Which of the following disease is mediated through complement activation

Ref Harrison 16/e p327,328,; Robbins 9/e p207 Immune Complex Diseases (Type III Hypersensitivity) Antigen-antibody (immune) complexes that are formed in the circulation may deposit in blood vessels, leading to complement activation and acute inflammation. The antigens in these com- plexes may be exogenous antigens, such as microbial pro- teins, or endogenous antigens, such as nucleoproteins. The mere formation of immune complexes does not equate with hypersensitivity disease; small amounts of antigen- antibody complexes may be produced during normal immune responses and are usually phagocytosed and destroyed. It is only when these complexes are produced in large amounts, persist, and are deposited in tissues that they are pathogenic. Pathogenic immune complexes may form in the circulation and subsequently deposit in blood vessels, or the complexes may form at sites where antigen has been planted (in situ immune complexes). Immune complex-mediated injury is systemic when complexes are formed in the circulation and are deposited in several organs, or it may be localized to paicular organs (e.g., kidneys, joints, or skin) if the complexes are formed and deposited in a specific site. The mechanism of tissue injury is the same regardless of the pattern of distribution; however, the sequence of events and the conditions leading to the formation of systemic and local immune complexes are different and are considered separately in the following descriptions. Immune complex diseases are some of the most common immunologic diseases (Table 4-4). Systemic Immune Complex Disease The pathogenesis of systemic immune complex disease can be divided into three phases: (1) formation of antigen- antibody complexes in the circulation and (2) deposition of the immune complexes in various tissues, thereby initiat- ing (3) an inflammatory reaction in various sites through- out the body (Fig. 4-11). Acute serum sickness is the prototype of a systemic immune complex disease. It was first described in humans when large amounts of foreign serum were administered for passive immunization (e.g., in persons receiving horse serum containing antidiphtheria antibody); it is now seen only rarely (e.g., in patients injected with rabbit or horse antithymocyte globulin for treatment of aplastic anemia or graft rejection, or patients with snakebite given anti-venom antibody made in animals). Although serum sickness is no longer common, the study of its pathogenesis sheds light on the mechanisms of human immune complex diseases. Approximately 5 days after the foreign protein is injected, specific antibodies are produced; these react with the antigen still present in the circulation to form antigen- antibody complexes. The complexes deposit in blood vessels in various tissue beds, triggering the subsequent injurious inflammatory reaction. Several variables determine whether immune complex forma- tion leads to tissue deposition and disease. Perhaps foremost among these factors is the size of the complexes. Very large complexes or complexes with many free IgG Fc regions (typically formed in antibody excess) are rapidly removed from the circulation by macrophages in the spleen and liver and are therefore usually harmless. The most pathogenic complexes are formed during antigen excess and are small or intermediate in size and are cleared less effectively by phagocytes and therefore circulate longer. In addition, the charge of the complex, the valency of the antigen, the avidity of the antibody, and the hemodynamics of a given vascular bed all influence the tendency to develop disease. The ored sites of deposition are kidneys, joints, and small blood vessels in many tissues. Localization in the kidney and joints is explained in pa by the high hemody- namic pressures associated with the filtration function of the glomerulus and the synovium. For complexes to leave the circulation and deposit within or outside the vessel wall, an increase in vascular permeability also must occur. This is probably triggered when immune complexes bind to leukocytes and mast cells by means of Fc and C3b recep- tors and stimulate release of mediators that increase vas- cular permeability. Once complexes are deposited in the tissue, the third phase, the inflammatory reaction, ensues. During this phase (approximately 10 days after antigen administration), clini- cal features such as fever, uicaria, ahralgias, lymph node enlargement, and proteinuria appear. Wherever immune complexes deposit, characteristic tissue damage occurs. The immune complexes activate the complement system, leading to the release of biologically active frag- ments such as the anaphylatoxins (C3a and C5a), which increase vascular permeability and are chemotactic for neutrophils and monocytes (Chapter 2). The complexes also bind to Fcg receptors on neutrophils and monocytes, activating these cells. Attempted phagocytosis of immune complexes by the leukocytes results in the secretion of a variety of additional pro-inflammatory substances, includ- ing prostaglandins, vasodilator peptides, and chemotactic substances, as well as lysosomal enzymes capable of digest- ing basement membrane, collagen, elastin, and cailage, and reactive-oxygen species that damage tissues. Immune complexes can also cause platelet aggregation and activate Hageman factor; both of these reactions augment the inflammatory process and initiate formation of micro- thrombi, which contribute to the tissue injury by producing local ischemia (Fig. 4-11). The resultant pathologic lesion is termed vasculitis if it occurs in blood vessels, glomerulo- nephritis if it occurs in renal glomeruli, ahritis if it occurs in the joints, and so on. Predictably, the antibody classes that induce such lesions are complement-fixing antibodies (i.e., IgG and IgM) and antibodies that bind to phagocyte Fc receptors (IgG). During the active phase of the disease, consumption of complement may result in decreased serum complement levels. The role of complement- and Fc receptor-dependent inflammation in the pathogenesis of the tissue injury is suppoed by the observation that experimental depletion of serum complement levels or knockout of Fc receptors in mice greatly reduces the severity of lesions, as does deple- tion of neutrophils. SUMMARY Pathogenesis of Diseases Caused by Antibodies and Immune Complexes * Antibodies can coat (opsonize) cells, with or without complement proteins, and target these cells for phagocy- tosis by macrophages, which express receptors for the Fc tails of IgG molecules and for complement proteins. The result is depletion of the opsonized cells. * Antibodies and immune complexes may deposit in tissues or blood vessels, and elicit an acute inflammatory reaction by activating complement, with release of breakdown products, or by engaging Fc receptors of leukocytes. The inflammatory reaction causes tissue injury. * Antibodies can bind to cell surface receptors or essential molecules, and cause functional derangements (either inhibition or unregulated activation) without cell injury. MORPHOLOGY The morphologic appearance of immune complex injury is dominated by acute necrotizing vasculitis, microthrombi, and superimposed ischemic necrosis accompanied by acute inflammation of the affected organs. The necrotic vessel wall takes on a smudgy eosinophilic appearance called fibrinoid necrosis, caused by protein deposition (see Fig. 1-13, Chapter 1). Immune complexes can be visualized in the tissues, usually in the vascular wall (examples of such deposits in the kidney in lupus are shown in Fig. 4-18, E). In due course, the lesions tend to resolve, especially when they were brought about by a single exposure to antigen (e.g., in acute serum sickness or acute poststreptococcal glomerulo- nephritis) (Chapter 13). However, chronic immune complex disease develops when there is persistent antigenemia or repeated exposure to an antigen. This occurs in some human diseases, such as systemic lupus erythematosus (SLE). Most often, even though the morphologic changes and other find- ings strongly implicate immune complex disease, the inciting antigens are unknown.