Immunotherapy for Infectious Diseases

18 Nara
excluded from follicles are also functionally anergic—that is, signaling by their B-cell
receptors (BCRs) is reversibly altered so that they make weak mitogenic responses to
antigen (45,50). Nevertheless, antigens with high avidity binding can deliver strong signals
to the B-cells that partially override anergy and induce modest proliferation and
antibody production by maturing self-reactive B-cells (50). Thus self-reactive B-cells
that have yet to complete development and negative selection might be recruited into
the functional immune repertoire if they crossreact avidly with a foreign antigen; the
public environment of the spleen seems to encourage this recruitment at the risk of
autoimmunity. Why risk autoimmunity by requiring so much of B-cell-negative selection
to occur where immune responses begin?
The Autoimmune Solution
The export of self-reactive short-lived cells into a splenic B-cell pool, in which lifespan
is inversely proportional to the degree of self-reactivity, might solve the problem
of holes in the B-cell repertoire, much as MHC polymorphism serves to solve the hole
problem in the generation of the T-cell repertoire. In any one individual in a population,
at a particular time, a proportion of the B-cell repertoire is contained in the shortlived
B-cell pool, being excluded from entry into the B-cell follicles. In the absence of
infection, self-reactive cells within this population will die within a few days and so
pose little risk of causing a pathogenic autoimmune response. Autoimmunity is also
avoided by requiring stronger signals to recruit autoreactive B-cells into an immune
response than are required to recruit naive B-cells and by producing smaller bursts
of progeny when autoreactive cells clear the higher activation hurdle (50). Because of
the huge potential B-cell repertoire encoded in the genome, the actual B-cell repertoire
available at any one time is likely to differ between individuals based on the probable
recombination and expression of BCRs. Accordingly, each individual within a population
will express a different B-cell repertoire, with varying propensity toward autoimmunity
when an infectious agent appears.
The repertoire diversity provided by the short-lived pool of B-cells might work in
concert with the probable differences in B-cell pool composition between individuals
to ensure that some individuals will mount effective B-cell responses against an infection.
This solution to plugging the holes in the repertoire might be buttressed by the
unique ability to fine-tune B-cell specificity further, by hypermutation and additional
rounds of negative selection in germinal centers. The independent processes of anergy
and negative selection in germinal centers might account for why these modest autoantibody
responses do not achieve high concentrations and do not normally exhibit sustained
or recall characteristics.
The effectiveness of this system depends on the availability of a diverse pool of
B-cells within each individual at any one time, as well as differences in pools between
individuals. Whereas T-cell deletion in the thymus helps to protect against selfreactivity
within the T-cell repertoire, the inherent short lifespan and more rigorous
signaling requirements of self-reactive B-cells helps to protect against self-reactivity
within the B-cell repertoire. Whereas MHC polymorphism provides diversity in T-cell
repertoires within populations, the probable generation of BCR specificities and the
short-term inclusion of weakly self-reactive specificities might provide diversity among
the B-cell repertoires within populations. Seen in this light, there might be a clear