|
pubmed:abstractText |
The relative ability of IgG subclasses to cause acute inflammation and the roles of specific effector mechanisms in this process are not clear. We explored this in an in vivo model of glomerular inflammation in the mouse. Trinitrophenol was planted on the glomerular basement membrane after conjugation to nephrotoxic Ab. The relative nephritogenicity of anti-trinitrophenol switch variant mAbs was then explored and shown to be IgG2a > IgG2b, with no disease caused by IgG1. Using knockout mice, we showed that FcgammaRIII was necessary for both neutrophil influx and glomerular damage induced by IgG2a and IgG2b. Surprisingly, IgG1 did not cause disease although it binds to FcgammaRIII. Using blocking Abs, we showed that this was explained by an additional requirement for FcgammaRIV, which does not bind to IgG1. IgG2a- or IgG2b-induced neutrophil influx was not affected by deficiency of either FcgammaRI or C3. Bone marrow chimeras were constructed to test the effect of combined deficiency of FcgammaRI and C3, and there was no effect on IgG2a- or IgG2b-mediated neutrophil influx. However, IgG2b-induced albuminuria and thrombosis were reduced in C3-deficient mice, showing an additional role for complement in IgG2b-mediated glomerular damage. The results show that IgG2a and IgG2b are the pathogenic subclasses in acute neutrophil-mediated glomerular inflammation, with an indispensable role for both FcgammaRIII and FcgammaRIV. Additionally, complement contributes to IgG2b-induced glomerular injury.
|
