title: Gammopathy with IgA mesangial deposition provides a monoclonal model of IgA nephritogenicity and offers new insights into its molecular mechanisms.
abstract: BACKGROUND
  Henoch-Schönlein purpura (HSP) and IgA nephropathy (IgAN) are characterized by mesangial deposition of polyclonal IgA eventually showing aberrant glycosylation, affinity for mesangial cells and/or co-precipitation with antigen, bacterial peptides, autoantibodies or soluble receptors. IgA were also suggested to be negatively charged and predominantly of λ type but rarely in a monoclonal form.
  
  
  METHODS
  A gammopathy case with HSP provided us with a unique molecularly defined nephritogenic IgA1λ. Immunological analysis, biological activities, glycosylation analysis and finally IgA sequence were determined.
  
  
  RESULTS
  Compared to IgA1 from healthy subjects or IgAN patients, IgA1 CAT showed hyposialylation but no hypogalactosylation, in agreement with underexpression of sialyltransferase genes by the plasma cell clone. IgA variable domains had low pIs with negatively charged complementarity-determining regions. Weak reactivity appeared against the cationic autoantigen lactoferrin, which was, however, absent from kidney deposits. Deposition also occurred in mice upon injection of only the polymeric form of IgA1 CAT, despite whether or not co-injected with lactoferrin.
  
  
  CONCLUSIONS
  This monoclonal model of IgA nephritogenicity strongly suggests that beside hinge region glycosylation, V domains play a role in IgA stability and pathogenicity and supports the hypothesis that responses against cationic epitopes from pathogens or autoantigens may select negatively charged complementarity-determining regions prone either to bind charged structures of the mesangium or to promote by themselves IgA aggregation and deposition.
authors: Universite de Limoges, Limoges, France.
authors: Ahmed
authors: A
authors: Boumediene
authors: Christelle
authors: C
authors: Oblet
authors: Zeliha
authors: Z
authors: Oruc
authors: Sophie
authors: S
authors: Duchez
authors: Willy
authors: W
authors: Morelle
authors: Anne
authors: A
authors: Huynh
authors: Jacques
authors: J
authors: Pourrat
authors: Jean-Claude
authors: JC
authors: Aldigier
authors: Michel
authors: M
authors: Cogné
mesh_terms: D000368:Aged; D005260:Female; D005920:Glomerular Mesangium; D005922:Glomerulonephritis, IGA / Q000150:complications / Q000276:immunology*; D006801:Humans; D011695:IgA Vasculitis / Q000150:complications; D007070:Immunoglobulin A; D010265:Paraproteinemias / Q000276:immunology*
chemical_list: D007070:Immunoglobulin A