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The complement system is a key player in innate immunity and a major effector arm of humoral immunity. Its activating components are a group of plasma proteins, whose triggering consists of a series of sequential protease-based steps similar to the coagulation, fibrinolytic, and contact pathways. Complement activation is linked to cellular responses by the recognition of cleaved complement protein fragments by receptors on leukocytes and vascular cells. The three primary roles of complement in host defense against infection are to (1) activate an inflammatory response; (2) opsonize microbial pathogens for immune adherence; and (3) damage membranes, including lysis of susceptible organisms. The complement cascade is amplified at several steps so that it has the potential to induce a rapid and massive opsonic and inflammatory response. Complement activation is normally highly targeted and strictly regulated to focus this response. However, complement activation also contributes to tissue injury in infectious, autoimmune, and acute and chronic inflammatory diseases. This chapter gives an overview of the “workings” of the complement system, a brief review of complement deficiency, and discussion of the role of complement in diseases of inflammation, autoimmunity, and debris disposal.

The pentraxins are an ancient family of proteins with a unique architecture found as far back in evolution as the Horseshoe crab. In humans the two members of this family are C-reactive protein and serum amyloid P. Pentraxins are defined by their sequence homology, their pentameric structure and their calcium-dependent binding to their ligands. Pentraxins function as soluble pattern recognition molecules and one of the earliest and most important roles for these proteins is host defense primarily against pathogenic bacteria. They function as opsonins for pathogens through activation of the complement pathway and through binding to Fc gamma receptors. Pentraxins also recognize membrane phospholipids and nuclear components exposed on or released by damaged cells. CRP has a specific interaction with small nuclear ribonucleoproteins whereas SAP is a major recognition molecule for DNA, two nuclear autoantigens. Studies in autoimmune and inflammatory disease models suggest that pentraxins interact with macrophage Fc receptors to regulate the inflammatory response. Because CRP is a strong acute phase reactant it is widely used as a marker of inflammation and infection.

Plasmacytoid dendritic cells (pDC) play an important role in host defense against viral infection by producing large quantities of type I IFN (including IFN-α, IFN-β and other subtypes that bind to the IFN-α receptor, IFNAR) (1, 2). Production of type I IFN by pDC is triggered by recognition of viral nucleic acids through intracellular sensors located in the cytoplasm and in endosomes. In the pDC endosomal pathway TLR7 recognizes RNA and TLR9 recognizes DNA resulting in MyD88-dependent signaling that culminates in the phosphorylation of interferon regulatory factor (IRF) 7, and transcription of type I IFN and other genes (2, 3). The intracellular sequestration of TLR7 and TLR9 prevents activation of this pathway by self RNA and DNA. However, activation can occur when IC containing nucleoprotein antigens derived from apoptotic cells are taken up by pDC through FcγRIIa (4, 5). The generation of autoantibodies against nucleoprotein autoantigens and subsequent formation of IC is characteristic of SLE. The majority of patients with SLE show an IFN signature of gene expression in their peripheral blood cells as the result of chronic overproduction of type I IFN and activation of IFN-inducible genes (6, 7). The IFN signature of gene expression is associated with recent onset of SLE and with a more severe clinical picture including renal and hematological disease (8). Type I IFN stimulates other immune cells including monocytes, dendritic cells, NK cells, T and B lymphocytes and it has been postulated that the activation of pDC by SLE IC may set up a self-perpetuating cycle of autoimmunity (7, 9). This makes the type I IFN pathway an attractive therapeutic target for SLE and several other autoimmune diseases (10). CRP is a soluble pattern recognition molecule and a major acute phase serum protein (11). Serum levels of CRP increase from less than 5 μg/ml at baseline to several hundred μg/ml following trauma, infection or inflammation. The majority of circulating CRP is produced in the liver in response to IL-6. Structurally CRP is a cyclic pentamer, which binds to microbial and host ligands through five identical calcium-dependent binding sites on one face. The other face interacts with the immune system through FcγR and FcαRI on cells (12) or C1q of the classical complement pathway. CRP ligands include apoptotic cells and protein components of the major SLE autoantigens, snRNPs and chromatin (13-15), as well as microbial polysaccharides and phospholipids. We and others have proposed that CRP contributes to the non-inflammatory removal of dead and damaged cells and prevents immunization with nucleoprotein autoantigens. Although there are no known CRP deficiencies or variations in amino acid sequence, a number of polymorphisms affect levels of CRP and single nucleotide polymorphisms (SNPs) in the CRP gene have been associated with SLE risk (16-19). In addition, IFN-α suppresses CRP synthesis (20) and CRP levels are inappropriately low in SLE flares in the absence of serositis or infection (21, 22). CRP administered by injection was first shown to have therapeutic benefit in chromatin-accelerated disease in the (NZB × NZW) F1 female mouse (23). Subsequently CRP expressed from a transgene or injected was found to prolong survival and decrease renal disease in the spontaneous (NZB × NZW) F1 female and the MRL/MpJ-Faslpr mouse models of SLE (24-26). The most pronounced effect of CRP in these models was the prevention and suppression of proteinuria and glomerulonephritis. Experiments in other autoimmune and IC disease models including nephrotoxic nephritis, immune thrombocytopenia and experimental autoimmune encephalomyelitis implicate macrophages, FcγR, and IL-10 as key elements in CRP suppression of autoimmune disease (24, 27, 28). Effects of CRP on the type I IFN pathway have not been reported previously. In this study we examined the effect of CRP on the IFN-α response of human peripheral blood mononuclear cells (PBMC) to IC containing nucleoprotein autoantigens. The results demonstrate a regulatory role for CRP in the type I IFN pathway and provide an additional mechanism for the therapeutic effects of CRP in autoimmune disease models.

C-reactive protein (CRP) is an important biomarker for inflammatory diseases. However, its role in inflammation beyond complement-mediated pathogen clearance remains poorly defined. We identified the major IgA receptor, FcαRI, as a ligand for pentraxins. CRP recognized FcαRI both in solution and on cells, and the pentraxin binding site on the receptor appears distinct from that recognized by IgA. Further competitive binding and mutational analysis showed that FcαRI bound to the effector face of CRP in a region overlapping with complement C1q and Fcγ receptor (FcγR) binding sites. CRP cross-linking of FcαRI resulted in extracellular signal-regulated kinase (ERK) phosphorylation, cytokine production, and degranulation in FcαRI-transfected RBL cells. In neutrophils, CRP induced FcαRI surface expression, phagocytosis, and TNF-α secretion. The ability of CRP to activate FcαRI defines a function for pentraxins in inflammatory responses involving neutrophils and macrophages. It also highlights the innate aspect of otherwise humoral immunity-associated antibody receptors.

C-reactive protein (CRP) is an acute-phase protein with therapeutic activity in mouse models of systemic lupus erythematosus and other inflammatory and autoimmune diseases. To determine the mechanism by which CRP suppresses immune complex disease, an adoptive transfer system was developed in a model of immune thrombocytopenic purpura (ITP). Injection of 200 μg of CRP 24 h before induction of ITP markedly decreased thrombocytopenia induced by anti-CD41. CRP-treated splenocytes also provided protection from ITP in adoptive transfer. Splenocytes from C57BL/6 mice were treated with 200 μg/ml CRP for 30 min, washed, and injected into mice 24 h before induction of ITP. Injection of 106 CRP-treated splenocytes protected mice from thrombocytopenia, as did i.v. Ig-treated but not BSA-treated splenocytes. The suppressive cell induced by CRP was found to be a macrophage by depletion, enrichment, and the use of purified bone marrow-derived macrophages. The induction of protection by CRP-treated cells was dependent on FcRγ-chain and Syk activation, indicating an activating effect of CRP on the donor cell. Suppression of ITP by CRP-treated splenocytes required FcγRI on the donor cell and FcγRIIb in the recipient mice. These findings suggest that CRP generates suppressive macrophages through FcγRI, which then act through an FcγRIIb-dependent pathway in the recipient to decrease platelet clearance. These results provide insight into the mechanism of CRP regulatory activity in autoimmunity and suggest a potential new therapeutic approach to ITP.

C-reactive protein (CRP) is an acute phase reactant with roles in innate host defense, clearance of damaged cells, and regulation of the inflammatory response. These activities of CRP depend on ligand recognition, complement activation, and binding to FcγR. CRP binds to phosphocholine in the Streptococcus pneumoniae cell wall and provides innate defense against pneumococcal infection. These studies examine the effect of this early innate defense molecule on the development of Abs and protective immunity to S. pneumoniae. Dendritic cells (DC) initiate and direct the adaptive immune response by integrating innate stimuli with cytokine synthesis and Ag presentation. We hypothesized that CRP would direct uptake of S. pneumoniae to FcγR on DC and enhance Ag presentation. CRP opsonization of the R36a strain of S. pneumoniae increased the uptake of bacteria by DC. DC pulsed with untreated or CRP-opsonized R36a were transferred into recipient mice, and Ab responses were measured. In mice challenged with free R36a, CRP opsonization resulted in higher secondary and memory IgG responses to both phosphocholine and pneumococcal surface protein A. Furthermore, mice immunized with DC that had been pulsed with CRP-opsonized R36a showed increased resistance to intranasal infection with virulent S. pneumoniae. The effects of CRP on Ag uptake, Ab responses, and protection from infection all required FcR γ-chain expression on DC. The results indicate that innate recognition by CRP enhances effective uptake and presentation of bacterial Ags through FcγR on DC and stimulates protective adaptive immunity.

C-reactive protein (CRP) is the prototypic marker of inflammation and a strong predictor of cardiovascular events in humans. There are questions regarding the validity of the biological effects reported for CRP, in spite of adherence to rigorous control measures minimizing endotoxin [lipopolysaccharide (LPS)] contamination in these in vitro studies. In this study, we addressed the key question of endotoxin contamination in CRP preparations using Toll-like receptor 4 (TLR4) knockdown endothelial cells. Human aortic endothelial cells (HAECs) transfected with prevalidated TLR4 small interfering RNA (siRNA) and scrambled siRNA controls were challenged with pleural fluid-derived CRP or LPS for 12-16 h. Secreted interleukin-6 (IL-6), IL-1beta, IL-8, and plasminogen activator inhibitor-1 (PAI-1) levels and endothelial Nitric oxide synthase (eNOS) activity were determined. TLR4 knockdown in HAECs significantly decreased LPS-induced IL-1beta, IL-6, and IL-8, whereas the stimulatory effects of CRP were similar in both scrambled control and TLR4 knockdown cells. Furthermore, CRP significantly stimulated PAI-1 levels in both control and TLR4-transfected cells and inhibited eNOS activity, whereas LPS effects were negated in TLR4-transfected cells. The data presented cogently demonstrate and further confirm that the biological effects of CRP on HAECs are independent of LPS and thus are attributable to native protein per se. This is the first study to positively authenticate the significance of earlier in vitro reports on CRP biological effects.

Streptococcus pneumoniae is the most common organism responsible for community acquired pneumonia and meningitis. In pneumococcal pneumonia, a strong local inflammatory cytokine response reduces the frequency of bacteremia and increases survival. The initiation of this cytokine response by innate recognition of bacterial cell wall components through TLR has been described, but the role of soluble innate mediators has received limited attention. C-reactive protein (CRP) is an acute phase protein that binds phosphocholine residues on S. pneumoniae cell walls. CRP interacts with phagocytic cells through FcγRI and FcγRII and activates the classical complement pathway. CRP is protective in mouse pneumococcal bacteremia by increasing complement-dependent clearance and killing of bacteria. We studied the cytokine response of PBMC stimulated with CRP-opsonized S. pneumoniae to determine the effect of CRP interaction with FcγR. CRP dramatically increased the production of TNF-α and IL-1β in response to S. pneumoniae. These increases were blocked by phosphocholine, which inhibits CRP binding to S. pneumoniae, by inhibitors of FcγR signaling, and by mAb to FcγRI and FcγRII. A mutated rCRP with decreased FcγR binding had a decreased ability to stimulate TNF-α release, compared with wild-type CRP. Individuals who were homozygous for the R-131 allele of FcγRIIA, which has a higher affinity for CRP, showed higher responses to CRP-opsonized bacteria than did individuals homozygous for the H-131 allele, further implicating this receptor. The results indicate that CRP recognition of S. pneumoniae and binding to FcγR may enhance the early protective cytokine response to infection.

C-reactive protein (CRP) is an acute-phase serum protein and a member of the pentraxin protein family. Its host defense functions predate the adaptive immune system by millions of years. Our current understanding of CRP interactions with complement and with Fcgamma receptors (FcgammaR) have led to an increased appreciation of the regulatory role of CRP in inflammation and autoimmunity. This review outlines the role of CRP in infection, inflammation, and autoimmune disease. We provide a description of recent studies, which suggest that CRP acts through FcgammaR to reduce inflammation and protect from certain autoimmune diseases. A general description of the proposed function of CRP is provided as a framework for future investigation.

C-reactive protein (CRP) is a component of the acute phase response to infection, inflammation, and trauma. A major activity of acute phase proteins is to limit the inflammatory response. It has been demonstrated that CRP protects mice from lethal doses of LPS. In the mouse, CRP binds to the regulatory receptor, FcγRIIb, and to the γ-chain-associated receptor, FcγRI. The goal ofthis study was to determine whether FcγRs are necessary for the protective effect of CRP. The ability of CRP to protect mice from a lethal dose of LPS was confirmed using injections of 500 and 250 μg of CRP at 0 and 12 h. CRP treatment of FcγRIIb-deficient mice increased mortality after LPS challenge and increased serum levels of TNF and IL-12 in response to LPS. CRP did not protect FcR γ-chain-deficient mice from LPS-induced mortality. Treatment of normal mice, but not γ-chain-deficient mice, with CRP increased IL-10 levels following LPS injection. In vitro, in the presence of LPS, CRP enhanced IL-10 synthesis and inhibited IL-12 synthesis by bone marrow macrophages from normal, but not γ-chain-deficient mice. The protective effect of CRP appears to be mediated by binding to FcγRI and FcγRII resulting in enhanced secretion of the anti-inflammatory cytokine IL-10 and the down-regulation of IL-12. These results suggest that CRP can alter the cytokine profile of mouse macrophages by acting through FcγR leading to a down-regulation of the inflammatory response.

Toxic oil syndrome (TOS) was caused by the consumption of rapeseed oil contaminated with derivatives of aniline. Many persons who survived the acute phase developed a puzzling, multi-year chronic disease considered to be inflammatory or autoimmune in nature. In attempting to characterize their autoantibodies, we found that 74% of TOS patients with chronic disease had IgG antibodies to C-reactive protein (CRP). This activity was detectable only when CRP was chemically or physically denatured and behaved like a previously described antibody produced by immunization with the CRP monomer. Significant antibody reactivities to other acute phase proteins, especially alpha 1-antitrypsin and fibrinogen (P0.025) and ceruloplasmin (P0.05) were also observed. IgG antibodies to cryptic epitopes in CRP and other major serum proteins that increase during the acute phase response may reflect an earlier toxin-mediated insult to the liver that included abnormal biosynthesis of and/or damage to acute phase proteins.

Severe injury remains a leading cause of death and morbidity in patients under 40, with the number of annual trauma-related deaths approaching 160,000 in the United States. Patients who survive the initial trauma and post-traumatic resuscitation are at risk for immune dysregulation, which contributes to late mortality and accounts for approximately 20% of deaths after traumatic injury. This post-traumatic immunosuppressed state has been attributed to over-expression of anti-inflammatory mediators in an effort to restore host homeostasis. We measured a panel of monocyte markers and cytokines in 50 severely injured trauma patients for 3 days following admission. We made the novel observation that the subpopulation of monocytes expressing high levels of CD14 and CD16 was expanded in the majority of patients. These cells also expressed CD163 consistent with differentiation into alternatively activated macrophages with potential regulatory or wound-healing activity. We examined factors in trauma plasma that may contribute to the generation and activation of these cells. The percentage of CD14(high)CD16(+) monocytes after trauma correlated strongly with plasma C-reactive protein (CRP) transforming growth factor-β (TGF-β), and macrophage colony-stimulating factor (M-CSF) levels. We demonstrate a role for TGF-β and M-CSF, but not CRP in generating these cells using monocytes from healthy volunteers incubated with plasma from trauma patients. CD16 is a receptor for CRP and IgG, and we showed that monocytes differentiated to the CD14(high)CD16(+) phenotype produced anti-inflammatory cytokines in response to acute phase concentrations of CRP. The role of these cells in immunosuppression following trauma is an area of ongoing investigation.

Ischemia/reperfusion injury and organ allograft rejection both entail excessive cell and tissue destruction. A number of innate immune proteins, including the pentraxins, participate in the removal of this potentially inflammatory and autoimmunogenic material. The classical pentraxins, C-reactive protein (CRP) and serum amyloid P component (SAP) are serum opsonins, which bind to damaged membranes and nuclear autoantigens. Understanding the role of pentraxins in inflammation has been advanced by the recent identification and structural analysis of their receptor interactions.The ligand-binding, complement-activating and opsonic properties of pentraxins have been known for some time. However, the establishment of Fcγ receptors as the primary receptors for pentraxins is a recent finding with important implications for CRP and SAP functions. The crystal structure of SAP in complex with FcγRIIa was recently solved, leading to new insights into function and new opportunities for pentraxin-based therapeutics. In addition, new approaches to inhibit CRP synthesis or binding are being developed based on clinical associations between CRP levels and cardiovascular disease.This review will summarize data on the function of pentraxins in clearance of injured tissue and cells and discuss the implications of this clearance pathway for autoimmunity and ischemia/reperfusion injury.

C-reactive protein (CRP) is a member of the pentraxin family of proteins and an acute phase reactant. CRP modulates the response to inflammatory stimuli including LPS and C5a. We recently demonstrated that CRP prevents and reverses proteinuria in accelerated nephrotoxic nephritis (NTN). NTN is a model of active inflammatory immune complex-mediated nephritis induced by injection of antiglomerular basement membrane. CRP treatment prevented the induction of NTN in C57BL/6 (B6) mice, increased survival, and reversed ongoing nephritis. Protection was associated with a decrease in IL-1β and chemokines in the kidney and peritoneal cells as measured by quantitative RT-PCR. However, IL-10−/− mice were not protected by CRP either when given before disease onset or when disease activity was maximal. FcγRI−/− mice developed NTN, but were only transiently protected by CRP treatment. This transient protection was abrogated by cobra venom factor depletion of complement from FcγRI−/− mice. However, complement depletion did not prevent CRP-mediated protection in B6 mice, and CRP was protective in C3−/− mice. The role of macrophages in the protection provided by CRP was tested by treating B6 mice with liposomes containing clodronate. Clodronate-containing liposomes deplete mice of splenic and hepatic macrophages for 5–7 days. Pretreatment of NTN mice with clodronate but not control liposomes completely prevented CRP-mediated protection. These studies suggest that CRP mediates protection from NTN through the induction of IL-10 and that macrophages are required. In addition, FcγRI plays an important role but is not the sole mediator of CRP-mediated protection.

Objective C-reactive protein (CRP) is an acute-phase serum protein with binding reactivity to nuclear autoantigens and immunomodulatory function. The MRL/lpr mouse is an important model of human systemic lupus erythematosus (SLE). These mice develop high-titer anti-DNA antibodies and immune complex–mediated nephritis and exhibit progressive lymphadenopathy. The mortality rate among these mice is 50% by age 18–20 weeks; the most frequent cause of death is glomerulonephritis. The present study was undertaken to determine whether treatment of mice with CRP would affect the course of lupus nephritis. Methods MRL/lpr mice were treated with a single 200-μg injection of CRP at either age 6 weeks (before disease onset) or age 13 or 15 weeks (when proteinuria had reached high levels). Proteinuria was measured weekly, and levels of anti–double-stranded DNA autoantibodies and blood urea nitrogen were determined monthly. Glomerular immune complex deposition and renal pathology were assessed in mice ages 15 weeks and 17 weeks. Results Early CRP treatment markedly delayed the onset of proteinuria and lymphadenopathy, increased survival, and reduced levels of autoantibodies to DNA. Treatment of mice with active disease reversed proteinuria and prolonged survival. Renal disease was decreased in CRP-treated mice, with a marked suppression of glomerular pathology, tubular degeneration, and interstitial inflammation, which correlated with the decrease in proteinuria and azotemia. Conclusion These findings demonstrate that systemic suppression of autoimmunity is initiated by a single injection of CRP. Long-term maintenance of CRP-mediated protection was reversed by injection of an anti-CD25 monoclonal antibody but not by macrophage depletion, suggesting that disease suppression is maintained by CD25-bearing T cells.

C-reactive protein (CRP) is the prototypical acute phase serum protein, rising rapidly in response to inflammation. CRP binds to phosphocholine (PC) and related molecules on microorganisms and plays an important role in host defense. However, a more important role may be the binding of CRP to PC in damaged membranes. CRP increases clearance of apoptotic cells, binds to nuclear antigens and by masking autoantigens from the immune system or enhancing their clearance, CRP may prevent autoimmunity. CRP binds to both the stimulatory receptors, FcgammaRI and FcgammaRIIa, increasing phagocytosis and the release of inflammatory cytokines; and to the inhibitory receptor, FcgammaRIIb, blocking activating signals. We have shown that, in two animal models of systemic lupus erythematosus (SLE), the (NZB x NZW)F1 mouse and the MRL/lpr mouse, a single injection of CRP before onset of proteinuria delayed disease development and late treatment reversed proteinuria. Thus, in these models, CRP plays an anti-inflammatory role.

Objective—In addition to being a cardiovascular risk marker, recent studies support a role for CRP in atherothrombosis. Several investigators have reported that CRP binds to Fcgamma receptors on leukocytes. The aim of the study is to determine the processing of CRP by human aortic endothelial cells (HAECs).Methods and Results—Binding studies were performed by incubation of HAECs with biotinylated CRP (B-CRP, 25 to 200 μg/mL) for 30 to 180 minutes at 4°C. B-CRP binding was quantitated using streptavidin-fluorescein isothiocyanate followed by flow cytometry. Saturable binding of CRP was obtained at 60 minutes with a CRP concentration between 100 to 150 μg/mL and Kd of 88 nM. CRP binding was inhibited by 10× cold CRP (58%). CRP (100 μg/mL) significantly upregulated surface expression of Fcgamma receptors, CD32, as well as CD64 on HAECs (PConclusions—We demonstrate that CRP mediates its biological effects on HAECs via binding and internalization through Fcgamma receptors, CD32 and CD64.

C-reactive protein (CRP) is an acute phase serum protein that binds to phosphocholine (PC) on phospholipids and polysaccharides and to protein components of chromatin and small nuclear ribonucleoproteins. Complexes between CRP and ligands activate complement and bind to receptors on phagocytic cells. Although complement is required for CRP-mediated clearance or phagocytosis of ligand-coated erythrocytes, the participation of complement and complement receptors in clearance of soluble CRP complexes has not been examined. We have used PC-conjugated BSA to prepare complexes containing either IgG antibody or CRP. We found similar complement-mediated binding of both types of complexes to human erythrocyte complement receptors (CR1, CD35). We also found that serum deficient in C4A or C4B supported binding of CRP and IgG complexes to erythrocytes. These findings indicate that complexes between CRP and soluble ligands may be cleared by the erythrocyte CR1 pathway described for soluble immune complexes.

Two highly sensitive immunoassays for measuring soluble DNA are described. These methods employ a purified mouse monoclonal anti-DNA antibody in enzyme-linked immunoassays. One assay is an antigen capture method utilizing immobilized antibody. Bound DNA is subsequently detected with biotinylated monoclonal anti-DNA antibody, avidin-coupled horseradish peroxidase and a chromogenic substrate. The limit of detection of the assay was 2 ng/ml of DNA. A competition assay relying on immobilized heat-denatured DNA was also designed. In this assay the solution to be analyzed is mixed in equal proportions with monoclonal anti-DNA antibody and the mixture is incubated in the DNA-containing microtiter plates. The inhibition of antibody binding as detected with peroxidase-conjugated anti-mouse IgG was proportional to the concentration of DNA in the sample. The competition assay was tested for its ability to detect DNA in human plasma. The detection limit of DNA in plasma was approximately 150 ng/ml. The assays were compared in their ability to detect various size fragments of DNA. The competition assay was capable of detecting DNA fragments as small as 30 base pairs. In contrast, the capture assay failed to detect low molecular weight fragments up to 150 base pairs although its sensitivity for undigested DNA was comparable to the competition assay. The assay may be of use in the rapid quantitation of low levels of DNA, especially low molecular weight DNA and may also be useful in measuring DNA in human plasma.

In the studies described here we have attempted to evaluate the hypothesis that CRP may function in host defense using two systems in which CRP in the presence of C appears to have opsonic properties. In the first, CRP and C were found to stimulate ingestion of erythrocytes by human monocyte or mouse macrophages in vitro, and to alter clearance patterns in vivo. In the second, we have studied opsonization of S. pneumoniae by CRP and C. Experiments with human neutrophils indicate that although CRP and C can enhance opsonization of S. pneumoniae, this effect is more pronounced in the absence of antibody. In vivo CRP was found to protect mice against intravenous infection with S. pneumoniae.