Distinctive Roles of Neutrophils and Monocytes in Anti-Thy-1 Nephritis

Westerhuis, Ralf; Straaten, Suzanne C. van; Dixhoorn, Mieneke G.A. van; Rooijen, Nico van; Verhagen, Nicole A.M.; Dijkstra, Christine D.; Heer, Emile de; Daha, Mohamed R.

doi:10.1016/s0002-9440(10)64731-1

Cited by 51 publications

(39 citation statements)

References 40 publications

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“…In addition to their potential impact on systemic T and B cells, it is conceivable that the hyperactive B6.Sle3 myeloid cells may also be responsible for the enhanced susceptibility to renal disease seen in B6.Sle3 congenics (Y. Fu and C. Mohan, unpublished observations). The notion that neutrophils and macrophages play an essential role in immune-mediated renal disease is well accepted (57,58), and these cells do appear to play a more prominent role in the renal disease seen in B6.Sle3 mice (Y. Fu and C. Mohan, unpublished observations).…”

Section: Discussionmentioning

confidence: 98%

T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells

et al. 2005

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Sle3 is an NZM2410-derived lupus susceptibility locus on murine chromosome 7. Congenic recombination has resulted in a novel mouse strain, B6.Sle3, associated with serum antinuclear autoantibodies (ANAs), T cell hyperactivity, and elevated CD4/CD8 ratios. An OVA-specific TCR transgene was used as a tool to demonstrate that Sle3 facilitated heightened T cell expansion in vitro, and in vivo, following antigen challenge. Indeed, continued T cell expansion was noted even in response to a tolerogenic signal. However, these phenotypes did not appear to be T cell intrinsic but were dictated by hyperstimulatory B6.Sle3 APCs. Importantly, B6.Sle3-derived DCs and macrophages appeared to be significantly more mature/activated, less apoptotic, and more proinflammatory and were better at costimulating T cells in vitro, compared with the B6 counterparts. Finally, the adoptive transfer of B6.Sle3-derived DCs into healthy B6 recipients elicited increased CD4/CD8 ratios and serum ANAs, 2 cardinal Sle3-associated phenotypes. We posit that their heightened expression of various costimulatory molecules, including CD80, CD106, I-A b , and CD40, and their elevated production of various cytokines, including IL-12 and IL-1β, may explain why Sle3-bearing DCs may be superior at breaching self tolerance. These studies provide mechanistic evidence indicating that intrinsic abnormalities in DCs and possibly other myeloid cells may dictate several of the phenotypes associated with systemic lupus, including ANA formation and T cell hyperactivity.

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Section: Discussionmentioning

confidence: 98%

T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells

et al. 2005

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“…This observation is compatible with the absence of Fc␥R-mediated activation of infiltrating neutrophils. It has been reasoned that secretion of proteolytic enzymes by activated neutrophils can lead to degradation of deposited C3 fragments, which may therefore determine the amount of activated C3 that remains deposited at the site of tissue injury (49). Histological analysis of kidney tissue revealed that ϳ50% of the WT mice developed sclerotic glomeruli on day 37 of the disease (Fig.…”

Section: Discussionmentioning

confidence: 99%

Both Complement and IgG Fc Receptors Are Required for Development of Attenuated Antiglomerular Basement Membrane Nephritis in Mice

Otten

Groeneveld

Flierman

et al. 2009

The Journal of Immunology

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To elucidate the mechanisms of glomerulonephritis, including Goodpasture’s syndrome, mouse models are used that use heterologous Abs against the glomerular basement membrane (GBM) with or without preimmunization with foreign IgG from the same species. These studies have revealed the requirement of either FcγR or complement, depending on the experimental model used. In this study, we provide evidence that both FcγR and complement are obligatory for a full-blown inflammation in a novel attenuated passive model of anti-GBM disease. We demonstrate that administration of subnephritogenic doses of rabbit anti-GBM Abs followed by a fixed dose of mouse mAbs to rabbit IgG, allowing timing and dosing for the induction of glomerulonephritis, resulted in reproducible complement activation via the classical pathway of complement and albuminuria in wild-type mice. Because albuminuria was absent in FcR-γ-chain−/− mice and reduced in C3−/− mice, a role for both FcγR and complement is postulated. Because C1q−/− and C4−/− mice lacking a functional classical and lectin pathway did develop albuminuria, we suggest involvement of the alternative pathway of complement. Anti-GBM glomerulonephritis occurs acutely following the administration of mouse anti-rabbit IgG, and proceeds in a chronic fashion dependent on both FcγR and complement. This novel attenuated model allows elucidating the relative contribution of different mediator systems of the immune system to the development of renal injury, and also provides a platform for the assessment of different treatment protocols and evaluation of drugs that ultimately may be beneficial for the treatment of anti-GBM mediated glomerulonephritides.

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“…Seminal studies using clodronatecontaining liposomes (Table 2) to ablate rMoPh show that recruited glomerular rMoPh are required for the spontaneous repair that occurs after glomerular injury in the Thy1.1 model of mesangioproliferative GN. 88 Ablation and adoptive transfer studies conducted later similarly showed that recruited rMoPh actively promote repair of injured renal tubules. 67,87,[89][90][91] These reparative rMoPh clear DAMPs and other cell and matrix debris, stimulate proliferation of surviving cells through elaboration of wnt ligands, and promote angiogenesis.…”

Section: Functions Of Rmoph In Immunity Tissue Injury and Tissue Rementioning

confidence: 99%

The Renal Mononuclear Phagocytic System

Nelson

Rees

Griffin

et al. 2012

Journal of the American Society of Nephrology

226

230

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The renal mononuclear phagocytic system, conventionally composed of macrophages (Mø) and dendritic cells (DCs), plays a central role in health and disease of the kidney. Overlapping definitions of renal DCs and Mø, stemming from historically separate research tracks and the lack of experimental tools to specifically study the roles of these cells in vivo, have generated confusion and controversy, however, regarding their immunologic function in the kidney. This brief review provides an appraisal of the current state of knowledge of the renal mononuclear phagocytic system interpreted from the perspective of immunologic function. Physical characteristics, ontogeny, and known functions of the main subsets of renal mononuclear phagocytes as they relate to homeostasis, surveillance against injury and infection, and immune-mediated inflammatory injury and repair within the kidney are described. Gaps and inconsistencies in current knowledge are used to create a roadmap of key questions to be answered in future research.

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Distinctive Roles of Neutrophils and Monocytes in Anti-Thy-1 Nephritis

Cited by 51 publications

References 40 publications

T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells

T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells

Both Complement and IgG Fc Receptors Are Required for Development of Attenuated Antiglomerular Basement Membrane Nephritis in Mice

The Renal Mononuclear Phagocytic System

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