trans

104 ANTIGENIC VARIATION
trypanosome antigens. There is a rapid and
large increase in the size of the spleen, with
the majority of the increase being caused by
rise in the population of macrophages, B cells
and plasma cells. The immune response to
African trypanosomiasis inevitably consists
of a series of primary IgM responses, leading
to a huge elevation of IgM levels in the
bloodstream, although IgG may be found later
in infection, as VSGs with overlapping antigenic
specificities are expressed. The vast rise
in IgM has generally been attributed to a polyclonal
B-cell response, rather than to specific
responses to the plethora of trypanosome
VSGs, but this issue has not been resolved.
Perhaps the IgM response represents a combination
of two effects: polyclonal activation and
pan-VSG stimulation. It is difficult to resolve
this question experimentally, because of the
vast repertoire of trypanosome-specific VSG
antigens involved, some of which may evoke
responses that cross-react with the nontrypanosome
antigens that fueled the idea
that most of the IgM response was polyclonal
and non-specific.
Many investigators have been able to demonstrate
that animals can be protected against
homologous challenge, using a range of antigen
preparations, but there are no firm examples of
trans-variant protection. Immunization with
purified VSG is sufficient to confer immunity
to challenge by trypanosomes expressing the
same variant. T. brucei is notoriously resistant
to complement-mediated lysis, for reasons that
can be rationalized by our knowledge of the
structure of the VSG coat, described above,
which probably prevents insertion of the C9
complex into the plasma membrane. Anti-VSG
antibody-dependent phagocytosis is probably
the main mechanism for eliminating trypanosomes.
Early studies suggested that T cells
had little or no role in controlling trypanosome
infections, but recent work has revisited the
potential role of T-cell responses to VSG and
demonstrated that VSG-specific Th1 cells are
generated. Interferon- knockout mice have
higher parasitemias, but still control them with
VSG-specific antibody responses, suggesting
that resistance is partly dependent upon a Th1
cell response to VSG, producing interferon-. It
has been suggested that Th1 generation against
non-surface-exposed epitopes on released VSG
may provide a selective pressure for variation in
‘buried’ regions of the VSG sequence, although
it is unclear what role such responses would
have in trypanosome clearance. Recent studies
suggest that T. brucei has an additional way of
dealing with the emerging anti-VSG response.
Binding of large amounts of anti-VSG antibodies
in vitro agglutinates trypanosomes, although
the clumps slowly disperse. When using subagglutinating
concentrations, a situation which
probably more accurately reflects the kinetics of
antibody build-up in vivo, antibodies bound to
VSG are rapidly internalized and degraded.
INNATE RESISTANCE,
HUMAN SUSCEPTIBILITY
AND SEX
This topic is included in a discussion of
antigenic variation because it is important, it
represents an innate mechanism that is independent
of acquired immunity, and because
human infection is linked to antigenic variation
in two respects (see below). Trypanosomes
that infect humans are classified as subspecies
of T. brucei: T. b. rhodesiense and T. b. gambiense.
These subspecies are generally distinguishable
by their geographic separation,
their symptoms, and their population structure,
but some aspects of their separation and
origin are somewhat controversial, and probably
will remain so until the molecular basis of
human infectivity is properly understood. The
MOLECULAR BIOLOGY