Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites

Abstract

To investigate the capacity of lupus autoAb to produce glomerular immune deposits (ID) and nephritis, 24 murine monoclonal (m) anti-DNA antibodies (Ab), derived from either MRL-lpr/lpr, SNF1 or NZB lupus-prone mice and selected based on properties shared with nephritogenic Ig, were administered i.p. (as hybridomas) and i.v. (as purified Ig) to normal mice; at least four mice/mAb were evaluated. Three general patterns of immune deposit formation (IDF) were observed: extracellular ID within glomeruli (+/- blood vessels, N = 8); intranuclear ID (N = 5); or minimal or no ID (N = 11). The four MRL m anti-DNA Ab that produced significant extracellular ID demonstrated different disease profiles including: (a) mesangial and subendothelial ID with anti-basement membrane staining, associated with proliferative glomerulonephritis, PMN infiltration, and proteinuria; (b) diffuse fine granular mesangial and extraglomerular vascular ID, associated with proliferative glomerulonephritis and proteinuria; (c) dense intramembranous ID and intraluminal ID, associated with capillary wall thickening, mesangial interposition and expansion, aneurysmal dilatation and intraluminal occlusion of glomerular capillary loops, and heavy proteinuria; and (d) mesangial and extraglomerular vascular ID, associated with mild segmental mesangial expansion, without proteinuria. These MRL mAb were derived from four different mice, and they had variable pIs and isotypes. They all cross reacted with multiple autoantigens (autoAg), however, their autoAg binding profiles were distinguishable. Among the SNF1 derived mAb, four produced histologically and clinically indistinguishable disease characterized by diffuse mesangial and capillary wall ID, associated with cellular proliferation/infiltration and proteinuria. Three of the four mAb were derived from the same mouse and were clonally related; they were: IgG2b with SWR allotype, relatively cationic, highly cross reactive with similar Ag binding patterns, idiotypically related and encoded by identical VH and nearly identical VL sequences. We conclude that both the capacity of lupus autoAb to form ID and the location of IDF are dependent on properties unique to individual Ig. The results also indicate that the Ag binding region of the autoAb is influential in this process, and they suggest that multiple Ab-Ag interactions contribute to IDF in individuals with lupus nephritis. Furthermore, these observations raise the possibility that the pathologic and clinical abnormalities resulting from these interactions are influenced by the location of IDF, and that the dominant interaction, in a given individual, may be highly influential in the phenotypic expression of nephritis.

Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus

“…AutoAbs typically arise before overt manifestations of disease, and high titers of anti-dsDNA are associated with greater severity (1,2). Similar findings are observed in lupus-prone mice and, importantly, passively administered anti-DNA mAbs can produce lupus-like immune complex kidney deposits (3). Thus, evidence points to a direct role of anti-nuclear Abs in SLE.…”

B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients

“…Of these functions, the production of Igs is central to certain other autoimmune disease models, for example, transfer of self-reactive Igs triggers the immediate onset of inflammatory immunopathology in arthritis, lupus nephritis, oophoritis, pemphigus, etc. (30)(31)(32)(33). Maternal Igs have been suggested to play a different role in type-1 diabetes by contributing to the eventual activation of islet-reactive T cells in the offspring.…”

IL-10 Regulates Murine Lupus

“…We also assessed renal disease in mice from the first cohort, described above in the mortality curves, that survived to 17 wk of age: MRL-Fas lpr IL-10 ϩ/ϩ (n ϭ 5, randomly selected of the 13 animals), MRL-Fas lpr IL-10 ϩ/Ϫ (n ϭ 11, randomly selected of the 21 survivors), and MRL-Fas lpr IL-10 Ϫ/Ϫ (n ϭ 4). Kidney specimens were blindly evaluated by light microscopy and scored on a scale of 0 to Ͼ4ϩ as described in detail previously (26,27). MRL-Fas lpr IL-10 Ϫ/Ϫ mice consistently developed more severe disease than IL-10 ϩ/ϩ animals with significantly enhanced glomerulonephritis ( Fig.…”