Complements immune complex binding

There are several relatively new therapeutic modalities for the treatment of SLE. Trying to eliminate pathogenic anti-dsDNAs, Ferguson etal. developed an antigen-based heteropolymer (AHP) (F3). AHP is a bispecific dsDNA x monoclonal antibody (mAb) complex (dsDNA x anti-CRl mAb) that enables the use of the unique immune complex-binding and clearing capacity of the complement receptor (CR1) on primate erythrocytes. In vitro studies of AHP show a substantial reduction (>90%) of anti-dsDNA titer (F20). In vivo studies in two rhesus monkeys indicate that the erythrocyte-bound antibodies are rapidly cleared from the circulation (F3). 

Type III reactions (immune-complex reactions) In type III reactions, formation of an immune complex and its deposition on tissue surface serve as primary initiators. Occasionally, immune complexes bind to endothelial cells and lead to immune-complex deposition with subsequent complement activation in the linings of blood vessels. Circumstances that govern immune formation or immune-complex disease remain unclear to date, and it usually occurs without symptoms. The clinical symptoms of a type III reaction include serum sickness (e.g. 3-lactams), drug-induced lupus erythematosus (e.g. quinidine) and vasculitis (e.g. minocycline). Type III reactions can result in acute interstitial nephritis or serum sickness (fever, arthritis, enlarged lymph nodes, urticaria and maculopapular rashes) [1-3]. 

A cascade of proteins of the immune response that can be triggered by antigen-antibody complexes and by the innate immune system (e.g. exposure to microbial polysaccharides) to raise the immune response. Complement proteins can detect and bind to foreign material or immune complexes and label them for phagocytosis. They can also cause inflammation by directly degranulating mast cells and releasing chemokines to recruit other immune cells into the affected area. 

The first component of complement is Cl. This is a complex of three molecules designated Clq, Clr and Cls. The classical pathway is only initiated by an immune complex (antibody bound to antigen) when Clq binds to the Fc portion of the complexed antibody (IgM or IgG). The binding of Clq activates the Clr and Cls molecules associated with it to yield activated Cl which now cleaves C4 and then C2 (subunits of... 

The classical pathway can become activated by immune complexes, bacteria, viruses, and F-XIIa. Binding occurs to the complement C1 q, a part of complement factor 1 (Cl). This initiates a cascade of activations, first of Clr, Cls, then of C4. This C4 activates C2, after which C3 becomes activated. Activated C3 initiates a cascade of activations, which are in common with the alternative pathway and which end up in activated C5-9, a membrane attack complex that lyses the target. 

Once deposited, there are multiple mechanisms by which an immune complex initiates an inflammatory reaction (Fig. 2). Foremost among these is activation of the complement system. Immune complexes can activate the classical complement pathway as well as, indirectly or directly, the alternative complement pathway. The biologic activities of complement activation which are relevant to tissue inflammation include the generation of anaphylatoxins C5a and C3a (H29) and chemotactic peptide C5a (H29, T6), direct and indirect membrane lysis by the terminal complement components C56789 (T17), leukocytosis by C3e (G8), macrophage activation by Bb (G12), immune complex solubilization by C3b (C21), and immune adherence, the binding and activation of cells bearing complement receptors. 

Foremost among these assays is the Raji cell assay developed by The-ofilopoulos and co-workers (T15). The Raji cell line, derived from a patient with Burkitt s lymphoma, lacks surface immunoglobulin, has Fc receptors that bind monomeric IgG only weakly, and possesses numerous receptors for Clq, C3b/C4b, C3d, and other complement components (G23, S4, S27, S28, T8, T12). Immune complexes which have fixed complement bind to... 

K2. Kammer, G., and Schur, P. H., Binding of circulating immune complexes to human peripheral blood lymphocytes Effect of complement. Clin. Immunol. Immunopathol. 10, 202-213 (1978). 

Non-IgE-antibody-mediated immunological reactions Modification of erythrocyte surface components due to binding of beta-lactams or their metabolic products is thought to be the cause of the formation of antierythrocyte antibodies and the development of a positive Coombs test implicated in the development of immune hemolytic anemia (211). About 3% of patients receiving large doses of intravenous penicillin (10-20 million units/ day) will develop a positive direct Coombs test (212). However, only a small fraction of Coombs positive patients will develop frank hemolytic anemia (213). Antibody-coated erythrocytes are probably eliminated by the reticuloendothelial system (extravascular hemolysis) (214), or less often by complement-mediated intravascular erythrocyte destruction (215). Another mechanism implicates circulating immune complexes (anti-beta-lactam antibody/beta-lactam complexes), resulting in erythrocyte elimination by an innocent bystander mechanism (82). Similar mechanisms have been implicated in thrombocytopenia associated with beta-lactam antibiotics (216,217). 

Complement activation also contributes to ischemic injury. Current evidence indicates that ischemia leads to the expression of neoantigen or ischemia antigen on cellular surfaces, and this induces binding of circulating IgM natural antibody. This immune complex causes Cl binding, complement activation and the formation of C3a and C3b. C3b activates the remainder of the complement cascade leading to the formation of the membrane attack complex, which is the principal mediator of injury. Complement inhibition results in less myocardial ischemia and reperfusion injury, reviewed by Chan.38... 

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