Control of the Complement System

Mk, Liszewski; Tc, Farries; Lublin, DM; Ia, Rooney; Jp, Atkinson

doi:10.1016/s0065-2776(08)60868-8

Cited by 453 publications

(308 citation statements)

References 361 publications

Supporting

Mentioning

301

Contrasting

Unclassified

Order By: Relevance

“…DG, Dentate gyrus. early activation pathway; rather, a diversity of complement regulatory proteins expressed on neurons and other cell types inhibits diverse steps in the complement cascade, seeking to limit the deleterious consequences of complement activation on host cells (Liszewski et al, 1996). Immunohistochemical evidence of MAC deposition on neurons in Alzheimer's brains implies that the endogenous defenses are not completely effective.…”

Section: Discussionmentioning

confidence: 99%

Formation of Complement Membrane Attack Complex in Mammalian Cerebral Cortex Evokes Seizures and Neurodegeneration

et al. 2003

View full text Add to dashboard Cite

The complement system consists of Ͼ30 proteins that interact in a carefully regulated manner to destroy invading bacteria and prevent the deposition of immune complexes in normal tissue. This complex system can be activated by diverse mechanisms proceeding through distinct pathways, yet all converge on a final common pathway in which five proteins assemble into a multimolecular complex, the membrane attack complex (MAC). The MAC inserts into cell membranes to form a functional pore, resulting in ion flux and ultimately osmotic lysis. Immunohistochemical evidence of the MAC decorating neurons in cortical gray matter has been identified in multiple CNS diseases, yet the deleterious consequences, if any, of MAC deposition in the cortex of mammalian brain in vivo are unknown. Here we demonstrate that the sequential infusion of individual proteins of the membrane attack pathway (C5b6, C7, C8, and C9) into the hippocampus of awake, freely moving rats induced both behavioral and electrographic seizures as well as cytotoxicity. The onset of seizures occurred during or shortly after the infusion of C8/C9. Neither seizures nor cytotoxicity resulted from the simultaneous infusion of all five proteins premixed in vitro. The requirement for the sequential infusion of all five proteins together with the temporal relationship of seizure onset to infusions of C8/C9 implies that the MAC was formed in vivo and triggered both seizures and cytotoxicity. Deposition of the complement MAC in cortical gray matter may contribute to epileptic seizures and cell death in diverse diseases of the human brain.

show abstract

Section: Discussionmentioning

confidence: 99%

Formation of Complement Membrane Attack Complex in Mammalian Cerebral Cortex Evokes Seizures and Neurodegeneration

et al. 2003

View full text Add to dashboard Cite

show abstract

“…2). An "activating" surface is, in large part, one without adequate regulatory protein function to control alternative pathway activation (22) or one that is not favorable to control of the alternative pathway by factor H (23). Congenital or acquired deficiency of the complement regulatory proteins can result from Abs that block endogenous regulatory mechanisms (24) or decreased expression of complement regulatory proteins (25,26).…”

Section: Continous Active Control Of Alternative Pathway Activation Imentioning

confidence: 99%

The Central Role of the Alternative Complement Pathway in Human Disease

Thurman

Holers

2006

The Journal of Immunology

391

350

View full text Add to dashboard Cite

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.

show abstract

“…The most important mCRP on tumor cells are CD46, a cofactor for factor I-mediated cleavage of C3b and C4b, CD55 which accelerates the decay of C3 and C5 convertases, both inhibiting the formation of the chemoattractants C3a and C5a and the deposition of iC3b on the cell surface, and CD59 that inhibits the formation of the membrane attack complex, thereby preventing direct complement-mediated lysis [11]. Several strategies can be deployed to overcome the effect of mCRP.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of the complement activating capacity of 17-1A mAb to overcome the effect of membrane-bound complement regulatory proteins on colorectal carcinoma

et al. 2002

View full text Add to dashboard Cite

Adjuvant immunotherapy with 17-1A mAb directed against colorectal carcinoma is found to be effective in patients. However, 52 % of the patients treated with mAb 17-1A showed recurrence within 7 years. This high recurrence rate might be due to inhibition of complement activation by membrane-bound complement regulatory proteins (mCRP). The effect of these complement regulatory proteins might be reduced by blocking mCRP, or be overcome by activating more complement at the tumor cell membrane. In this study the complementactivating capacity of the 17-1A mAb was enlarged by conjugating it to cobra venom factor (CVF) or C3b. The most important C3 regulatory protein, CD55, was blocked using a bispecific mAb directed against the 17-1A/Ep-CAM antigen and CD55. Up to a 13-fold increase in C3 deposition was observed due to 17-1A-CVF and 17-1A-C3b, as compared to 17-1A. CD55 was shown to partly inhibit complement activation by these conjugates. The effect of the bispecific anti-17-1A/Ep-CAM*anti-CD55 mAb was compared with 17-1A conjugates with CVF or C3, and bispecific mAb were shown to be equally or more efficient in complement activation than the 17-1A-CVF or 17-1A-C3b conjugates. Therefore, 17-1A conjugates and anti-17-1A/EpCAM*anti-CD55 bispecific mAb may be promising immunotherapeutic agents for patients with colorectal cancer.

show abstract

Control of the Complement System

Cited by 453 publications

References 361 publications

Formation of Complement Membrane Attack Complex in Mammalian Cerebral Cortex Evokes Seizures and Neurodegeneration

Formation of Complement Membrane Attack Complex in Mammalian Cerebral Cortex Evokes Seizures and Neurodegeneration

The Central Role of the Alternative Complement Pathway in Human Disease

Enhancement of the complement activating capacity of 17-1A mAb to overcome the effect of membrane-bound complement regulatory proteins on colorectal carcinoma

Contact Info

Product

Resources

About