long-lived cells and persistent antigen. For Slifka & Ahmed (1998) the rationale behind this is that:
Although antigen may persist in the form of immune complexes on the surface of follicular dendritic cells for months or longer, it is difficult to understand how antigen may persist in an immunogenic form for decades. An alternative mechanism that is not exclusive to the persisting antigen theory, is that plasma cells may actually live longer than a few days. (p 111)
They cite other studies (such as those by Ho et al 1986; Miller 1964;Okadaira & Ishizaka 1981) that support their own findings to suggest that this is possible. While acknowledging that “the factors involved with sustaining long-term antibody
production are still open to debate” (p 111), they suggest the following model for the maintenance of long-term memory:
During the early stages of a humoral response, large quantities of antigen induce a high degree of stimulation and proliferation. As antigen levels decline, the amount of stimulation and proliferation also decline but antibody levels are still maintained by a long-lived population of plasma cells. Later (ie > 10 years), little to no specific antigenic stimulation exists and antibody production wanes as a function of the number of plasma cells remaining. (Slifka & Ahmed 1998, p 111)
This theory therefore combines the use of persistent antigen and long-lived cells. It has the benefit of offering an explanation not only of how immunological memory may persist for years, or even decades, but also of how it may gradually wane and then disappear over this time. The persistent antigen maintains the stimulation of the long-lived plasma cells, and as this store of antigen declines, so does the population of long-lived cells. However, that these cells are long-lived provides an explanation for the gradual decline in long-term memory.
Since effective memory can often persist for the lifetime of an animal, often in the apparent absence of a source of . . . Ag [antigen], it seems likely that other mechanisms besides circulating Ab [antibody], must play a major protective role. Indeed it is clear that an increased frequency of T and B cells specific for Ag, are maintained as small resting cells for years or decades after initial immunization. (p 144)
Their study examined the movement of memory cells throughout the body as a whole, not just the lymphatic system, and the role of cytokines on the production of memory cells. They noticed that:
Transfer of effectors [T cells] to adoptive hosts, without Ag [antigen], leads to development of a population of resting memory cells. (Swain et al 1996, p 162)
The lack of involvement of antigen here is seen as “paradoxical” because it means that there is little opportunity for the development of specific T cell clones. They note that a small number of memory cells circulate throughout the body. Various aspects of this migration, such as capacity for migration, recirculation, and
sensitivity to stimulation by antigen are governed or influenced by cytokines. They found evidence that different cytokine patterns (Th1, Th2 or even Th0) influence important factors such as apoptosis, or the rate of death, for different types of cells. They can either stimulate or retard apoptosis, and this can influence the rate of expansion of various effector cells.
We have yet to directly study memory populations or memory effectors for the status of cell death. . . We also hypothesize that changes resulting in lack of susceptibility to both unstimulated and Ag [antigen]-driven cell death are important characteristics that contribute to the longevity of memory cells and that the regulation of cell death is a critical element in the regulation of the size and duration of the immune response. (Swain et al 1996, p 157)
Factors affecting cell death, longevity of memory cells, and the regulation of the size and duration of an immune response are all vital to successful immunisation. In the time since the publication of the paper by Swain et al in 1996, these issues have still not been clearly or specifically discussed in the scientific literature
available through databases such as Medline and The Web of Science, including Science Citation Index. Consideration of issues such as these have led Swain et al to conclude that:
Perhaps there is more than one pathway to memory generation . . . Clearly a lot more needs to be done to clearly identify the changes that occur . . . Many key questions remain to be resolved. (p 162)
6.5.2. LONG-LIVED PLASMA CELLS
Slifka et al (1998) examine an alternative pathway to memory generation. They look at the role of long-lived plasma cells. Although they find it plausible that immunological memory may be maintained by the continuous stimulation of memory B cells by persistent antigen maintained on the surface of follicular dendritic cells, this would require a high rate of B cell proliferation and
differentiation into plasma cells. They find it hard to understand how the antigen could be maintained for so long without being consumed. Slifka et al (1998)
perceive the main problem with this theory is that it is based on the presumption of short-lived plasma cells.
Plasma cells differ in function from memory T or B cells. B cells need appropriate stimulation from T helper cells before they can proliferate and differentiate into antibody secreting cells, whereas plasma cells do not divide and “are unlikely to participate in antigen processing and presentation” (p 363). Plasma cells produce “the majority of serum antibody” (p 363), and continuous secretion of “large
quantities of specific antibody” (p 363) is their primary function. They therefore play a significant part in immunological memory because it is important to have specific antibody present in the serum or on mucosal surfaces to deal with subsequent exposure to a pathogen.
The mechanisms underlying long-term antibody production are not fully understood, but the conventional model postulates that the maintenance of serum antibody requires the continuous proliferation and differentiation of memory B cells into antibody-secreting plasma cells. This model is based
on the belief that plasma cells are short-lived. . . current immunological dogma holds that plasma cells have a half-life of only a few days. (p 363)
However, these studies all focused on the acute phase of an infection (the first two weeks after the mice were vaccinated), when plasma migrate in response to the infection, and are indeed short lived. After the acute phase of an infection, that is two months to over a year later, the plasma cells in the spleen showed life spans of over a year, and it is postulated that
. . . at least a subpopulation of plasma cells can survive and continue to secrete antibody for the natural life-span of the immune host. (p 367)
Slifka et al (1998) put forward the convincing argument that this variation in life- span makes sense in terms providing an effective long-term memory response. Early in an infection with a new pathogen, the antibody secreted lacks specificity. Specificity is gradually obtained by the proliferation and selection of the most appropriate clones. It is these specific clones that the body needs to maintain, to provide defence on subsequent exposure. Therefore, effective long-term protection is provided if the early non-specific clones are short-lived, and the later more specific and therefore more effective ones are long-lived and remain to provide long-term protection against subsequent exposure. However, more recently Sze et al (2000) have cast doubts on this argument by providing evidence that:
. . . early plasma cell death relates to a finite capacity of the spleen to sustain plasma cells rather than a life span endowed by the cell’s origin or the quality of antibody it produces. (p 813)
Of the long-lived plasma cells, they assert that only a proportion showed evidence of changing to provide increased specificity of response. They did not, however, dispute that some plasma cells are long-lived, and this now seems to be generally accepted (Manz et al 1998). However, it must be kept in mind that all these
experiments have been done on mice, and the assertion that at least some plasma cells “can survive and continue to secrete antibody for the natural life-span of the immune host” (Slifka et al 1998, p 367) is made in reference to mice. “It remains to be seen” (p 367) whether these findings can be extrapolated in any way to the life- span of plasma cells in humans.
Leyendeckers et al (1999) also provide support for the existence of long-lived plasma cells, however they find that there is no correlation between antibody-based immunity “as determined by measuring serum immunoglobulin titers against a particular antigen” (p 1406) and memory B cell immunity “as determined by
counting circulating memory B cells with specificity for that same antigen” (p 1406). This leads them to the conclusion that:
This lack of a statistically significant linear correlation is in accordance with the idea that B memory cells and plasma cells represent independently controlled forms of immunological memory. (p 1406)
Swain et al (1996) hypothesized that there may be “more than one pathway to memory generation” (p 162) and this result would tend to support this view. The lack of understanding of the function, role and mechanism of these pathways serves as a further indicator of the complexity of the area of immunological memory, and how much is yet to be clarified.