Complement Factor H Deficiency Accelerates Development of Lupus Nephritis

Bao, Lihua; Haas, Mark; Quigg, Richard J.

doi:10.1681/asn.2010060647

Cited by 112 publications

(85 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Animal model data supporting complement activation as pathogenic in lupus nephritis include the observation that fH-deficient MRL/lpr mice died with severe, diffuse GN (48). Conversely, administration of a CR2-Crry fusion protein that targets complement regulation to C3b deposits (CR2 binds C3b) prevented expression of disease (49).…”

Section: Complement and Kidney Diseasementioning

confidence: 99%

Molecules Great and Small

Mathern

Heeger

2015

Clinical Journal of the American Society of Nephrology

242

192

View full text Add to dashboard Cite

The complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement membrane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell-derived complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell-mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit testing of the intriguing concept that targeting complement in patients with an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health.

show abstract

Section: Complement and Kidney Diseasementioning

confidence: 99%

Molecules Great and Small

Mathern

Heeger

2015

Clinical Journal of the American Society of Nephrology

242

192

View full text Add to dashboard Cite

show abstract

“…7,9,10,187 Disease severity is reduced in murine models that lack selected complement proteins and is increased with deficient regulatory proteins. 184,187,188 Blocking studies in murine models suggest that the AP of complement is more important in mediating kidney damage than the classic pathway. 189 The observation that deficiencies of classic pathway proteins C1.C4.C2 are associated with increased risk for lupus suggests protective roles for complement as well.…”

Section: T Cellsmentioning

confidence: 99%

“…[196][197][198][199] Hypocomplementemia with a classic pathway profile, and increased disease susceptibility in the presence of C2 and C4 deficiency, is also common to both entities. 7,9,10,188,200 The histologic features of capillary wall thickening, cellular proliferation, and infiltrating inflammatory cells associated with primarily mesangial and subendothelial deposits of IgG, IgM, and C3 are similar to lupus nephritis and are also seen in a variety of chronic neoplasias (especially monoclonal gammopathies), infections, and other autoimmune processes. [196][197][198][199]201 However, in contrast to lupus, MPGN I in adults is seen almost exclusively (.90%) in association with hepatitis C viral (HCV) infection, and the glomerular deposits often have prominent ultrastructural features of cryoglobulins.…”

Section: T Cellsmentioning

confidence: 99%

Basic and Translational Concepts of Immune-Mediated Glomerular Diseases

Couser

2012

Journal of the American Society of Nephrology

179

155

View full text Add to dashboard Cite

Genetically modified immune responses to infections and self-antigens initiate most forms of GN by generating pathogen-and danger-associated molecular patterns that stimulate Toll-like receptors and complement. These innate immune responses activate circulating monocytes and resident glomerular cells to release inflammatory mediators and initiate adaptive, antigen-specific immune responses that collectively damage glomerular structures. CD4 T cells are needed for B cell-driven antibody production that leads to immune complex formation in glomeruli, complement activation, and injury induced by both circulating inflammatory and resident glomerular effector cells. Th17 cells can also induce glomerular injury directly. In this review, information derived from studies in vitro, well characterized experimental models, and humans summarize and update likely pathogenic mechanisms involved in human diseases presenting as nephritis (postinfectious GN, IgA nephropathy, antiglomerular basement membrane and antineutrophil cytoplasmic antibodymediated crescentic GN, lupus nephritis, type I membranoproliferative GN), and nephrotic syndrome (minimal change/FSGS, membranous nephropathy, and C3 glomerulopathies). Advances in understanding the immunopathogenesis of each of these entities offer many opportunities for future therapeutic interventions.

show abstract

“…12 When crossed with the MRL-lpr mouse strain, a model of lupus, the originated CFH − / − MRLlpr mice exhibit accelerated lupus nephritis and die at younger age than their CFH +/+ MRL-lpr littermates. 13,14 AMD is the leading cause of visual impairment in the elderly, and the FH polymorphism Y402H is the major genetic risk factor for AMD development. 15,16 The presence of drusen (extracellular deposits of debris) between the retinal pigmented epithelium (RPE) and the choroid of the macula is characteristic of AMD.…”

mentioning

confidence: 99%

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes

et al. 2016

View full text Add to dashboard Cite

Factor H (FH) binds apoptotic cells to limit the inflammatory potential of complement. Here we report that FH is actively internalized by apoptotic cells to enhance cathepsin L-mediated cleavage of endogenously expressed C3, which results in increased surface opsonization with iC3b. In addition, internalized FH forms complexes with nucleosomes, facilitates their phagocytosis by monocytes and induces an anti-inflammatory biased cytokine profile. A similar cytokine response was noted for apoptotic cells coated with FH, confirming that FH diminishes the immunogenic and inflammatory potential of autoantigens. These findings were supported by in vivo observations from CFH − / − MRL-lpr mice, which exhibited higher levels of circulating nucleosomes and necrotic cells than their CFH +/+ littermates. This unconventional function of FH broadens the established view of apoptotic cell clearance and appears particularly important considering the strong associations with genetic FH alterations and diseases such as systemic lupus erythematosus and age-related macular degeneration. Factor H (FH), one of the most abundant plasma proteins, is the major soluble inhibitor of the alternative complement pathway. Apoptotic cells bind FH while triggering complement activation by binding of C1 complex, which ensures efficient opsonization and removal of apoptotic debris but prevents excessive complement activation and inflammation. 1,2 Dysregulation of complement contributes significantly to the pathology of many diseases. 3 Recently, novel roles and intracellular location for complement have been identified suggesting that its functions exceed our current understanding. 4 After previously identifying the ligands for FH on the apoptotic cell surface as dsDNA, histones and annexin A2, 5 we sought to explore the functional consequences of the FH-apoptotic cell interaction in the context of the chronic autoimmune disorder systemic lupus erythematosus (SLE) and age-related macular degeneration (AMD). Aberrant apoptosis and impaired clearance of apoptotic cells are of central importance in the pathogenesis of SLE and lead to formation of autoantibodies. 6-8 Anti-chromatin autoantibodies are a hallmark of SLE and anti-annexin A2 autoantibodies are also frequently observed in SLE patients. 9 Interestingly, the corresponding autoantigens are exactly those that we identified as ligands for FH on the apoptotic cell surface, suggesting a possibility of disturbance of FH function in SLE. Glomerulonephritis is one typical manifestation of human SLE 10 and mutations in FH and another complement inhibitor CD46 are associated with earlier onset of nephritis in SLE patients. 11 FH-deficient (CFH − / − ) mice spontaneously develop membranoproliferative glomerulonephritis, which is dependent on C3 activation. 12 When crossed with the MRL-lpr mouse strain, a model of lupus, the originated CFH − / − MRLlpr mice exhibit accelerated lupus nephritis and die at younger age than their CFH +/+ MRL-lpr littermates. 13,14 AMD is the leading cause of visual impairm...

show abstract

Complement Factor H Deficiency Accelerates Development of Lupus Nephritis

Cited by 112 publications

References 70 publications

Molecules Great and Small

Molecules Great and Small

Basic and Translational Concepts of Immune-Mediated Glomerular Diseases

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes

Contact Info

Product

Resources

About