Solubilization of Antigen-Antibody Complexes: A New Function of Complement as a Regulator of Immune Reactions1

Takahashi, Masako; Takahashi, Satoshi; Hirose, Shunichi

doi:10.1159/000403239

Cited by 32 publications

(42 citation statements)

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“…Factor B is an essential protein in the alternative pathway. Factor B also helps solubilize immune complexes, has been reported to act as a B cell growth factor, and can activate monocytes (15)(16)(17). Bb, one of its split products, may induce apoptosis (18).…”

Section: Lack Of a Functionalmentioning

confidence: 99%

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

Thurman

Ljubanović

Edelstein

et al. 2003

The Journal of Immunology

252

231

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Ischemia/reperfusion (I/R) injury of the kidney is a common cause of acute renal failure (ARF) and is associated with high morbidity and mortality in the intensive care unit. The mechanisms underlying I/R injury are complex. Studies have shown that complement activation contributes to the pathogenesis of I/R injury in the kidney, but the exact mechanisms of complement activation have not been defined. We hypothesized that complement activation in this setting occurs via the alternative pathway and that mice deficient in complement factor B, an essential component of the alternative pathway, would be protected from ischemic ARF. Wild-type mice suffered from a decline in renal function and had significant tubular injury, particularly in the outer medulla, after I/R. We found that factor B-deficient mice (fB−/−) developed substantially less functional and morphologic renal injury after I/R. Furthermore, control wild-type mice had an increase in tubulointerstitial complement C3 deposition and neutrophil infiltration in the outer medulla after I/R, whereas fB−/− mice demonstrated virtually no C3 deposition or neutrophil infiltration. Our results demonstrate that complement activation in the kidney after I/R occurs exclusively via the alternative pathway, and that selective inhibition of this pathway provides protection to the kidneys from ischemic ARF.

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Section: Lack Of a Functionalmentioning

confidence: 99%

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

Thurman

Ljubanović

Edelstein

et al. 2003

The Journal of Immunology

252

231

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“…Complement factor B (fB) is a key protein required for the activation of the alternative pathway [6] and is increased in circulation and in tissues of lupus mice [7][8][9]. In addition, fB solubilizes immune complexes, inhibits proliferation, acts as a B cell growth factor and activates monocytes [10][11][12]. Brain cells intrinsically synthesize fB, along with other complement components, enabling the assembly of the complement cascade in response to inflammatory stimuli [13].…”

Section: Introductionmentioning

confidence: 99%

Absence of functional alternative complement pathway alleviates lupus cerebritis

et al. 2007

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The complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (fB). Immune deposits (IgG and C3) were reduced in the brains of MRL/lpr fB-deficient (fB -/-MRL/lpr) compared to fBsufficient (MRL/lpr) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL/lpr mice) and apoptosis (caspase-3 activity was reduced to 33% of MRL/lpr mice) in these mice indicates that the absence of the alternative pathway was neuroprotective. Furthermore, expression of phospho (p)-Akt (0.16 AE 0.02 vs. 0.35 AE 0.13, p <0.03) was increased, while expression of p-PTEN (0.40 AE 0.06 vs. 0.11 AE 0.07, p <0.05) was decreased in fB -/-MRL/lpr mice compared to their MRL/lpr counterparts. The expression of fibronectin, laminin and collagen IV was significantly decreased in fB -/-MRL/lpr mice compared to MRL/lpr mice, indicating that in the lupus setting, tissue integrity was maintained in the absence of the alternative pathway. Absence of fB reduced behavioral alterations in MRL/lpr mice. Our results suggest that in lupus, the alternative pathway may be the key mechanism through which complement activation occurs in brain, and therefore it might serve as a therapeutic target for lupus cerebritis. IntroductionSystemic lupus erythematosus (SLE) is an autoimmune disease, with central nervous system (CNS) involvement occurring in 20-70% of patients. Complement activation is believed to play a key role in the pathogenesis of SLE [1]. The relevance of complement in lupus cerebritis is supported by enhanced C3 and C4 index values in the cerebrospinal fluid of patients [2] and increased levels of the anaphylatoxins, C3a and C5a, which correlate with the CNS flares [3]. This is also true in experimental lupus cerebritis, and is supported by our recent studies, in which systemic inhibition of the C3/C5 convertases reduced pathological alterations in the CNS of the lupus mouse model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice [4,5]. Complement can be activated through classical, alternative and lectin pathways. Complement factor B (fB) is a key protein required for the activation of the alternative pathway [6] and is increased in circulation and in tissues of lupus mice [7][8][9]. In addition, fB solubilizes immune complexes, inhibits proliferation, acts as a B cell growth factor and activates monocytes 15]. Mice with targeted deletion of the fB gene (fB -/-) were protected from lupus nephritis and ischemiareperfusion injury [7,16]. However, the role of fB in the pathogenesis of lupus cerebritis has not been defined. Bb, one of the split products of fB, can induce apoptosis [17], which is a key feature in the brains of MRL/lpr mice [5,18]. Apoptosis can also be induced by several other factors such as nitric oxide (NO), edema, and the extracellular matrix (ECM) proteins through integrin si...

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“…cis elements responsible for the constitutive and regulated expression of Bf are located in the C2-Bf intergenic region (4). Factor B not only is a component of the alternative complement pathway but also serves as a B cell growth factor (12,13), stimulates mononuclear cell cytotoxicity (14,15), induces macrophage spreading (16), and solubilizes immune complexes (ICs) (17)(18)(19). Bf is found in glomeruli in immune complex glomerulonephritis (20), is produced by glomeruli during inflammation (20), and forms split products (5).…”

mentioning

confidence: 99%

Modulation of Renal Disease in MRL/lpr Mice Genetically Deficient in the Alternative Complement Pathway Factor B

Watanabe

Garnier

Circolo

et al. 2000

The Journal of Immunology

187

138

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In systemic lupus erythematosus, the renal deposition of complement-containing immune complexes initiates an inflammatory cascade resulting in glomerulonephritis. Activation of the classical complement pathway with deposition of C3 is pathogenic in lupus nephritis. Although the alternative complement pathway is activated in lupus nephritis, its role in disease pathogenesis is unknown. To determine the role of the alternative pathway in lupus nephritis, complement factor B-deficient mice were backcrossed to MRL/lpr mice. MRL/lpr mice develop a spontaneous lupus-like disease characterized by immune complex glomerulonephritis. We derived complement factor B wild-type (B+/+), homozygous knockout (B−/−), and heterozygous (B+/−) MRL/lpr mice. Compared with B+/− or B+/+ mice, MRL/lpr B−/− mice developed significantly less proteinuria, less glomerular IgG deposition, and decreased renal scores as well as lower IgG3 cryoglobulin production and vasculitis. Serum C3 levels were normal in the B−/− mice compared with significantly decreased levels in the other two groups. These results suggest that: 1) factor B plays an important role in the pathogenesis of glomerulonephritis and vasculitis in MRL/lpr mice; and 2) activation of the alternative pathway, either by the amplification loop or by IgA immune complexes, has a prominent effect on serum C3 levels in this lupus model.

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Solubilization of Antigen-Antibody Complexes: A New Function of Complement as a Regulator of Immune Reactions1

Cited by 32 publications

References 0 publications

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

Absence of functional alternative complement pathway alleviates lupus cerebritis

Modulation of Renal Disease in MRL/lpr Mice Genetically Deficient in the Alternative Complement Pathway Factor B

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