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Published on: July 8, 2020
Characterization of IgA, IgA immune complexes and complement depositions in IgA nephropathy using laser
Anila Cara1, Raman Deep Singh1, Gian Marco Berti1
1Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
Introduction:
IgA nephropathy is characterized by accumulation of mesangial IgA immune complexes. These IgA immune complexes result in glomerular inflammation and subsequent sclerosis. Glomerular inflammation is mediated in part by activation of the complement pathway by these immune complexes.
Methods:
In this study of 22 cases of IgA nephropathy, using laser microdissection and mass spectrometry (LMD/MS), we characterized both IgA and complement deposits.
Results:
LMD/MS detected abundant IgA1 but also IgA2; detected in 100% and 82% of cases, respectively. Furthermore, J chains, that link IgA monomers to form dimeric IgA on mucosal surfaces, was detected in 91% of cases, while the polymeric Ig receptor found in secretory IgA was found in only 9% of the cases. IgG1 was the dominant IgG subclass and was detected in 100% of cases. IgG subclass staining and confocal immunofluorescence microscopy confirmed the IgG1 subclass and colocalization of IgG1 with IgA1 and IgA2.Evaluation of the complement pathways revealed abundant C3, C9, C5, C6, C7 and C8 with lesser amounts of C4 indicating activation of predominantly the alternative and terminal pathways of complement. LMD/MS also detected abundant complement regulating proteins including CFH, CFHR1, CFHR2 and CFHR5, CD59, and smaller amounts of CFB, indicating active regulation of the complement pathways. Although it did not reach statistical significance, high counts of C3, C5 and C9 were present in lesions with endocapillary hypercellularity/crescentic lesions. High counts of complement regulating proteins, particularly CFHR5, were also present in active lesions. C3 sequence coverage data showed the majority of amino acids detected belong to C3dg along with smaller amounts of C3c.
Conclusion:
Our data shows that the IgA immune complexes are composed of mucosal-derived dimeric IgA1/IgA2 and IgG1. The majority of complement proteins detected are components of the alternative and terminal complement pathway.
