Arvind Batra1, Alice C Smith, John Feehally, Jonathan Barratt. 1. Department of Infection, Immunity and Inflammation, University of Leicester, and John Walls Renal Unit, Leicester General Hospital, Leicester LE5 4PW, UK.
Abstract
BACKGROUND: IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA (pIgA). In IgAN, mucosal pIgA production is reduced while systemic production is increased, making the latter the likely source of mesangial pIgA, and suggesting a displacement of pIgA-producing cells from mucosal to systemic sites. Upon activation, lymphocytes migrate through the circulation up-regulating homing receptors (HR) which direct their return to appropriate effector locations. We investigated the HR expression of T-cell subsets in IgAN, healthy adults and membranous nephropathy (MN). METHODS: Peripheral blood cells were labelled for CD3, CD4 and CD8, and for L-selectin (naive cells), integrin alpha4beta1 (systemically homing cells) and integrin alpha4beta7 (mucosally homing cells) and analysed by flow immunocytometry. RESULTS: In IgAN, CD3 T cells displayed reduced L-selectin and increased alpha4beta1hi expression, with no difference in alpha4beta7. No abnormality of T-cell HR expression was found in MN. Both IgAN and healthy adults maintained their patterns of T-cell HR expression when studied again at a later time point, and the changes in IgAN were entirely accounted for by the CD4 T-cell subset with CD8 HR expression being normal. CONCLUSIONS: The consistently reduced L-selectin expression by CD4 T cells indicates increased activation of this subset in IgAN. These activated cells express alpha4beta1 rather than alpha4beta7, and therefore home to systemic effector sites. CD4 T cells regulate antibody production, including IgA. As pIgA is overproduced in systemic sites in IgAN, we hypothesize that these activated systemic homing CD4 T cells may direct the aberrant systemic pIgA production observed in IgAN.
BACKGROUND:IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA (pIgA). In IgAN, mucosal pIgA production is reduced while systemic production is increased, making the latter the likely source of mesangial pIgA, and suggesting a displacement of pIgA-producing cells from mucosal to systemic sites. Upon activation, lymphocytes migrate through the circulation up-regulating homing receptors (HR) which direct their return to appropriate effector locations. We investigated the HR expression of T-cell subsets in IgAN, healthy adults and membranous nephropathy (MN). METHODS: Peripheral blood cells were labelled for CD3, CD4 and CD8, and for L-selectin (naive cells), integrin alpha4beta1 (systemically homing cells) and integrin alpha4beta7 (mucosally homing cells) and analysed by flow immunocytometry. RESULTS: In IgAN, CD3 T cells displayed reduced L-selectin and increased alpha4beta1hi expression, with no difference in alpha4beta7. No abnormality of T-cell HR expression was found in MN. Both IgAN and healthy adults maintained their patterns of T-cell HR expression when studied again at a later time point, and the changes in IgAN were entirely accounted for by the CD4 T-cell subset with CD8 HR expression being normal. CONCLUSIONS: The consistently reduced L-selectin expression by CD4 T cells indicates increased activation of this subset in IgAN. These activated cells express alpha4beta1 rather than alpha4beta7, and therefore home to systemic effector sites. CD4 T cells regulate antibody production, including IgA. As pIgA is overproduced in systemic sites in IgAN, we hypothesize that these activated systemic homing CD4 T cells may direct the aberrant systemic pIgA production observed in IgAN.
Authors: Mai Tuyet Vuong; Sigrid Lundberg; Iva Gunnarsson; Lars Wramner; Maria Seddighzadeh; Mirjana Hahn-Zoric; Anders Fernström; Lars A Hanson; Lieu Thi Do; Stefan H Jacobson; Leonid Padyukov Journal: Nephrol Dial Transplant Date: 2009-03-03 Impact factor: 5.992