The Etiology of Glomerulonephritis
The Etiology of Glomerulonephritis
Despite major advances in understanding the genetic predispositions, the autoimmune responses, and the mediators of tissue injury in immunologically mediated GN, there remains a remarkable dearth of knowledge about the etiologic events, or 'second hits', which actually trigger the onset of these diseases. Current evidence suggests that infections may initiate many of the autoimmune or other reactions in genetically susceptible individuals, which lead to glomerular disease through numerous simultaneous and/or sequential pathways that begin with activation of the innate immune response. These pathways vary depending on the nature of the infectious pathogen and the genetically regulated immune response of the host. These mechanisms include immune dysregulation, adjuvant or bystander effects, epitope spreading, molecular mimicry, epitope conformational changes, and antigen complementarity. Infections may also have direct effects on podocytes and other glomerular cells, either due to direct infection or the induction of innate immune responses.
Continued efforts are essential to clarify the genetic basis for susceptibility to GN, as are efforts to improve therapy with new agents directed against the immune response and the myriad mediators it activates in the glomerulus. However, most therapeutic initiatives continue to target downstream events rather than causes. New technologies involving systems biology approaches and the rapidly expanding understanding of the diverse roles of the human microbiome in health and disease are now scientifically feasible and clinically necessary if we are to supplement the existing information reviewed here to further define the infectious triggers of GN. Achieving this goal will allow approaches toward prevention to be added to our currently inadequate therapeutic armamentarium.
Conclusions
Despite major advances in understanding the genetic predispositions, the autoimmune responses, and the mediators of tissue injury in immunologically mediated GN, there remains a remarkable dearth of knowledge about the etiologic events, or 'second hits', which actually trigger the onset of these diseases. Current evidence suggests that infections may initiate many of the autoimmune or other reactions in genetically susceptible individuals, which lead to glomerular disease through numerous simultaneous and/or sequential pathways that begin with activation of the innate immune response. These pathways vary depending on the nature of the infectious pathogen and the genetically regulated immune response of the host. These mechanisms include immune dysregulation, adjuvant or bystander effects, epitope spreading, molecular mimicry, epitope conformational changes, and antigen complementarity. Infections may also have direct effects on podocytes and other glomerular cells, either due to direct infection or the induction of innate immune responses.
Continued efforts are essential to clarify the genetic basis for susceptibility to GN, as are efforts to improve therapy with new agents directed against the immune response and the myriad mediators it activates in the glomerulus. However, most therapeutic initiatives continue to target downstream events rather than causes. New technologies involving systems biology approaches and the rapidly expanding understanding of the diverse roles of the human microbiome in health and disease are now scientifically feasible and clinically necessary if we are to supplement the existing information reviewed here to further define the infectious triggers of GN. Achieving this goal will allow approaches toward prevention to be added to our currently inadequate therapeutic armamentarium.