Reevaluation of the Mucosa-Bone Marrow Axis in IgA Nephropathy with Animal Models

Impaired immune regulation along the ‘mucosa-bone marrow axis’ has been postulated to play an important role in the pathogenesis of IgA nephropathy (IgAN). Animal models have allowed us to study such changes in detail. Recently, we established several useful animal models, including IgAN-prone mice. Using these animal models, our group is approaching the underlying mechanisms by which bone marrow and mucosal cell interrelate and finally induce this disease. Accumulating evidence from these approaches suggests that there is dysregulation of innate and cellular immunity in IgAN resulting in changes in the mucosal immune system. These changes appear to be closely linked to disruption of mucosal tolerance, resulting in abnormal priming and dissemination of cells to sites such as the bone marrow where they are responsible for synthesis of nephritogenic IgA. Our clinical studies further support these ideas and indicate that the tonsils may be a major mucosal priming site in human IgAN. In addition, our findings also suggest clinical application of nephritogenic IgA (IgA1) as a biological marker and possible future treatment strategies that focus on manipulating the priming and dissemination of these memory cells in order to prevent the appearance of nephritogenic IgA (IgA1) in the systemic compartment.