of IA in nephrotic syndrome of other etiologies remains unknown. Nine patients with nephrotic syndrome secondary to membranous nephropathy (four cases), diabetes mellitus (one case), IgA nephropathy (two cases), and amyloidosis (two cases) had three to five IA of 2.5 plasma volumes over 4 to 8 d. Patients received no concomitant immunosuppressive treatment, and antihypertensive drugs were left unchanged. Proteinuria decreased from 12.64 +/- 5.49 to 3.35 +/- 2.2 g/24 h (mean +/- SD) in all patients after three to five IA. Hematocrit decreased from 37.32 to 32.64% (12.5% hemodilution) and serum albumin from 25.43 to 18.6 g/L (26.4% decrease). Proteinuria returned to baseline levels within 1 mo, as described in recurrent FSGS following transplantation. When serum albumin balance was controlled by albumin infusion after IA in two patients, comparable decreases in proteinuria were observed. Therefore, IA is effective in producing short-term reduction of proteinuria in nephrotic syndromes related not only to FSGS but also to membranous and IgA nephropathies, diabetes mellitus, and amyloidosis, which suggests that IA removes a nonspecific circulating hemodynamic-altering or permeability-increasing factor.

Amyloidosis↗
PubMed1998

The presence of cytoplasmic antineutrophil cytoplasmic antibodies (C-ANCA) in the course of subacute bacterial endocarditis with glomerular involvement, coincidence or association?

Antineutrophil cytoplasmic antibodies positivity with cytoplasmic pattern (C-ANCA) and proteinase-3 (PR-3) specificity was found in two patients with both subacute bacterial endocarditis (SBE) and glomerular involvement. Renal biopsy showed membranoproliferative glomerulonephritis in one case and focal segmental glomerulonephritis in the second case. Immunofluorescence study showed granular immune deposits in both cases evocating immune complex glomerulonephritis. Renal and biological manifestations disappeared with clinical improvement secondary to antibiotherapy. Physicians have to consider the possible occurrence of such C-PR-3 ANCA, claimed to be specific markers for Wegener's granulomatosis, in infectious diseases such as SBE. Hence we focus on the necessity of performing a renal biopsy with light microscopy and immunofluorescence studies in all patients with ANCA associated glomerular disease.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1996

Treatment of mixed cryoglobulinemia with recombinant interferon alpha and adjuvant therapies. A prospective study on 20 patients.

In order to evaluate the efficacy of interferon alpha (IFNa) in mixed cryoglobulinemia (MC), a prospective multicenter clinical trial was conduced in April 1992. It consisted of treating 20 clinically symptomatic MC patients with IFNa for 26 weeks. Hepatitis C virus (HCV) infection was detected in 16 patients. A complete or partial clinical remission was obtained in 12 patients (60%). Eleven of these 12 responders (91.6%) experienced a clinical relapse less than 12 months after the end of therapy. Side effects were noted in 10 patients (50%). It was concluded that subcutaneously administered IFNa does not provide long-term remission.

Adrenal Cortex Hormones↗
PubMed1995

Contribution of parathyroid hormone-related peptide to the evaluation of hypercalcemia.

Hypercalcemia of malignancy is due either to local osteolysis at the site of bone metastases or to production by the malignancy of parathyroid hormone-related peptide, which shares some of the effects of parathyroid hormone. We used a radioimmunoassay (antiserum specific to the amino-terminus) to measure serum parathyroid hormone-related peptide levels in controls (n = 61), chronic renal failure patients (n = 10), patients with primary hyperparathyroidism (n = 19), cancer patients with (n = 35) or without (n = 57) hypercalcemia and/or bone metastases (n = 53 and n = 39, respectively), and patients with hematologic malignancies (n = 15). We set the upper limit of normal of the parathyroid hormone-related peptide assay at 2.7 pmol/L. The peptide was undetectable in two-thirds of healthy controls. Renal failure did not interfere with the assay. Eighteen of the 19 patients with primary hyperparathyroidism had normal levels. In contrast, 82% of patients with humoral hypercalcemia of malignancy (i.e., without detectable bone metastases) had increased levels; in this subgroup there was a significant inverse correlation between serum levels of the peptide and phosphorus. Elevation of parathyroid hormone-related peptide levels was less common among hypercalcemic patients with metastatic bone disease (38%). Four of the seven hypercalcemic patients with hematologic malignancies had elevated parathyroid hormone-related peptide levels. In our overall study population, serum calcium levels were weakly but significantly correlated with parathyroid hormone-related peptide levels. In conclusion, elevated parathyroid hormone-related peptide in a patient with hypercalcemia suggests a malignant disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Anti-myeloperoxidase antibodies and associated diseases.

Thirty five (41%) sera presented anti MPO specificity, 26 of them (74%) having a p-ANCA pattern. They were present in patients with vasculitis and isolated or predominant renal involvement, but also in 24% of Wegener patients.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1993

[Role of the titration of anti-neutrophil cytoplasmic antibodies in therapeutic follow-up of patients with systemic vasculitis].

We studied clinical and biological data of 18 patients presenting ANCA associated diseases for 16 months at least. Five relapses were preceded by ANCA elevation, 1 relapse was not. Four transient elevations were noted without any clinical event. We think ANCA level elevation by itself is not enough for deciding therapy intensification, clinical data are necessary for doing so.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1992

Determination of anti-neutrophil cytoplasm antibodies (ANCA) specificity by immunofluorescence on chronic myelocytic leukemia cells.

ANCA positive sera, detected by the standard immunofluorescence method, derived from 37 patients with vasculitis were studied using formalin-acetone fixed chronic myelocytic leukemia cells (CML). All 37 sera were positive on CML cell smears. Furthermore formalin-actone fixation selectively impaired antinuclear antibody binding without reducing ANCA staining and thus facilitated differentiation of these autoantibodies which is often difficult with the standard immunofluorescence method. Two unequivocal and mutually exclusive ANCA binding patterns were identified using the CML smears: (1) type I with diffuse granular binding confined to the polymorphonuclear (PMN) cell lineage and preferentially staining immature cells; (2) type II with similar binding to the PMN cell lineage and, in addition, granular staining of the basophils. All type I antibodies were associated with a c-ANCA pattern suggesting that the major antigen recognized by these antibodies, recently identified as proteinase 3, is not detectable in basophils. The type II pattern was detected in both p-ANCA (84%) and c-ANCA (16%) positive sera. The type I sera remained positive on PMN cells from a myeloperoxidase (MPO) deficient subject and anti-MPO antibodies could not be detected in this group by ELISA. Conversely the type II pattern occurred in the presence of anti-MPO antibodies identified by immunofluorescence, ELISA and dot-blot with the exception of a single serum with antilactoferrin antibody. Type I binding only was observed in Wegener's granulomatosis (WG) but both patterns were found in microscopic polyarteritis (MPA) and rapidly progressive glomerulonephritis (RPGN).

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1991

Aluminium determination in the skin of patients with and without end-stage renal failure.

Aluminium (Al) concentration in the skin was determined by inductively coupled plasma optical emission spectrometry to look for a correlation between Al exposure and skin content in patients with end-stage renal failure. Skin Al concentrations were higher in dialyzed patients than in the nondialyzed group (1.02 +/- 0.30 vs. 0.26 +/- 0.10 micrograms/g; p less than 0.001). Moreover, in the dialyzed group, the patients treated for more than 100 months had a higher concentration of Al in the skin than the others (1.20 +/- 0.26 vs. 0.80 +/- 0.18 micrograms/g; p less than 0.05). Al skin content correlated better with the deferoxamine infusion test (DIT) than with Al blood plasma concentration. In conclusion, our data confirm that the DIT is a valuable tool for the evaluation of body Al content.

Adult↗