Plasma cellsB lymphocytes and antibodies

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Antibody has been the traditional focus of virologists interested in the immediately practical concern of making effective vaccines. Techniques for generating strong serum antibody response to pathogens, or their products, were known through much of the 20th century, and provided our first opportunity to exploit immunotherapy with products like antitoxins and antivenenes. Many of the first immunologists were, in fact, called serologists. Early pioneering work on the immune system, including the discovery of the role of the plasma cell in antibody production [44] by Astrid Fagraeus (1913-1993), was done, for example, at the State Serum Institute in Copenhagen.

Measurement of serum neutralizing antibody is still the best correlate of vaccine-induced immunity for many viruses. In the main, the protective, virus-specific immunoglobulin (Ig) molecules are targeted to tertiary, conformed determinants of glycoproteins expressed on the surface of the virion [76]. Such pre-existing Ig may not completely block infection at (for example) mucosal surfaces [99], but it does prevent the systemic spread of blood-born virus to distal sites of potential pathology such as the large motor neurons in poliomyelitis. One of the challenges for immunologists is to develop strategies for maintaining high levels of mucosal antibody [72]. Can we hope to vaccinate against HIV if the virus cannot be stopped at the initial site of entry?

Antibody-mediated selection pressure drives the diversification of the influenza A viruses manifested as antigenic drift in the broader ecological context [46, 127], while the continuing emergence of antibody escape variants within an infected individual is a depressingly familiar characteristic [54, 63] of pathogens like HIV and hepatitis C virus (HCV). Recent strategies for developing neutralizing antibody response to (for example) the M2 channel protein that is expressed on the surface of the influenza A viruses [84] suggest that it may be possible to generate protective antibodies directed at conserved determinants expressed on molecular structures that have little, if any, capacity to vary. This would, of course, be the "holy grail" for HIV research [23].

Serum antibody is often detected indefinitely after vaccination or primary infection. Recent experiments have shown that B lymphocytes specific for vaccinia virus may be circulating in peripheral blood for as long as 50 years after exposure to the DryVax vaccine [31]. Vaccinia virus is not present in the normal human environment, and it is unlikely that (at least) most urban dwellers will have encountered even a distantly related poxvirus that infects, for example, domestic animals. Memory in the B cell/plasma cell compartment can apparently be maintained in the very long term without further challenge by the inducing antigen.

Antibody production is a property of plasma cells, the terminally-differentiated stage of the B cell lineage. During the acute phase of an infectious process, activated B cells/plasmablasts circulate in the blood and localize to various distal sites. In the viral encephalitides, for instance, B cells/plasmablasts can be seen to transit [32] from the blood to the central nervous system (CNS), where they become plasma cells and continue local antibody production in the long term [52, 98]. Persistent infection with a defective variant of measles virus in subacute sclerosing panencephalitis is characterized by massive, long-term local antibody production [114]. Subclinical infection of the CNS with an encephalitic virus can also lead to the sustained presence of neutralizing Ig in cerebrospinal fluid (CSF) at titers that are clearly discordant with levels in serum, providing a clear indication of local Ig synthesis in the brain [98].

Other B cells/plasmablasts find their home in the bone marrow (BM), a process that is clearly independent of antigen [60,111] localization to that site. Long term Ig production seems, in fact, to be a function of the BM compartment [112]. The mammalian BM functions to provide continuous replacements for cells in the hemopoietic lineages, including naive B cell precursors. Perhaps the spectrum of growth and differentiation factors that are required for this purpose also act to sustain the antibody-producing plasma cells [26].

Though we have been studying antibodies for a very long time, there are still big gaps in our understanding of topics like virus neutralization. The traditional neutralization assay done in tissue culture does not, for example, take account of the possible role of complement activation [132], or of opsonization and destruction by macrophages, mechanisms that are likely to be operational in the in vivo situation. The possible role of enhancing antibodies as a mechanism for promoting virus growth and damage in macrophages and epithelial cells has been a major focus for those interested in hemorrhagic dengue [55]. Similar questions have been raised for HIV, though more in the context of promoting virus growth and persistence [80].The structural basis of antibody neutralization is clearly an important focus [8]. More research is being done on antibody neutralization, particularly as attempts are made to develop immunization strategies to limit the ravages of the AIDS pandemic [23, 70].

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