IgA nephropathy is the most common form of primary glomerulonephritis worldwide. The immunopathologic hallmark of the disease is the mesangial deposition of IgA1 and components of the complement system. Deposition of IgA triggers a chronic glomerular inflammation, resulting in end-stage renal failure in about 30 0% of patients after two decades. In about half of the patients with IgA nephropathy, circulatory IgA1 levels are increased, The factors that determine the mesangial accumulation of IgA are still not clearly understood. IgA1 from IgA nephropathy patients shows an aberrant glycosylation pattern, which may be involved in its mesangial deposition as well as in complement activation. Complement deposition, prominently present in the diseased glomeruli, is a major factor in disease progression. The mechanism of complement activation in IgA nephropathy is still controversial. The deposition of C3 together with C5b-9 and properdin as well as several in vitro studies suggest involvement of the alternative pathway of complement activation. Recent reports and additional studies from our own group on the other hand suggest activation of complement by IgA via the recently discovered lectin pathway.
The major initiator of the lectin pathway is mannan-binding lectin (MBL), a carbohydrate-binding protein that plays an important role in innate host defense. In initial studies, we demonstrated that MBL binds to IgA and thereby can activate the complement system. Altered glycosylation of IgA in IgA nephropathy may in addition allow its interaction with novel complement-activating lectins such as L-ficolin. Therefore, we hypothesize an important contribution of the lectin pathway to IgA-mediated complement activation in IgA nephropathy. Localization of these lectins together with IgA in the mesangial area may further enhance mesangial cell activation. These processes are likely to play a role in induction of mesangial injury and progression of disease in IgA nephropathy.
The present proposal is aimed at resolving the following main questions:
1. Which mechanisms are involved in complement activation by IgA obtained from IgA nephropathy patients?
2. What are the consequences of the interaction between IgA and MBL for the induction of mesangial cell activation? |
