Identification of IgG subclasses and C‐reactive protein in lupus nephritis: The relationship between the composition of immune deposits and FCγ receptor type IIA alleles

Abstract

Objective. To characterize the subclass composition of IgG deposited in lupus glomeruli, to examine its relationship to allelic polymorphisms of IgG receptors (Fc␥ receptors [Fc␥R]), and to determine whether C-reactive protein (CRP), a ligand for Fc␥RIIa, is present in these immune deposits.Methods. Renal biopsy samples from 80 patients with lupus nephritis were examined by light microscopy and indirect immunofluorescence with IgG-subclassspecific monoclonal antibodies. Fc␥RIIA genotypes were determined using allele-specific polymerase chain reaction. Immunostaining for CRP was performed on lupus and nonlupus glomerulonephritis specimens.Results. IgG2 and IgG3 were the predominant subclasses in immune deposits in all World Health Organization classes of nephritis. The frequency of genotypes containing the low-binding IgG2 allele, Fc␥RIIa-R131, was significantly greater than expected in patients with class III or class IV nephritis and in patients with intense IgG2 deposition. CRP, a ligand with particular affinity for Fc␥RIIa-R131, was consistently present in the renal immune deposits of lupus nephritis specimens. Conclusion.Fc␥RIIA genes are associated with proliferative renal disease and may contribute to disease pathogenesis. Fc␥RIIa-R131, the variant with low affinity for IgG2, has high affinity for CRP. Thus, Fc␥RIIa-R131 may contribute to impaired removal of circulating immune complexes, as well as efficiently triggering phagocyte activation and the release of inflammatory mediators within glomeruli.Systemic lupus erythematosus (SLE), the prototype human immune complex disease, is characterized by the presence of antigen-antibody complexes within tissues, leading to local release of inflammatory mediators and the influx of inflammatory cells. These events are considered crucial for the development of lupus nephritis. The morphologic and clinical expression of lupus nephritis is closely related to the location, quantity, and inflammatory properties of the immune complexes deposited. IgG is the predominant isotype found in the glomeruli of patients with lupus nephritis, and the severity of nephritis correlates best with the overall quantity of glomerular IgG (1). Few studies, however, have addressed the question of IgG-subclass distribution in the glomeruli of patients with different types of lupus nephritis, despite evidence that different subclasses have different biologic properties (2-9).Little is known about the factors that govern glomerular localization and distribution of immune deposits, both of which are considered critical determinants of glomerular cellular response patterns. It is not clear whether, in the kidney, immune complexes form by passive entrapment of preformed immune complexes, by in situ formation with binding of autoantibodies to endogenous glomerular antigens, or by in situ binding of

High prevalence of autoantibodies to C-reactive protein in patients with chronic hepatitis C infection: association with liver fibrosis and portal inflammation

“…This could indicate that anti-CRP antibodies in HCV patients may partially be targeted against native epitopes of CRP and not to hidden neo-epitopes (monomeric) CRP as is the case in lupus. Potential pathogenic roles for anti-CRP include impaired clearance of immune complexes and apoptotic debris as well as loss of complement-inhibitory effects of CRP in solution [14,[39][40][41][42]; both scenarios could result in advanced damage in targeted organs [16,37,[43][44][45].…”

Pathogenic implications for autoantibodies against C-reactive protein and other acute phase proteins

“…Anti-CRP may also have other pathogenic implications, for instance by reacting with surfacebound CRP on cells and tissue surfaces. Hypothetically, mCRP exposed on surfaces of apoptotic bodies, for instance in the renal glomeruli [158,159], could constitute a target for circulating anti-CRP antibodies in situ, which may subsequently initiate or amplify inflammation in the target organs [63,160]. In analogy, both anti-C1q antibodies and presence of C1q-containing ICs in glomerulus are needed to induce renal exacerbation in lupus-prone mouse models [161] (Figure 5).…”

Practice guidelines for the renal biopsy

“…Additional antibodies may be required in specific circumstances, for example, amyloid speciation, 16,17 collagen IV alpha chains in hereditary nephritis, 18,19 IgG subclasses, 20,21 virus identification, [22][23][24][25] lymphocyte phenotyping in allografts in suspected cases of PTLD, 26,27 C4d in allograft biopsies, 28,29 etc. In the absence of appropriate tissue in the IF sample, paraffin-embedded material can be examined using IP techniques (see later).…”