print
2/8/2010
IgA-Fibronectin and IgG-Fibronectin Aggregates
Guo-Qiu Shen, M.D.* & Pamela Bean, Ph.D., MBA

Fibronectin (Fn) binding accelerates immune complex (IC) clearance from circulation and inhibits IC deposition in the mesangial area.1 IgA-fibronectin aggregates (IgA-Fn) are associated with IgA nephropathy (IgAN; mesangial IgA glomerulonephritis), the most common form of primary glomerulonephritis worldwide.2,3 Centromere antibody-positive patients have a high percentage of IgA-Fn aggregates and IgG-Fn aggregates, but IgAN patients have only IgA-Fn aggregates.3,4 Other immune abnormalities in IgAN patients include high serum concentrations of IgA, IgA circulating immune complexes and immune complexes containing IgA rheumatoid factor and autologous IgG.5 IgG and IgA antibodies to the glomerular antigens (entactin and nidogen), (distinct from Goodpasture antigen) are also reported.6-8 The association of IgAN and ankylosing spondylitis/sacroiliitis is unexplained.9 The eluted IgA from renal biopsies of primary IgAN patients is anionic and multimeric and forms circulating or in situ IgA complexes.10 IgA-Fn aggregates are not related to serum IgA concentrations or IgA rheumatoid factor.11-13 The ability of polymeric IgA to directly bind to Fn in a normal binding process is involved in the formation of circulating IgA-Fn complexes; this binding is not observed with IgG or IgM.5 Using an ELISA assay, a recent study shows that the interaction between Fn and IgG is not influenced by any other constituent of plasma, is unaffected by temperature and has an estimated Kd of 3.77 x  10-9 M.14

Normal, healthy donors, and some patients with high serum IgA, do not have IgA-Fn aggregates.3,11-13,15 IgA-Fn aggregates occur in ninety-three percent (28/30) of patients with IgAN, but are found in only 11.75% (12/103) of patients with other types of glomerulonephritis.15 Twenty-six out of 51 idiopathic IgAN patients (50.9%), 2 out of 7 Henoch-Schönlein purpura (HSP) (28.5%), 2 out of 14 lupus GN (14.2%), 0 out of 9 membranous GN and 3 out of 9 cirrhosis patients (33%) had IgA-Fn aggregates. Sequential evaluation of sera slightly increases the possibility of detecting positive results (54.6% of 86 sera from IgAN patients.1 Only IgA-Fn aggregates mean levels significantly distinguished IgAN children from others with non-IgA immunologically mediated GN (p<0.0005). Sensitivity and specificity are 61.9% and 80%, respectively.16 Low concentrations of Ig-Fn aggregates involving all three classes of Ig's can circulate normally in plasma, but are markedly enhanced in certain disorders, such as IgAN and HSP.17,18 In spite of these complexities, assays which detect IgA-Fn and IgG-Fn aggregates are useful in the investigation of hematuria and suspected glomerulonephritis and, if cut-offs for the indeterminate range are appropriately adjusted, negative results are strong evidence against IgAN and the presence of only IgA-Fn aggregates (without IgG-Fn aggregates) is strong evidence for IgAN.11,12 Studies of IgA-Fn and IgG-Fn aggregates in thin basement membrane diseases and other autoimmune diseases will be of special interest. IgAN is characterized immunopathologically by relative excess of IgA in the glomeruli as are Henoch-Schönlein nephritis, lupus, and some cases of nephropathy.19 However, no pathogenic role of enhanced plasma IgA binding capacity to fibronectin and IgA-fibronectin aggregates in Henoch-Schonlein purpura has been found.18

Forty three out of 150 patients with SLE had antibodies to Fn.20 The new study showed that Fn binds to the Fc fragment of IgG. The binding of Fn to the Fc region of IgG potentially functions to increase the insolubility of immune aggregates, contributing to progressive complexes of Ics. Interaction between Fn and Ig may contribute to the pathophysiology of immune complex related disorders.14 Considering the entire GN patient population and assuming as 'true positive subjects' the patients with IgAN or HSP nephritis, sensitivity of the assay was 58%, specificity 90%. In this selected biopsy-proven GN population predictive value of positive and negative results were 90.3% and 40.0%, respectively.1 The chronic nephritis rats were treated with injections of Fn; Fn reduces the proteinuria and histologic lesions due to improved clearance of immune complexes, decreased glomerular deposition, and perhaps, to better renal processing of immune complexes.21 The presence of antineutrophil cytoplasmic autoantibodies (ANCA) or IgA-Fn indicates a strong probability for the presence of extraculitis and/or GN.22

A recent study showed that the level of IgA-FN aggregates increased markedly in the serum of patients with IgA nephropathy and 61.5% of them reached the positive standard. Only 8.8% of  the patients with non-IgA nephritis, none of the in-patients with non-renal diseases and 5.1% of the normal controls were beyond the positive criteria.23   
*Not licensed in California

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