Abrogation of the alternative complement pathway by targeted deletion of murine factor B

To investigate the role of mannose-binding lectin-A (MBL-A) in protection against infectious disease, MBL-A−/−-deficient mice were generated. Using a well-characterized mouse model of human filarial nematode infection, nematode survival and protective immune responses were tested in vivo. Blood-borne Brugia malayi microfilariae survived for significantly longer time periods in MBL-A−/− than in wild-type (WT) mice. However, no differences in either splenic cytokine responses or induction of leukocytes in the blood were observed. A profound abrogation of Ag-specific IgM levels was measured in B. malayi-infected MBL-A−/− mice, and some IgG isotypes were higher than those observed in WT animals. To establish whether there was a defect in Ab responses per se in MBL-A−/− mice or the effect was specific to filarial infection, we immunized these mice with OVA or a carbohydrate-free protein. Significantly, Ag-specific IgM responses were defective to both of these Ags, and Ag-specific IgG responses were largely unaffected. Furthermore, in naive mice, total IgM levels did not differ between MBL-A−/− and WT mice. This article describes the first demonstration that MBL-A may function independently of MBL-C and suggests that MBL-A, like other C-type lectins and members of the complement cascade, is intimately involved in the priming of the humoral Ab response.

Section: Discussionmentioning

confidence: 99%

Mannose-Binding Lectin A-Deficient Mice Have Abrogated Antigen-Specific IgM Responses and Increased Susceptibility to a Nematode Infection

Carter

Sumiya

Reilly

et al. 2007

“…Factors B and D have been studied in vivo using specific inhibitors and gene-targeted mice. Serum from these mice has been used to demonstrate that both proteins are required for efficient alternative pathway activation by zymosan (12,13).…”

Section: Components Of the Alternative Pathwaymentioning

confidence: 99%

The Central Role of the Alternative Complement Pathway in Human Disease

Thurman

Holers

2006

386

349

The complement system is increasingly recognized as important in the pathogenesis of tissue injury in vivo following immune, ischemic, or infectious insults. Within the complement system, three pathways are capable of initiating the processes that result in C3 activation: classical, alternative, and lectin. Although the roles that proinflammatory peptides and complexes generated during complement activation play in mediating disease processes have been studied extensively, the relative contributions of the three activating pathways is less well understood. Herein we examine recent evidence that the alternative complement pathway plays a key and, in most instances, obligate role in generating proinflammatory complement activation products in vivo. In addition, we discuss new concepts regarding the mechanisms by which the alternative pathway is activated in vivo, as recent clinical findings and experimental results have provided evidence that continuous active control of this pathway is necessary to prevent unintended targeting and injury to self tissues.

“…Factor B is predominantly produced by hepatocytes, but it can be produced by other cells such as epithelial and endothelial cells, and its production can by up-regulated by cytokines such as IFN-␥ (19). Although only one human patient with congenital deficiency of factor B has been reported (20), studies of factor B knockout mice ( fB Ϫ/Ϫ ) have not yet demonstrated an immune-modulating effect for this factor (21). The lymphoid organs, IgG1 Ab response to T-dependent Ags, and sensitivity to endotoxic shock appeared normal in fB Ϫ/Ϫ mice.…”

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

247

231

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.