IMMUNOLOGY TEXTBOOK - Mercury Podillia 2013

STRUCTURE AND PRINCIPLES OF FUNCTIONING OF THE IMMUNE SYSTEM

Molecules involved in and resulting from the immune response

The Complement System is a complex of soluble and Cell-surface Proteins whose interactions mediate various biological effects: cell destruction (lysis), recruitment of leukocytes to the site of infection or inflammation (chemotaxis), enhancement of phagocytosis (opsonization), and stimulation of inflammation and hypersensitivity reactions (anaphylatoxins). The majority of complement components are synthesized by hepatocytes and mononuclear phagocytes. Complement components circulate in the Blood in an inactive form. There are two interrelated pathways of complement activation: the classical and the alternative pathways. The complement cascade is triggered either by immune complexes (the classical pathway) or by the direct Cleavage of C3 (The alternative pathway).

The classical pathway begins with the binding of the C1 component to an antigen-antibody complex (IgG or IgM). Upon binding, C1 is activated and acquires The ability to cleave C4 into C4a and C4b, and C2 into C2a and C2b. This results in The formation of the C4bC2a complex, which Functions as a C3 convertase and cleaves C3 into C3a and C3b. Subsequently, C3b binds to the complex, forming C4bC2aC3b. This complex functions as a C5 convertase, cleaving C5 into C5a and C5b. The C5b fragment can independently attach to The Cell membrane and serve as a core for the Formation of the membrane attack (lytic) complex. C6, C7, C8, and C9 then bind sequentially to C5b on the membrane. In its Structure and properties, the C9 component resembles perforin, a cytotoxin produced by natural killer Cells and cytotoxic lymphocytes.

The alternative pathway is initiated by the C3b fragment, which is present in serum at low concentrations. Factor B binds to C3b to form the C3bB complex, which serves as a substrate for factor D. Under METABOLISM/18.html">The Influence of factor D, factor B within this complex is cleaved into Ba and Bb, with Bb remaining part of the complex. This complex exhibits proteolytic activity against C3, cleaving it into C3a and C3b. The C3bBb complex is highly unstable and, to maintain its activity, complexes with a serum protein known as properdin. Properdin effectively stabilizes Polysaccharides, Glycolipids, and Glycoproteins On the surface of microorganisms. Consequently, the C3bBb complex binds to the microbial surface and catalyzes The production of large amounts of C3b. The resulting complex acquires C5 convertase properties and triggers the lytic effect.

Complement activation results in the generation of: 1) inflammatory mediators; 2) opsonins that bind to target cells and facilitate their phagocytosis; and 3) the membrane attack complex, which destroys target cells.

Adhesion molecules. The migration of leukocytes into a site of inflammation or infection begins with a series of adhesive events, each involving specific types of leukocytes: neutrophils, monocytes, or lymphocytes. Circulating leukocytes typically engage in only transient contacts with the endothelial cells of postcapillary venules, effectively "rolling" along the vascular endothelial surface. This phase is mediated by the initial interaction of P-, followed by L- and E-selectins, with carbohydrate moieties on the cell membranes. L-selectin is expressed on the majority of leukocytes. Endothelial P-selectin mediates the adhesion of neutrophils and monocytes to the endothelium, while E-selectin is expressed on activated endothelial cells and Supports lymphocyte adhesion.

The rolling phase occurs without leukocyte activation; however, as rolling leukocytes contact the endothelial surface, they receive activation signals that lead to their immobilization. This initiates a second phase of firm adhesion, mediated by the Upregulated ability of leukocyte Integrins to bind ligands from the immunoglobulin superfamily on endothelial cells. Activation signals can include cytokines (chemokines) such as macrophage inflammatory protein-1 beta (MIP-1β), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), macrophage migration inhibitory factor (MIF), platelet-activating factor (PAF), and the complement fragment C5a, all of which are capable of binding to glycosaminoglycans on the endothelial cell surface and acting on rolling leukocytes.