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Papers by Landino Allegri
médecine/sciences, 1989
P. Roneo : professeur à l'université Pa ris VI. M. Géniteau : maître de conférences à l'uni versi... more P. Roneo : professeur à l'université Pa ris VI. M. Géniteau : maître de conférences à l'uni versité Pa ris XI. F. Châtelet : maître de confé rences à l'université Pa ris VI.
Journal of Hypertension, 2015
Objective: Evidences indicate that in addition to long term regulation of blood pressure, in the ... more Objective: Evidences indicate that in addition to long term regulation of blood pressure, in the kidney resides the initial trigger for the development of hypertension. Altered capacity of the kidney to excrete sodium and water in relation to intake has been proposed as a basic mechanism of initiating hypertension. Betaine is one of the major organic osmolytes and the upregulation of its betaine/gamma-aminobutyric acid transporter (BGT1) in the renal medulla is related to high extracellular tonicity and urinary osmolality. Design and method: The present study investigated the abnormalities in water and sodium balance and osmoregulation in a model of polygenic multifactorial arterial hypertension, the spontaneously hypertensive rats (SHR, n = 58) and compared with their normotensive controls Wistar Kyoto (WKY, n = 46 from their prehypertensive phase (4 weeks of age) until the development hypertension and of organ damage (28–30 weeks of age). Rats were housed in metabolic cages to mon...
American Journal of Human Genetics, 2017
(The American Journal of Human Genetics 101, 789–802; November 2, 2017) In the version of this pa... more (The American Journal of Human Genetics 101, 789–802; November 2, 2017) In the version of this paper originally published, the author's name Anna Materna-Kiryluk was incorrectly hyphenated. It appears correctly here and online. The authors apologize for this error.
Annali italiani di medicina interna : organo ufficiale della Societa italiana di medicina interna, 2005
Mixed cryoglobulinemia (MC) and glomerulonephritis are the most important extrahepatic manifestat... more Mixed cryoglobulinemia (MC) and glomerulonephritis are the most important extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. MC is a non-neoplastic B cell lymphoproliferative process induced by HCV in an antigen-driven mechanism. The clinical expression of cryoglobulinemia varies from an indolent course to the development of systemic vasculitis. Glomerulonephritis is predominantly associated with MC, and almost always takes the form of membranoproliferative glomerulonephritis. The renal manifestations may range from isolated proteinuria to overt nephritic or nephrotic syndrome with variable progression towards chronic renal insufficiency. The treatment of these virus-related diseases must be individualized on the basis of the severity of clinical symptoms. Antiviral therapy with interferon alpha and ribavirin (the currently recommended treatment of HCV infection) may be successful in patients with mild-to-moderate disease, but sustained responses are uncommon....
Nature Communications
Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome... more Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 ( rs230540, OR = 1.25, P = 3.4 × 10−12) and IRF4 ( rs9405192, OR = 1.29, P = 1.4 × 10−14), fine-map the PLA2R1 locus ( rs17831251, OR = 2.25, P = 4.7 × 10−103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10−49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10−93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10−23 and OR = 3.39, P = 5.2 × 10−82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20–37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with ...
Internal and emergency medicine, Jun 23, 2018
The New England journal of medicine, Feb 25, 2017
Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multipl... more Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and c...
Clinical Kidney Journal, 2009
Annali italiani di medicina interna: organo ufficiale della Societa italiana di medicina interna
The Authors discuss the etiologic, pathogenetic and immunopathologic aspects of Heymann nephritis... more The Authors discuss the etiologic, pathogenetic and immunopathologic aspects of Heymann nephritis, in order to compare the numerous acquisitions concerning this nephropathy with the scanty knowledge of human membranous nephropathy, of which it represents the experimental counterpart. This rat disease can be obtained by inoculation of tubular brush border preparations (active form) or of the relevant antibodies (passive form); after an initial hypothesis of glomerular deposition of circulating immune complexes, studies on its pathogenetic mechanisms, instead demonstrated that in situ immunoaggregates, caused by an interaction between circulating antibodies and fixed glomerular antigens, are formed. Recent investigations have led to the identification of a major nephritogenic antigen (gp330), which is a tubular brush border glycoprotein expressed by coated pits located at the glomerular epithelial cell surface. Studies on antigen-antibody interactions at this level have demonstrated that there is a quick redistribution and accumulation of the so-formed immune complexes, and when polyclonal antibodies were utilized, growth of subepithelial electron dense deposits was observed. Although other tubulo-glomerular antigens, which can also be expressed by endothelial cells, play an uncertain role, they seem to favour transmembrane passing of anti-gp330 antibodies. Immune complex formation gives rise to the onset of proteinuria through complement system activation, without leukocyte involvement: in particular a MAC and C9 fraction lytic effect was demonstrated on cultured epithelial cells. In conclusion, studies on Heymann nephritis contribute to our understanding of the etiopathogenetic mechanisms regarding human membranous nephropathy, and emphasize a possible role played by tubular antigens and in situ formed immune complexes.
Annali italiani di medicina interna: organo ufficiale della Societa italiana di medicina interna
Annali italiani di medicina interna: organo ufficiale della Societa italiana di medicina interna
Experimental nephrology
A role for renal antigenic targets has been supposed and sometimes convincingly demonstrated in t... more A role for renal antigenic targets has been supposed and sometimes convincingly demonstrated in the development of various types of experimental glomerulonephritides. In this report we describe a reliable protocol for accurate ultrastructural investigation of antigens on the renal cell surface by means of a pre-embedding technique associated with colloidal gold staining. Sprague-Dawley rats were injected with a monoclonal antibody specific for a 90-kD cell membrane glycoprotein and killed 12 or 48 h later; after prefixation, renal fragments were cryoprotected and snap-frozen. Cryostat sections were incubated with a 5-nm colloidal gold-goat antimouse antibody, postfixed in osmium tetroxide reduced with potassium ferrocyanide and embedded in Durcupan ACM. At the glomerular level, gold granules were localized on the endothelial cell surface. In the proximal tubules uniform labelling was noticed on the brush border microvilli, followed by later marking of the basolateral membranes. By t...
Autoimmunity Reviews, 2015
Research on autoimmune processes involved in glomerulonephritis has been for years based on exper... more Research on autoimmune processes involved in glomerulonephritis has been for years based on experimental models. Recent progress in proteomics has radically modified perspectives: laser microdissection and proteomics were crucial for an in vivo analysis of autoantibodies eluted from human biopsies. Lupus nephritis has been the subject of recent independent researches. Main topics have been the definition of renal autoimmune components in human lupus biopsies; methods were laser capture of glomeruli and/or of single cells (CD38+ or Ki-67+) from tubulointerstitial areas as starting step followed by elution and characterization of renal antibodies by proteomics. The innovative approach highlighted different panels of autoantibodies deposited in glomeruli and in tubulo-interstitial areas that actually represented the unique autoimmune components in these patients. IgG2 was the major isotype; new podocyte proteins (αenolase, annexin AI) and already known implanted molecules (DNA, histone 3, C1q) were their target antigens in glomeruli. Vimentin was the antigen in tubulo-interstitial areas. Matching renal autoantibodies with serum allowed the definition of a typical autoantibody serum map that included the same anti-αenolase, anti-annexin AI, anti-DNA, and anti-histone 3 IgG2 already detected in renal tissue. Serum levels of specific autoantibodies were tenfold increased in patients with lupus nephritis allowing a clear differentiation from both rheumatoid arthritis and other glomerulonephritis. In all cases, targeted antigens were characterized as components of lupus NETosis. Matching renal/serum autoantibody composition in vivo furnishes new insights on human lupus nephritis and allows to refine composition of circulating antibodies in patients with lupus. A thoughtful passage from bench to bedside of new knowledge would expand our clinical and therapeutic opportunities.
médecine/sciences, 1989
P. Roneo : professeur à l'université Pa ris VI. M. Géniteau : maître de conférences à l'uni versi... more P. Roneo : professeur à l'université Pa ris VI. M. Géniteau : maître de conférences à l'uni versité Pa ris XI. F. Châtelet : maître de confé rences à l'université Pa ris VI.
Journal of Hypertension, 2015
Objective: Evidences indicate that in addition to long term regulation of blood pressure, in the ... more Objective: Evidences indicate that in addition to long term regulation of blood pressure, in the kidney resides the initial trigger for the development of hypertension. Altered capacity of the kidney to excrete sodium and water in relation to intake has been proposed as a basic mechanism of initiating hypertension. Betaine is one of the major organic osmolytes and the upregulation of its betaine/gamma-aminobutyric acid transporter (BGT1) in the renal medulla is related to high extracellular tonicity and urinary osmolality. Design and method: The present study investigated the abnormalities in water and sodium balance and osmoregulation in a model of polygenic multifactorial arterial hypertension, the spontaneously hypertensive rats (SHR, n = 58) and compared with their normotensive controls Wistar Kyoto (WKY, n = 46 from their prehypertensive phase (4 weeks of age) until the development hypertension and of organ damage (28–30 weeks of age). Rats were housed in metabolic cages to mon...
American Journal of Human Genetics, 2017
(The American Journal of Human Genetics 101, 789–802; November 2, 2017) In the version of this pa... more (The American Journal of Human Genetics 101, 789–802; November 2, 2017) In the version of this paper originally published, the author's name Anna Materna-Kiryluk was incorrectly hyphenated. It appears correctly here and online. The authors apologize for this error.
Annali italiani di medicina interna : organo ufficiale della Societa italiana di medicina interna, 2005
Mixed cryoglobulinemia (MC) and glomerulonephritis are the most important extrahepatic manifestat... more Mixed cryoglobulinemia (MC) and glomerulonephritis are the most important extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. MC is a non-neoplastic B cell lymphoproliferative process induced by HCV in an antigen-driven mechanism. The clinical expression of cryoglobulinemia varies from an indolent course to the development of systemic vasculitis. Glomerulonephritis is predominantly associated with MC, and almost always takes the form of membranoproliferative glomerulonephritis. The renal manifestations may range from isolated proteinuria to overt nephritic or nephrotic syndrome with variable progression towards chronic renal insufficiency. The treatment of these virus-related diseases must be individualized on the basis of the severity of clinical symptoms. Antiviral therapy with interferon alpha and ribavirin (the currently recommended treatment of HCV infection) may be successful in patients with mild-to-moderate disease, but sustained responses are uncommon....
Nature Communications
Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome... more Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 ( rs230540, OR = 1.25, P = 3.4 × 10−12) and IRF4 ( rs9405192, OR = 1.29, P = 1.4 × 10−14), fine-map the PLA2R1 locus ( rs17831251, OR = 2.25, P = 4.7 × 10−103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10−49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10−93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10−23 and OR = 3.39, P = 5.2 × 10−82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20–37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with ...
Internal and emergency medicine, Jun 23, 2018
The New England journal of medicine, Feb 25, 2017
Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multipl... more Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and c...
Clinical Kidney Journal, 2009
Annali italiani di medicina interna: organo ufficiale della Societa italiana di medicina interna
The Authors discuss the etiologic, pathogenetic and immunopathologic aspects of Heymann nephritis... more The Authors discuss the etiologic, pathogenetic and immunopathologic aspects of Heymann nephritis, in order to compare the numerous acquisitions concerning this nephropathy with the scanty knowledge of human membranous nephropathy, of which it represents the experimental counterpart. This rat disease can be obtained by inoculation of tubular brush border preparations (active form) or of the relevant antibodies (passive form); after an initial hypothesis of glomerular deposition of circulating immune complexes, studies on its pathogenetic mechanisms, instead demonstrated that in situ immunoaggregates, caused by an interaction between circulating antibodies and fixed glomerular antigens, are formed. Recent investigations have led to the identification of a major nephritogenic antigen (gp330), which is a tubular brush border glycoprotein expressed by coated pits located at the glomerular epithelial cell surface. Studies on antigen-antibody interactions at this level have demonstrated that there is a quick redistribution and accumulation of the so-formed immune complexes, and when polyclonal antibodies were utilized, growth of subepithelial electron dense deposits was observed. Although other tubulo-glomerular antigens, which can also be expressed by endothelial cells, play an uncertain role, they seem to favour transmembrane passing of anti-gp330 antibodies. Immune complex formation gives rise to the onset of proteinuria through complement system activation, without leukocyte involvement: in particular a MAC and C9 fraction lytic effect was demonstrated on cultured epithelial cells. In conclusion, studies on Heymann nephritis contribute to our understanding of the etiopathogenetic mechanisms regarding human membranous nephropathy, and emphasize a possible role played by tubular antigens and in situ formed immune complexes.
Annali italiani di medicina interna: organo ufficiale della Societa italiana di medicina interna
Annali italiani di medicina interna: organo ufficiale della Societa italiana di medicina interna
Experimental nephrology
A role for renal antigenic targets has been supposed and sometimes convincingly demonstrated in t... more A role for renal antigenic targets has been supposed and sometimes convincingly demonstrated in the development of various types of experimental glomerulonephritides. In this report we describe a reliable protocol for accurate ultrastructural investigation of antigens on the renal cell surface by means of a pre-embedding technique associated with colloidal gold staining. Sprague-Dawley rats were injected with a monoclonal antibody specific for a 90-kD cell membrane glycoprotein and killed 12 or 48 h later; after prefixation, renal fragments were cryoprotected and snap-frozen. Cryostat sections were incubated with a 5-nm colloidal gold-goat antimouse antibody, postfixed in osmium tetroxide reduced with potassium ferrocyanide and embedded in Durcupan ACM. At the glomerular level, gold granules were localized on the endothelial cell surface. In the proximal tubules uniform labelling was noticed on the brush border microvilli, followed by later marking of the basolateral membranes. By t...
Autoimmunity Reviews, 2015
Research on autoimmune processes involved in glomerulonephritis has been for years based on exper... more Research on autoimmune processes involved in glomerulonephritis has been for years based on experimental models. Recent progress in proteomics has radically modified perspectives: laser microdissection and proteomics were crucial for an in vivo analysis of autoantibodies eluted from human biopsies. Lupus nephritis has been the subject of recent independent researches. Main topics have been the definition of renal autoimmune components in human lupus biopsies; methods were laser capture of glomeruli and/or of single cells (CD38+ or Ki-67+) from tubulointerstitial areas as starting step followed by elution and characterization of renal antibodies by proteomics. The innovative approach highlighted different panels of autoantibodies deposited in glomeruli and in tubulo-interstitial areas that actually represented the unique autoimmune components in these patients. IgG2 was the major isotype; new podocyte proteins (αenolase, annexin AI) and already known implanted molecules (DNA, histone 3, C1q) were their target antigens in glomeruli. Vimentin was the antigen in tubulo-interstitial areas. Matching renal autoantibodies with serum allowed the definition of a typical autoantibody serum map that included the same anti-αenolase, anti-annexin AI, anti-DNA, and anti-histone 3 IgG2 already detected in renal tissue. Serum levels of specific autoantibodies were tenfold increased in patients with lupus nephritis allowing a clear differentiation from both rheumatoid arthritis and other glomerulonephritis. In all cases, targeted antigens were characterized as components of lupus NETosis. Matching renal/serum autoantibody composition in vivo furnishes new insights on human lupus nephritis and allows to refine composition of circulating antibodies in patients with lupus. A thoughtful passage from bench to bedside of new knowledge would expand our clinical and therapeutic opportunities.