Septicemic shock and the adult respiratory distress syndrome
The cytokine release triggered by bacterial components has a protective and immunoregulatory role as described above, but when excessive, as during septicemia, there can be excessive systemic activation of phagocytes and of endothelial cells. The latter leads to adhesion of phagocytes to the endothelium, initiation of the clotting cascade via expression of tissue thromboplastin, and eventually to diffuse intravascular coagulation that exhausts the clotting system and leads to a clotting defect. Mediators such as platelet-activating factor (PAF) and NO are released, blood pressure falls and hemorrhage may occur. Neutralizing antibodies to tissue thromboplastin or inhibitors of PAF can attenuate this syndrome. A neutralizing antibody to TNFa is protective in a model of septicemic shock in the baboon. The systemic toxicity of TNFa is greatly increased in the presence of IL-1 or LPS and these are both likely to be present during bacterial infections. High serum levels of TNFa correlate with a poor clinical outcome in septicemia, and in the adult respiratory distress syndrome (ARDS), which is a similar condition that targets the lungs.
Cytokine release can also cause local rather than systemic pathology. Microbial products and certain types of inflammatory response (both T cell dependent and independent) 'prepare' tissue sites so that they become exquisitely sensitive to cytokines, particularly TNFa, and liable to undergo hemorrhagic necrosis if TNFa release is subsequently induced sys-temically, or if TNFa is directly injected into the same site. This may explain the rash often seen during meningococcal septicemia. If bacteria released during a previous subclinical septicemic episode have lodged in skin capillaries, these will become 'prepared' sites, and a later septicemic episode severe enough to trigger systemic cytokine release will cause these sites to undergo necrosis via a cascade of events similar to those occurring systemically in endotoxin shock.
Koch phenomenon and necrotizing T cell-dependent granulomas
Robert Koch observed that when tuberculous guinea pigs were skin-tested with tuberculosis bacilli or culture supernatant (tuberculin), there was a necrotic reaction at the skin-test site within 24-48 h, and if a large dose of tuberculin was used there was additional necrosis in distant tuberculous lesions. The same is true in human tuberculosis patients. This phenomenon is described in the section on mycobacteria, and probably represents a pattern of tissue destruction and eventual fibrosis that occurs when there is local release of TNFa and other cytokines into T cell-dependent inflammatory sites mediated by a mixed TH1 plus TH2 lymphocyte response. A similar argument holds for tissue damage around granulomas evoked by schistosome ova, so the Koch phenomenon may be a model of an important immunopathological entity.
Heat shock proteins and the possibility of autoimmunity
It was discovered recently that several dominant antigens of infectious agents are 'heat shock' or 'stress' proteins. The sequences of these microbial antigens are similar to the sequences of the mammalian homo-logs. The fact that the immune response focuses much 'attention' on these conserved proteins may increase the chances of recognizing any pathogen, but also increase the chance of autoimmunity.
See also: Bacillus, infection and immunity; Bacterial cell walls; Bacteroides, infection and immunity; Bord-etella, infection and immunity; Borrelia, infection and immunity; Brucella, infection and immunity; Campylobacter, infection and immunity; Complement, alternative pathway; Chlamydia, infection and immunity; Coccidioides, infection and immunity; Complement, classical pathway; Complement deficiencies; Complement fixation test; Complement, genetics; Complement, membrane attack pathway; Complement receptors; Coryneform bacteria, infection and immunity; Cryptococcus, infection and immunity; Cytokines; Cytotoxicity, assays for; Cytotoxicity, mechanisms of; Effector lymphocytes; Endotoxin (lipopolysaccharide (LPS)); Escherichia coli, infection and immunity; Francisella, infection and immunity; Fusobacterium, infection and immunity; Granuloma; Haemophilus, infection and immunity; Klebsiella, infection and immunity; Legionella, infection and immunity; Leptospira, infection and immunity; Listeria, infection and immunity; Microbicidal mechanisms, oxygen-dependent; Microbicidal mechanisms, oxygen-independent; Mycobacteria, infection and immunity; Neisseria, infection and Immunity; Nocardia, infection and immunity; Opsonization; Pas-teurella, infection and immunity; Phagocytosis; Proteus, infection and immunity; Pseudomonas aeruginosa, infection and immunity; Rickettsia, infection and immunity; Salmonella, infection and immunity; Shigella, infection and immunity; Staphylococcus, infection and immunity; Streptobacillus, infection and immunity; Streptococcus, infection and immunity; Stress and the immune system; T lymphocyte differentiation; Treponema, infection and immunity; Vibrio cholerae, infection and immunity; Vitamin D and the immune system; Yersinia, infection and immunity.
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