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PubMed2006

Structure of C3b in complex with CRIg gives insights into regulation of complement activation.

The complement system is a key part of the innate immune system, and is required for clearance of pathogens from the bloodstream. After exposure to pathogens, the third component of the complement system, C3, is cleaved to C3b which, after recruitment of factor B, initiates formation of the alternative pathway convertases. CRIg, a complement receptor expressed on macrophages, binds to C3b and iC3b mediating phagocytosis of the particles, but it is unknown how CRIg selectively recognizes proteolytic C3-fragments and whether binding of CRIg to C3b inhibits convertase activation. Here we present the crystal structure of C3b in complex with CRIg and, using CRIg mutants, provide evidence that CRIg acts as an inhibitor of the alternative pathway of complement. The structure shows that activation of C3 induces major structural rearrangements, including a dramatic movement (>80 A) of the thioester-bond-containing domain through which C3b attaches to pathogen surfaces. We show that CRIg is not only a phagocytic receptor, but also a potent inhibitor of the alternative pathway convertases. The structure provides insights into the complex macromolecular structural rearrangements that occur during complement activation and inhibition. Moreover, our structure-function studies relating the structural basis of complement activation and the means by which CRIg inhibits the convertases provide important clues to the development of therapeutics that target complement.

Complement Activation↗
PubMed2003

Role for complement in mediating intestinal nitric oxide synthase-2 and superoxide dismutase expression.

Inducible nitric oxide synthase (iNOS) and superoxide dismutase (SOD) play an important role in the pathology of ischemia-reperfusion. This study sought to determine if the proinflammatory effects of complement modulate iNOS and SOD in the rat after gastrointestinal ischemia and reperfusion (GI/R). An inhibitory or noninhibitory anti-complement component 5 (C5) monoclonal antibody (18A or 16C, respectively) was administered before GI/R. RT-PCR revealed a significant increase in intestinal iNOS mRNA compared with sham after GI/R that was attenuated significantly by 18A. Immunohistochemistry demonstrated increased iNOS protein expression within the intestinal crypts after GI/R. Cu/Zn SOD (mRNA and protein) was unaffected by GI/R, whereas Cu/Zn SOD activity was reduced significantly. Mn SOD protein expression was decreased significantly by GI/R. Anti-C5 preserved Cu/Zn SOD activity and Mn SOD protein expression. Staining for nitrotyrosine showed that anti-C5 treatment reduced protein nitration in the reperfused intestine. Immunohistochemistry demonstrated prominent phosphorylated (p) inhibitory factor-kappaB (IkappaB)-alpha staining of intestinal tissue after GI/R, whereas anti-C5 reduced p-IkappaB-alpha expression. These data indicate that complement may mediate tissue damage during GI/R by increasing intestinal iNOS and decreasing the activity and protein levels of Cu/Zn SOD and Mn SOD, respectively.

Animals↗
PubMed1986

Impairment of antibacterial defense mechanisms of the lung by extrapulmonary infection.

To determine whether extrapulmonary infection alters antibacterial defenses of the lung, we challenged mice with peritonitis due to Escherichia coli by aerosol inhalation with either Staphylococus aureus or Pseudomonas aeruginosa. In animals without peritonitis, 14% +/- 5% and 11% +/- 1% of the initially deposited viable S. aureus and P. aeruginosa, respectively, remained in the lungs at 4 hr. In contrast, in mice with peritonitis, at 4 hr 45% +/- 9% of the staphylococci were recoved, and the P. aeruginosa had increased to 948% +/- 354% of the initial inoculum. Proliferation of P. aeruginosa in mice with peritonitis was associated with impaired recruitment of polymorphonuclear neutrophils (PMNs) into the lungs. In contrast, a noninfectious stimulus induced more PMNs into the peritoneal cavity than did intraabdominal sepsis but only minimally impaired PMN recruitment into the lungs after aerosol challenge with P. aeruginosa. Sterile intraperitoneal stimulation did not significantly impair intrapulmonary killing of P. aeruginosa. Levels of antigenic C3 and functionally active C5 were significantly depleted in mice with peritonitis due to E. coli. We conclude that the systemic effects of sepsis, including complement depletion, contribute to the decreased pulmonary PMN recruitment and to impaired intrapulmonary bacterial killing of animals with peritonitis due to E. coli.

Animals↗
PubMed1984

The role of C5 in polymorphonuclear leukocyte recruitment in response to Streptococcus pneumoniae.

Polymorphonuclear leukocytes (PMN) play an important functional role in early pulmonary clearance of Streptococcus pneumoniae. The factors responsible for PMN recruitment to the lung after challenges with this organism are poorly defined. We used congenic C5-sufficient B10.D2/nSn (C5+) and C5-deficient B10.D2/oSn (C5-) mice to determine the importance of the C5 molecule in the PMN response to S. pneumoniae. The C5+ and C5- mice were injected with water and varying inoculums of pneumococci via an endobronchial catheter. Bronchoalveolar lavage (BAL) was performed on the inoculated lung at 0 and at 4 h after injection. Cellular response was measured and chemotactic activity was assayed in BAL supernatants at each time interval using human PMN in modified Boyden chambers by the leading front technique. Clearance of bacteria was studied by quantitative lung culture. The C5+ mice recruited significantly more PMN after challenges with both 10(4) and 10(6) pneumococci than did the C5- mice (p less than 0.05), but significant PMN accumulation did occur in C5- mice. Similarly, C5+ mice generated significantly more intraalveolar chemotactic activity than did C5- mice (p less than 0.05) but chemotactic activity was present in both C5+ and C5- mice in checkerboard assays. Pulmonary clearance of bacteria was significantly impaired in the absence of C5 at both inoculums (p less than 0.05). Our results indicate that the C5 molecule yields important PMN chemotaxins during the early time period after intrapulmonary inoculation of S. pneumoniae. However, PMN recruitment after this insult also results from other chemotaxins because both chemotactic activity and PMN recruitment occur within the alveoli of C5- mice.

Animals↗
PubMed1988

Solubilization of the functional C5a receptor from human polymorphonuclear leukocytes.

The C5a receptor has been extracted in an active state from the membranes of human polymorphonuclear leukocytes with the detergents digitonin and beta-dodecyl maltoside. The solubilized receptor exhibits a single class of high affinity binding sites with a Kd = 90 pM, a value similar to that found with intact membranes. Physical studies with the soluble receptor demonstrate that it exists in two forms which differ in molecular mass. Gel filtration experiments with receptor to which C5a has been bound give an apparent molecular mass for the complex of 150-200 kDa. When the experiments were repeated with nonliganded receptor, most of the C5a binding activity eluted with an apparent mass of 150-200 kDa. However, the peak had a pronounced trailing shoulder indicating that, in the nonliganded state, a portion of the receptor population exists in a smaller form, which may be converted to the larger form on binding C5a. The molecular mass of the smaller form, estimated to be 30-70 kDa, is consistent with that of the binding subunit of the receptor. These data imply that the larger form, and therefore the bulk of the solubilized receptor, is oligomeric, a conclusion which is supported by cross-linking studies. When C5a was cross-linked to the soluble receptor two specific complexes with molecular masses of 52 and 95 kDa were formed. The former is the covalent adduct of C5a and the binding subunit of the receptor and the latter appears to be a complex between the 52-kDa species and an additional polypeptide.

Cell Membrane↗
PubMed2002

Indications for the immunological evaluation of patients with meningitis.

Although people with bacterial meningitis lack adequate protective antibody against the invading pathogen, most do not have an underlying immunodeficiency. Certain comorbid conditions increase the risk for development of bacterial sepsis and meningitis. In addition, certain congenital complement deficiencies, defects of antibody production, or asplenia may be first recognized by the occurrence of bacterial meningitis, particularly when it occurs in infants or young children. Deficiencies of the terminal components of complement (C5-C9) or properdin have been associated with recurrent or invasive neisserial infections, and asplenia, agammaglobulinemia, and deficiencies of the early components of complement (e.g., C1-C3) are associated with risks of infections caused by Streptococcus pneumoniae, Haemophilus influenzae, and meningococci. The presence of congenital or acquired immunodeficiencies should be considered in persons who present with bacterial meningitis on the basis of the etiology, clinical epidemiology, and presence of other risk factors.

Complement System Proteins↗
PubMed1981

Polymorphism of human c5.

C5 is polymorphic in Melanesians and related peoples. The polymorphism is demonstrated by isoelectric focusing and functional detection. Inheritance is autosomal and codominant. Preliminary linkage data suggest that C5 is not close to HLA.

Complement C5↗
PubMed1990

The role of the complement system in shock and tissue injury induced by tumour necrosis factor and endotoxin.

It has previously been shown that tumour necrosis factor-alpha (TNF), together with bacterial lipopolysaccharide (LPS), induces shock and bowel necrosis in the rat. Since the complement system plays an important role in inflammation and tissue injury, its role has been studied in a similar model in mice. In most of the present experiments, a low dose (0.2 micrograms/g) of TNF was used for priming, followed 30 min later by LPS (3 micrograms/g), and the experiment was terminated in 150 min. It is shown that: (i) TNF exerts no systemic effects by itself; LPS elicits only mild hypotension but causes no lethality; (ii) TNF-primed mice show exaggerated effects of shock, hypothermia, haemoconcentration and bowel injury after LPS; the majority of these mice died within 150 min; (iii) administration of LPS alone mildly activates the complement system in vivo, while TNF alone has no effect; (iv) the effects of TNF and LPS on complement activation are synergistic; (v) the acute development of shock and bowel injury in response to TNF-LPS is dependent on an intact complement system, more specifically C5, since C5-deficient mice were protected from TNF-LPS-induced shock and tissue injury; C5-deficient mice also showed less hypotension, hypothermia, haemoconcentration and better intestinal perfusion compared with C5-sufficient animals; (vi) however, when the priming dose of TNF was raised to 0.5 micrograms/g, most of the C5-deficient mice developed marked hypothermia, hypotension, haemoconcentration, bowel injury and died. Thus, it is concluded that TNF and LPS act synergistically in activating the complement system, which plays an important role in mediating the tissue injury and lethality induced by these agents.

Animals↗