Batoul Wehbi1,2, Christelle Oblet1, François Boyer1, Arnaud Huard1, Anne Druilhe1, François Paraf3, Etienne Cogné4, Jeanne Moreau1, Yolla El Makhour5, Bassam Badran2, Marjolein Van Egmond6, Michel Cogné7, Jean-Claude Aldigier7. 1. Immunology Department, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Santé et de la Recherche Médicale 1262, Limoges University, Limoges, France. 2. Biochemistry Department, Cancer Biology and Molecular Immunology Laboratory, Lebanese University Section I, Beirut, Lebanon. 3. Anatomy-Histopathology Department, Centre Hospitalier Universitaire Dupuytren, Limoges, France. 4. Nephrology Department, Centre Hospitalier Universitaire Dupuytren, Limoges, France. 5. Life and Earth Sciences Department, Environmental Health Research Laboratory, Lebanese University Section V, Nabatieh, Lebanon; and. 6. Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. 7. Immunology Department, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Santé et de la Recherche Médicale 1262, Limoges University, Limoges, France; michel.cogne@unilim.fr jean-claude.aldigier@unilim.fr.
Abstract
BACKGROUND: IgA nephropathy (IgAN) often follows infections and features IgA mesangial deposition. Polymeric IgA deposits in the mesangium seem to have varied pathogenic potential, but understanding their pathogenicity remains a challenge. Most mesangial IgA1 in human IgAN has a hypogalactosylated hinge region, but it is unclear whether this is required for IgA deposition. Another important question is the role of adaptive IgA responses and high-affinity mature IgA antibodies and whether low-affinity IgA produced by innate-like B cells might also yield mesangial deposits. METHODS: To explore the effects of specific qualitative variations in IgA and whether altered affinity maturation can influence IgA mesangial deposition and activate complement, we used several transgenic human IgA1-producing models with IgA deposition, including one lacking the DNA-editing enzyme activation-induced cytidine deaminase (AID), which is required in affinity maturation. Also, to explore the potential role of the IgA receptor CD89 in glomerular inflammation, we used a model that expresses CD89 in a pattern observed in humans. RESULTS: We found that human IgA induced glomerular damage independent of CD89. When comparing mice able to produce high-affinity IgA antibodies with mice lacking AID-enabled Ig affinity maturation, we found that IgA deposition and complement activation significantly increased and led to IgAN pathogenesis, although without significant proteinuria or hematuria. We also observed that hinge hypoglycosylation was not mandatory for IgA deposition. CONCLUSIONS: In a mouse model of IgAN, compared with high-affinity IgA, low-affinity innate-like IgA, formed in the absence of normal antigen-driven maturation, was more readily involved in IgA glomerular deposition with pathogenic effects.
BACKGROUND:IgA nephropathy (IgAN) often follows infections and features IgA mesangial deposition. Polymeric IgA deposits in the mesangium seem to have varied pathogenic potential, but understanding their pathogenicity remains a challenge. Most mesangial IgA1 in humanIgAN has a hypogalactosylated hinge region, but it is unclear whether this is required for IgA deposition. Another important question is the role of adaptive IgA responses and high-affinity mature IgA antibodies and whether low-affinity IgA produced by innate-like B cells might also yield mesangial deposits. METHODS: To explore the effects of specific qualitative variations in IgA and whether altered affinity maturation can influence IgA mesangial deposition and activate complement, we used several transgenic humanIgA1-producing models with IgA deposition, including one lacking the DNA-editing enzyme activation-induced cytidine deaminase (AID), which is required in affinity maturation. Also, to explore the potential role of the IgA receptor CD89 in glomerular inflammation, we used a model that expresses CD89 in a pattern observed in humans. RESULTS: We found that human IgA induced glomerular damage independent of CD89. When comparing mice able to produce high-affinity IgA antibodies with mice lacking AID-enabled Ig affinity maturation, we found that IgA deposition and complement activation significantly increased and led to IgAN pathogenesis, although without significant proteinuria or hematuria. We also observed that hinge hypoglycosylation was not mandatory for IgA deposition. CONCLUSIONS: In a mouse model of IgAN, compared with high-affinity IgA, low-affinity innate-like IgA, formed in the absence of normal antigen-driven maturation, was more readily involved in IgA glomerular deposition with pathogenic effects.
Authors: M van Egmond; A J van Vuuren; H C Morton; A B van Spriel; L Shen; F M Hofhuis; T Saito; T N Mayadas; J S Verbeek; J G van de Winkel Journal: Blood Date: 1999-06-15 Impact factor: 22.113
Authors: P Launay; B Grossetête; M Arcos-Fajardo; E Gaudin; S P Torres; L Beaudoin; N Patey-Mariaud de Serre; A Lehuen; R C Monteiro Journal: J Exp Med Date: 2000-06-05 Impact factor: 14.307