The central role of the alternative complement pathway in human disease
Joshua M Thurman1, V Michael Holers
1Division of Nephrology and Hypertension, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Insights
The alternative complement pathway is crucial for initiating tissue injury during immune responses. Continuous control of this pathway is vital to prevent self-tissue damage.
Area of Science:
- Immunology
- Complement System Biology
- Pathogenesis of Tissue Injury
Background:
- The complement system plays a significant role in tissue injury following immune, ischemic, or infectious insults.
- Three pathways (classical, alternative, lectin) initiate C3 activation, but their distinct roles in disease are not fully understood.
Purpose of the Study:
- To examine the role of the alternative complement pathway in generating inflammatory products in vivo.
- To discuss novel mechanisms of alternative pathway activation and regulation.
Main Methods:
- Review of recent experimental and clinical findings.
- Analysis of evidence supporting the alternative pathway's role in complement activation products.
Main Results:
- The alternative complement pathway is a key, often essential, driver of proinflammatory complement activation products in vivo.
- Continuous regulation of the alternative pathway is necessary to prevent self-tissue injury.
Conclusions:
- The alternative complement pathway is critically important in mediating complement-driven tissue injury.
- Understanding and controlling alternative pathway activation is essential for preventing autoimmune and inflammatory diseases.
Abstract:
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.
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