Interactions between Leukocytes and Complement

Leukocytes have specific high-affinity cell surface receptors for the activator-bound and soluble fragments of C3, C4, and C5 that are produced by complement activation (Table 1). The complement ligand-leukocyte receptor interactions cause influx of cells to the site of activation (inflammation) with an increased cellular functionality. Such a mechanism leads to "opsonization" of complement activators with the result that activated leukocytes perform their functions with respect to the opsonized material. Receptors for C3a, C4a, C5a, C1q, factor H, C3b and its degradation products, and C4b have been described. Engagement of a specific complement fragment with its corresponding receptor has a specific effect, depending on which fragment and on which type of cell is expressing the receptor. The receptors of acute inflammation, C5aR, CR1, CR3, and CR2, are discussed next.

C5aR is a 40 to 50 Mr membrane protein of granulocytes and macrophages and has nanomolar affinity for C5a. When exposed to C5a dispersing from a site of complement activation, granulocytes migrate toward the C5a source (chemo-taxis) and simultaneously become more activated, exposing, among other functions, more opsonic receptors, such as the C3b-C4b receptor (CR1) and the iC3b receptors (CR3), on their cell surfaces. When the C5aR become saturated with C5a, the cell loses its capacity to respond to a subsequent C5a exposure, as a result of internalization of engaged receptors without replacement. Thus, granulocytes exposed to a C5a solution (rather than a gradient) lose their responsiveness to a C5a gradient, a phenomenon termed desensiti-zation. Clinically, neutrophils from a patient with an injury large enough to produce concentrations of C5a that saturate local neutrophil C5aR and that then penetrate the vascular compartment may lose their capacity to migrate to the point of injury. Because C5a causes both neutrophil and endothelial activation, such an injury may produce pulmonary leukocyte extravasation and acute respiratory distress syndrome (ARDS) (see later discussion). This interaction of C5a with granulocytes is the most apparent effect of complement activation in vivo and has the presumably beneficial effect of concentrating immuno- and phagocytosis-competent cells at the site of injury and complement activation. C5a has other proinflammatory immunoregulatory properties with respect to lymphocytes.

CR1 is one of the opsonic receptors for granulocytes, as well as being a potent inhibitor of complement activation. The natural ligands for CR1 are C3b and C4b that have covalently interacted through the thiolester site, for which it has nanomolar affinity. CR1 is also expressed by human erythrocytes, eosinophils, macrophages, and some lymphocytes. Although granulocytes express a limited number of CR1 molecules on their cell surfaces, a large intracellular pool is pre-synthesized and available. This pool rapidly translocates to the cell surface after exposure of cells to activators, such as C5a, FMLP, endotoxin, TNF, GM-CSF, and PDGF, causing peak numbers of about 75,000 CR1 per cell surface. CR1 in this functional state adheres C3b-coated activators to the leukocyte surfaces. As each activator surface will have many C3bs on it arrayed around the initial C3bs deposited, and, therefore, multiple sites of CR1 engagement, CR1 molecules become effectively immobilized on the granulocyte cell surface after ligating C3b. Increased diglyceride production, indicative of increased cellular function, results from this CR1 cross-linking. If antibody is also present on the activator, enhanced phagocytosis (compared to antibody alone) takes place. Thus, granulocyte CR1 participates in phagocytosis and, by its activity as a cofactor for the degradation of C3b on its own surface, protects granulocytes from being damaged by the intensity of the complement activation.

CR3 (CD 18, CD 11b) shares many of the properties of CR1; however, its complement ligand is iC3b, the degraded form of cell-bound C3b that follows interaction with factor I and cofactor proteins (factor H, MCP, DAF, CR1). CR3 is expressed by the same cells that express CR1 and has a constitutive level of cell-surface expression with the capacity to be quickly translocated to the cell surface by the same activators that affect CR1. CR3 is independent of CR1, as it is a member of the b2-integrin family with a two-chain structure that bears little relationship to CR1. CR3 functions to promote the attachment of granulocytes to endothelium at the site of inflammation with extravasation of granulocytes and engulfment of iC3b-opsonized complement activator. The lung injury caused by systemic complement activation and pulmonary leukosequestration appears to be CR3 dependent. Such injury can be experimentally prevented by white cell depletion, complement depletion, complement inhibition, anti-CD18 antibodies, anti-CD11b and 11a antibodies, and anti-ICAM-1 antibodies.

Since a similar spectrum of inhibitors prevent the inflammatory response to a local injury, it would appear that complement activation triggers a simple integrated response. Complement responds innately to local injury or microbial invasion by activation, simultaneously generating C5a and opsonizing the foreign material with C3b. Elaborated C5a both activates local endothelium and causes passing granulocytes to adhere and then extravasate at the site. This reaction requires iC3b on the endothelium and the C5a-induced expression of CR3 on granulocytes and ICAM-1 on endothelium. Granulocytes migrate through the interstitium to the site of C5a generation and engulf the complement activator, using the C3 fragments bound to the activator for targeting through CR1 and CR3.

CR2 (CD22) forms the link between the phagocytic response to acute injury and the lymphocyte response to produce antibody and future immunity. This cell surface protein of B-lymphocytes ligates to the activator-bound degradation fragments of C3b, iC3b, and C3dg. Experimental immunogens do not generate an IgG response either after depletion of C3 or in the presence of soluble CR2 used to compete with native lymphocyte CR2. Absence of CR2 may interfere with the development of the B-cell repertoire of antibody altogether. Just as the absence of CR2 interferes with B-cell function, the absence of CR1 interferes with the response of T-cells to antigen.

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