Jean-François Subra

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

Summary: 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‐β 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 CD45RChigh/CD45RClow ratio between LEW and BN rats are genetically determined by regions on chromosomes 9, 10 and 20.

Systemic and immune manifestations in myelodysplasia: A multicenter retrospective study

The presence of systemic and/or immune manifestations in myelodysplasia has been currently reported. The influence of these manifestations on the natural outcome of myelodysplastic syndrome has to be considered. We present a multicenter retrospective study (2002–2009) of patients with myelodysplastic syndrome disclosing systemic and/or immune manifestations.

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, CD45RChigh and CD45RClow, 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 CD45RChigh/CD45RClow CD4 T cell ratios. The CD45RChigh subpopulation predominates in LEW rats, and the CD45RClow 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 CD45RClow CD4 T cells. Using bone marrow chimeras, we showed that the difference in the CD45RChigh/CD45RClow 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 × BN) F2 intercross. Genome scanning identified one quantitative trait locus on chromosome 9 (∼17 centiMorgan (cM); log of the odds ratio (LOD) score 3.9). In addition, two regions on chromosomes 10 (∼28 cM; LOD score 3.1) and 20 (∼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 CD45RChigh/CD45RClow Th cell subpopulations may shed light on key regulatory mechanisms of pathogenic immune responses.

Long‐term outcomes of the WEGENT trial on remission‐maintenance for granulomatosis with polyangiitis or microscopic polyangiitis

Findings from the WEGENT trial and other short‐term studies have suggested that azathioprine (AZA) or methotrexate (MTX) could effectively maintain remission of granulomatosis with polyangiitis (Wegeners) (GPA) or microscopic polyangiitis (MPA). This study was undertaken to examine whether differences in rates of relapse or adverse events would appear after discontinuation of these 2 maintenance regimens, when assessed over a longer followup period.

Role of Angiotensin II in the Remodeling Induced by a Chronic Increase in Flow in Rat Mesenteric Resistance Arteries

Angiotensin II is a potent growth factor involved in arterial wall homeostasis. In resistance arteries, chronic increases in blood flow induce a rise in diameter associated with arterial wall hypertrophy. Nevertheless, the role of angiotensin II in this remodeling is unknown. We investigated the effect of blocking angiotensin II production or receptor activation on flow-induced remodeling of mesenteric resistance arteries. Arteries were ligated in vivo to generate high-flow arteries compared with normal flow (control) vessels located at a distance. Arteries were isolated after 1 week for in vitro analysis. Arterial diameter, media surface, endothelial NO synthase expression, superoxide production, and extracellular signal–regulated kinase 1/2 phosphorylation were higher in high-flow than in control arteries. Angiotensin-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) prevented arterial wall hypertrophy without affecting diameter enlargement. The nonselective vasodilator hydralazine had no effect on remodeling. Although perindopril and candesartan increased endothelial NO synthase expression in high-flow arteries, hypertrophy remained in rats treated with NG-nitro-l-arginine methyl ester and mice lacking endothelial NO synthase. Perindopril and candesartan reduced oxidative stress in high-flow arteries, but superoxide scavenging did not prevent hypertrophy. Both Tempol and the absence of endothelial NO synthase prevented the rise in diameter in high-flow vessels. Extracellular signal–regulated kinase 1/2 activation in high-flow arteries was prevented by perindopril and candesartan and not by hydralazine. Extracellular signal–regulated kinase 1/2 inhibition in vivo (U0126) prevented hypertrophy in high-flow arteries. Thus, a chronic rise in blood flow in resistance arteries induces a diameter enlargement involving NO and superoxide, whereas hypertrophy was associated with extracellular signal–regulated kinase 1/2 activation by angiotensin II.

A case of sulphasalazine-induced DRESS syndrome with delayed acute interstitial nephritis

Drug rash with eosinophilia and systemic symptoms (DRESS syndrome) is a rare and severe drug-induced hypersensitivity syndrome characterized by haematological abnormalities (hypereosinophilia and/or mononucleosis) and multiorgan involvement. Renal failure has been rarely described. We report the case of a 77-year-old female with sulphasalazine-induced DRESS syndrome who improved rapidly on corticosteroid treatment. After prednisone withdrawal, the patient developed renal failure that necessitated a session of haemodialysis. A kidney biopsy showed acute tubulointerstitial nephritis with an intense lymphocytic infiltrate and tubular necrosis. Kidney function normalized after a further 2 weeks of corticosteroid treatment. This is the first histologically proven case of acute tubulointerstitial nephritis in the setting of sulphasalazine-induced DRESS syndrome.

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.

Long-Term Outcomes Among Participants in the WEGENT Trial of Remission-Maintenance Therapy for Granulomatosis With Polyangiitis (Wegener's) or Microscopic Polyangiitis

Findings from the WEGENT trial and other short‐term studies have suggested that azathioprine (AZA) or methotrexate (MTX) could effectively maintain remission of granulomatosis with polyangiitis (Wegeners) (GPA) or microscopic polyangiitis (MPA). This study was undertaken to examine whether differences in rates of relapse or adverse events would appear after discontinuation of these 2 maintenance regimens, when assessed over a longer followup period.

Renal biopsy practice in France: results of a nationwide study

BACKGROUNDnAlthough several risk factors associated with complications after renal biopsy (RB) have been identified, the gold standard for RB procedures remains to be defined. Practices vary widely among nephrologists, depending on personal experience and the availability of particular techniques. The purpose of our study was to depict the main aspects of the practice of RB in adults in France.nnnMETHODSnMembers of the Société de Néphrologie in France were asked to participate in a questionnaire survey on RB procedures.nnnRESULTSnEighty-eight nephrologists from 74 units (27 in teaching hospitals, 35 in public general hospitals and 12 in private centres) participated in our study. Native kidney and graft biopsies were performed in 73 and 35 units, respectively. RB activity was highly variable among units, ranging from several hundred to <10 per year. Transjugular renal biopsy was judged to be smoothly accessible in 28 out of 73 units (38.4%). Significant variations in practices were observed regarding patient information before RB, assessment of haemorrhagic risk factors, management of patients with antiplatelet agents and haemorrhagic risk factors, and radiological guidance. Early discharge (<12xa0h) was the rule in 3 (4.1%) units for native kidney biopsies and in 10 (28.6%) units for graft biopsies.nnnCONCLUSIONSnOur study is the first to provide a representative picture of everyday RB practices in a country. Important variations in procedures were observed. Our study may represent a preliminary step for the elaboration of guidelines for all aspects of RB practices.

Studies of Congenic Lines in the Brown Norway Rat Model of Th2-Mediated Immunopathological Disorders Show That the Aurothiopropanol Sulfonate-Induced Immunological Disorder (Aiid3) Locus on Chromosome 9 Plays a Major Role Compared to Aiid2 on Chromosome 10

Brown Norway (BN) rats treated with aurothiopropanol-sulfonate (Atps) constitute a model of Th2-mediated immunological disorders associated with elevated IgE responses and renal IgG deposits. Using F2 offspring between Atps-susceptible BN and Atps-resistant Lewis rats, we had previously mapped three quantitative trait loci on chromosomes 9, 10, and 20 for which BN alleles increased susceptibility to Atps-induced immunological disorders (Aiid). In this study we have used congenic lines for the latter two quantitative trait loci, formerly called Atps2 and Atps3 and now named Aiid2 (chromosome 10) and Aiid3 (chromosome 9), for fine mapping and characterization of their impact on Atps-triggered reactions. In Aiid2 congenic lines, the gene(s) controlling part of the IgE response to Atps was mapped to an ∼7-cM region, which includes the IL-4 cytokine gene cluster. Two congenic lines in which the introgressed segments shared only a portion of this 7-cM region, showed an intermediate IgE response, indicating the involvement of several genes within this region. Results from BN rats congenic for the Lewis Aiid3 locus, which we mapped to a 1.2-cM interval, showed a stronger effect of this region. In this congenic line, the Atps-triggered IgE response was 10-fold lower than in the BN parental strain, and glomerular IgG deposits were either absent or dramatically reduced. Further genetic and functional dissections of these loci should provide insights into pathways that lead to Th2-adverse reactions.