Inflammation complement

Endogenous histamine has a modulating role in a variety of inflammatory and immune responses. Upon injury to a tissue, released histamine causes local vasodilation and leakage of plasma-containing mediators of acute inflammation (complement, C-reactive protein) and antibodies. Histamine has an active chemotactic attraction for inflammatory cells (neutrophils, eosinophils, basophils, monocytes, and lymphocytes). Histamine inhibits the release of lysosome contents and several T- and B-lymphocyte functions. Most of these actions are mediated by H2 or H4 receptors. Release of peptides from nerves in response to inflammation is also probably modulated by histamine, in this case acting through presynaptic H3 receptors. 

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. 

These proteins are called acute phase proteins (or reactants) and include C-reactive protein (CRP, so-named because it reacts with the C polysaccharide of pneumococci), ai-antitrypsin, haptoglobin, aj-acid glycoprotein, and fibrinogen. The elevations of the levels of these proteins vary from as little as 50% to as much as 1000-fold in the case of CRP. Their levels are also usually elevated during chronic inflammatory states and in patients with cancer. These proteins are believed to play a role in the body s response to inflammation. For example, C-reactive protein can stimulate the classic complement pathway, and ai-antitrypsin can neutralize certain proteases released during the acute inflammatory state. CRP is used as a marker of tissue injury, infection, and inflammation, and there is considerable interest in its use as a predictor of certain types of cardiovascular conditions secondary to atherosclerosis. Interleukin-1 (IL-1), a polypeptide released from mononuclear phagocytic cells, is the principal—but not the sole—stimulator of the synthesis of the majority of acute phase reactants by hepatocytes. Additional molecules such as IL-6 are involved, and they as well as IL-1 appear to work at the level of gene transcription. 

The Complement System Comprises About 20 Plasma Proteins Is Involved in Cell Lysis, Inflammation, Other Processes... 

Complement is not a single protein but comprises a group of functionally linked proteins that interact with each other to provide mar of the effector functions of humoral immunity and inflammation. Most of the components of the system are present in the serum as proenzymes, i.e. enzyme precursors. Activation of a complement molecule occurs as a result of proteolytic cleavage of the molecule, which in itself confers proteolytic activity on the molecule. Thus, many components of the system serve as the substrate of a prior component and, in turn, activate a subsequent component. This pattern of sequential activation results in the system being called the complement cascade. ... 

Teat cistern, glandular cistern, glandular lobuli Infection, inflammation (infection disease) Chemotaxis, cellular influx, immunoglobulins, complement, further mediators... 

Lukacs, N.W., Glovsky, M.M., and Ward, P.A., Complement-dependent immune complex-induced bronchial inflammation and hyperreactivity, Am. J. Physiol. Lung Cell Mol. Physiol. 280, 3, L512, 2001. 

Type III reactions are the result of antigen-antibody (IgG or IgM) complexes that accumulate in tissues or the circulation, activate macrophages and the complement system, and trigger the influx of granulocytes and lymphocytes (inflammation). Examples include an Arthrus reaction when soluble antigen is injected into the skin of a sensitized individual and serum sickness, which occurs 7 to 10 days following the administration... 

Two of the soluble factors generated during complement activation, C3a and C5a, also play important roles in inflammation. Both are termed ana-... 

Figure 17.23 Killing by antibodies and complement working together. Antibodies form a complex with bacteria. The anti-body-bacterium complex can stimulate phagocytosis by macrophages, directly. The complex also activates complement, which stimulates phagocytosis or causes lysis and hence death of bacteria. Activated complex can also lead to inflammation which attracts other immune cells to the site of infection (see Figure 17.24).

Type 3, immune complex vasculitis (serum sickness, Arthus reaction). Drug-antibody complexes precipitate on vascular walls, complement is activated, and an inflammatory reaction is triggered. Attracted neutrophils, in a futile attempt to phagocytose the complexes, liberate lysosomal enzymes that damage the vascular walls (inflammation, vasculitis). Symptoms may include fever, exanthema swelling of lymph nodes, arthritis, nephritis, and neuropathy. 

Assessment of inflammation is another important goal. Both albumin- and lipid-coated PFC microbubbles are retained in inflamed tissue, for example, after myocardial ischemia-reperfusion injury. This is because of a2-integrin- and complement-mediated attachment to and phagocytosis by activated leukocytes that adhere to vascular endothelium. 

Rituximab is a chimeric monoclonal antibody that targets CD20 lymphocytes (see Chapter 55). This depletion takes place through cell-mediated and complement-dependent cytotoxicity and stimulation of cell apoptosis. Depletion of lymphocytes reduces inflammation by decreasing the presentation of antigens to T lymphocytes and inhibiting the secretion of proinflammatory cytokines. Rituximab rapidly depletes peripheral cells although this depletion neither correlates with efficacy nor with toxicity. 

There are thus various autoantibodies present, and if the auto-antigens are released by cellular breakdown, a type III immune reaction can occur where an immune complex is formed, which is deposited in small blood vessels and joints, giving rise to many of the symptoms. The immunoglobulins IgG and IgE act as both autoantibody and antigen, and hence immune complexes form. Such complexes stimulate the complement system leading to inflammation, infiltration by polymorphs and macrophages, and the release of lysosomal enzymes. 

Immunoglobulins, oq-trypsin inhibitor and a2-macroglobulin,k ten or more blood clotting factors and proteins of the complement system all have protective functions that are discussed elsewhere in this book. Hormones, many of them proteins, are present in the blood as they are carried to their target tissues. Many serum proteins have unknown or poorly understood functions. Among these are the acute phase proteins, whose concentrations rise in response to inflammation or other injury. 

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