A wide range of microorganisms can replicate in macrophages, and cell entry of these pathogens via non-neutralising IgG antibody complexes can result in increased intracellular infection through idiosyncratic Fc-receptor signalling. extrinsic ADE, whereby complexes of infectious agents with non-neutralising antibodies lead to an increased number of infected cells. Intrinsic ADE might be involved in many protozoan, bacterial, and viral infections. We review insights into intracellular mechanisms and implications of enhanced pathogenesis after ligation of macrophage Fc receptors by infectious immune complexes. Introduction Over the past four decades, information from different lines of scientific inquiry has improved our understanding Belinostat of antibody-mediated mechanisms that modulate severity of infections by diverse microorganisms. Independent studies of pathogenesis of cellular and host responses to acute and chronic human and animal infectious diseases have generated evidence that cross-linking of immune complexes with Fc receptors increases cellular infection, contributing to disease severity by a mechanism we call intrinsic antibody-dependent enhancement (ADE) of infection. Intrinsic ADE is distinct from extrinsic ADE, whereby complexes of infectious agents with non-neutralising antibodies lead to an increased number of infected cells. Hawkes1 made early observations in studies of the neutralisation of Murray Valley encephalitis virus by use of the serum-dilution, virus-constant method. Chick embryo fibroblast monolayers exposed to virus mixed with high dilutions of chicken antisera had more plaques than did those exposed to virus alone.1 In follow-up studies,2 this finding seemed to result from antibody stabilisation of infectivity by the Murray Valley encephalitis virus. A different explanation emerged when sequential infections with dengue viruses resulted in dengue haemorrhagic fever.3 When monocytes and macrophages were identified as the main hosts of dengue infection, ADE was implicated.4,5 Infection with the Murray Valley encephalitis virus was increased by ADE in the 2% of functional chicken macrophages identified in chick Belinostat embryo fibroblasts. Because of the conformational requirement that Fc receptors and Fc termini must be of the same phylogenetic class, ADE in chick embryo fibroblasts was reported only when Murray Valley encephalitis virus antibodies were raised in chickens, not in mammals.6,7 Macrophage biology Monocytes are produced in the bone marrow by haemopoietic stem-cell precursors and then circulate in the bloodstream for about 1C3 days; about half of these cells are stored in the spleen. Monocytes adult to replenish resident macrophages and dendritic cells. Macrophages are scavengers that remove worn-out cells and Belinostat additional debris. They also present antigens that initiate the immune response. Macrophages have receptors for lymphokines that enhance their function. Two signals are needed to produce macrophages activated from the classic pathway: interferon and tumour necrosis element (TNF) or interferon and exogenous toll receptor ligands such as lipopolysaccharide, resulting in macrophages that are able to kill intracellular organisms.8 Macrophages activated from the vintage pathway are essential components of the sponsor defence system, but their activation must be tightly controlled because the cytokines and mediators that they produce can lead to sponsor tissue damage and immunopathological disorders such as rheumatoid arthritis and inflammatory bowel disease. Macrophages have great plasticity and may respond to numerous environmental cues by adopting many different claims of activation.8 T-helper-2 (Th2) immune responses, commonly elicited by disturbances at mucosal surfaces, result in the production of interleukin 4 and interleukin 13, which stimulate macrophages to secrete components of the extracellular matrix, making the cells effective in wound healing.8 These activated or wound-healing macrophages produce minimum amounts of proinflammatory cytokines and are less efficient at killing intracellular microbes than are macrophages activated from the vintage pathway. Regulatory macrophages typically arise during late phases of adaptive immune responses having a Rabbit polyclonal to CENPA. main part of reducing immune reactions and restricting swelling. These cells can occur in response to toll-like receptor activation in the presence of glucocorticoids, prostaglandin E2, interleukin 10, or immune complexes. Regulatory macrophages are programmed to produce high concentrations of interleukin 10 and to suppress Belinostat production of interleukin 12.9 Many other unique populations of activated macrophages with distinct phenotypes are likely to arise in response to specific diseases.8 Protozoan parasitism of macrophages Leishmaniasis is caused by protozoan parasites of the genus that are transmitted from the bite of sandflies. About 21 of 30 varieties that infect mammals can cause human being infection. The disease is present as two major forms: cutaneous and visceral leishmaniasis. Cutaneous leishmaniasis is definitely endemic to many parts of the world, and is closely linked to specific geographical regionswith villages as little as 15 miles apart having different illness rates. Visceral leishmaniasis, also known as kala-azar, is the most severe form of leishmaniasis and, after malaria, is the second-leading cause of death from parasitic illness, with an estimated 500 000 instances each year worldwide.10 Some varieties are closely linked to human beings and are commonly reported in cities (eg, varieties are transmitted as promastigotes, motile forms that infect macrophages, and spread within hosts as amastigotes, the obligate parasites of macrophages. In human being hosts, the reactions to infection vary with varieties and the individuals immune reactions. Individuals whose lymphocytes create high amounts of interferon.