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Biological Consequences of Complement Activation - I
This Sqadia video is the demonstration of The Complement System - III. Complement serves as an important mediator of the humoral response. Amplifies the response and converts it into an effective defense mechanism. Finally destroying the invading microorganisms. Complement components or split products participate in Inflammatory response, Opsonization of antigen, Viral neutralization, and Clearance of immune complexes. Biological activities of the complement system depend on the binding of complement fragments to complement receptors expressed by various cells. Some complement receptors play an important role in regulating complement activity, binding biologically active complement components, and degrading them into inactive products. Different complement binding receptors have different activity and they differ in cellular differentiation. Such as major ligand of receptors CR1 (CD 35) is C3b and C4b, blocking the formation of C3 convertase and binding immune complexes to cells, and, they are distributed in erythrocytes, neutrophils, monocytes, macrophages, eosinophils, follicular dendritic cells, B cells, some T cells. Major ligand of receptors CR2 (CD 21) is C3d, C3dg, iC3b. They are part of B-cell activation, binds to the Epstein-Bar virus. They are distributed in B cells, follicular dendritic cells, and in some T cells.
Biological Consequences of Complement Activation - II
The membrane-attack complex formed by complement activation can lyse gram-negative bacteria, parasites, viruses, erythrocytes, and nucleated cells. Because the alternative and lectin pathways of activation generally occur without an initial antigen-antibody interaction, these pathways serve as important innate immune defenses against infectious microorganisms. The requirement for an initial antigen-antibody reaction in the classical pathway supplements these nonspecific innate defenses with a more specific defense mechanism. The requirement for antibody in the activating event may be supplied by so-called natural antibodies. All enveloped viruses are susceptible to complement mediated lysis. The viral envelope is largely derived from the plasma membrane of infected host cells. Therefore, susceptible to pore formation by MAC. Among the pathogenic viruses susceptible to lysis by complement-mediated lysis are herpesviruses, orthomyxoviruses, paramyxoviruses, and retroviruses. A few gram-negative bacteria can develop resistance to complement-mediated lysis. In E.coli and Salmonella, resistance to complement is associated with the smooth bacterial phenotype characterized by the presence of long polysaccharide side chains in the cell-wall LPS component.
Biological Consequences of Complement Activation - III
Strains of Neisseria gonorrhea resistant to complement-mediated killing is associated with disseminated gonococcal infections in humans. Some evidence suggests that the membrane proteins of resistant Neisseria strains undergo noncovalent interactions with the MAC and prevent its insertion into the outer membrane. These examples are the exception. Most gram-negative bacteria are susceptible to complement mediated lysis. Gram-positive bacteria are generally resistant to complement- mediated lysis because of the thick peptidoglycan layer in their cell wall. Complement activation can occur on the cell membrane of encapsulated bacteria such as streptococcus pneumoniae. Some bacteria possess an elastase that inactivates C3a and C5a. Lysis of nucleated cells requires formation of multiple membrane attack complexes. Complement-mediated lysis by antibodies specific for tumor-cell antigens are potential weapon against cancer may be rendered ineffective by endocytosis of the MAC. The smaller fragments resulting from complement cleavage are called anaphylatoxins. The anaphylatoxins also induce smooth-muscle contraction and increased vascular permeability. The activities of these highly reactive anaphylatoxins are regulated by serum protease called carboxypeptidase N. It cleaves an Arg residue from the C terminus of the molecules yielding so-called des-Arg forms.
Biological Consequences of Complement Activation - IV
C3b is the major opsonin of the complement system. C4b and iC3b also have opsonizing activity. The amplification that occurs with C3 activation results in a coating of C3b on immune complexes and particulate antigens. Antigen coated with C3b binds to cells bearing CR1. Activation of phagocytic cells by various agents has been shown to increase. Recent studies indicate that complement fragment C3b acts as an adjuvant when coupled with protein antigens. C3b targets the antigen directly to the phagocyte, enhancing the initiation of antigen processing and accelerating specific antibody production. The complement system mediates viral neutralization through number of mechanisms. Some degree of neutralization is achieved by formation of larger viral aggregates. The C3b component facilitates aggregate formation as little as two molecules of antibody per virion. The binding of antibody and/or complement to the surface of a viral particle creates a thick protein coating that can be visualized by electron microscopy. The importance of the complement system in clearing immune complexes is seen in patients with the autoimmune disease systemic lupus erythematosus (SLE). Complement plays a significant role in the development of tissue damage in SLE. The complement deficiencies interfere with effective solubilization and clearance of immune complexes; as a result, these complexes persist, leading to tissue damage.
Genetic deficiencies have been described for each of the complement components. Homozygous deficiencies in any of the early components of the classical pathway (C1q, C1r, C1s, C4, and C2) exhibit similar symptoms. Individuals with complement deficiencies suffer from recurrent infections by pyogenic (pus forming) bacteria i.e. Streptococci and Staphylococci. the early complement components ordinarily prevent recurrent infection by mediating a localized inflammatory response and opsonizing the bacteria. Deficiencies in factor D and properdin appear to be associated with Neisseria infections but not with immune-complex disease. Patients with C3 deficiencies have the most severe clinical manifestations, reflecting the central role of C3 in activation of C5 and formation of the MAC. Individuals with homozygous deficiencies in the components involved in the MAC develop recurrent meningococcal and gonococcal infections. MAC-deficient individuals rarely have immune-complex disease. Interestingly, a deficiency in C9 results in no clinical symptoms. Deficiency of C1Inh regulates activation of the classical pathway. An autosomal dominant condition result in hereditary angioedema which manifests clinically as localized edema of the tissue.