Page 429 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 28 Host Defenses to Spirochetes 409

bactericidal monoclonal antibody (mAb), M131, which provides
Innate Immune Responses partial protection to experimental syphilis. M131 binds to a
Similar to B. burgdorferi lipoproteins, treponemal lipoproteins phosphorylcholine surface epitope of T. pallidum and is the
appear to be the major proinflammatory agonists during trepo- first demonstration of such an antigen on the surface of the
nemal infection through engagement with their cognate receptors, spirochete. 24
TLR1/2 and CD14. The inflammatory milieu established by
treponemal lipoproteins is a principal driving force for immune Adaptive Immune Responses
cell recruitment to T. pallidum–infected tissues. The importance T Cell–Mediated Responses
of this immune system compartment during the response to T. The infiltration of T cells (CD4 and CD8) and macrophages
pallidum is further supported by the systemic upregulation of into the primary and secondary syphilitic lesion facilitates local
innate immune cells during treponemal dissemination and by clearance of the majority of treponemes and lesion resolution
demonstration that macrophages are principal effectors of via a vigorous cell-mediated immune response characteristic of
treponemal clearance during infection. 22 a delayed-type hypersensitivity or Th1 response. 25,26 CD4 T cells
are the principal T-cell subset found in the lesions and are believed
Early Pathogen Recognition to promote macrophage activation and subsequent treponeme
Because of their location in the skin, DCs (i.e., Langerhans cells), clearance through IFN-γ secretion. The role of CD8 cells is not
likely mediate the initial responses to treponemes at the primary clear, but throughout the course of primary lesion development
syphilitic lesion. Because of the denuded outer membrane of T. during experimental syphilis, their proportion related to CD4
pallidum, extremely high treponeme to DC ratios (500 : 1 and cells increases. Once the treponemes are cleared and the lesion
higher) are required for observable levels of phagocytosis in heals, a latency stage ensues, which is characterized by long-lasting,
vitro. Thus unhindered replication of spirochetes at the initial protective T-cell memory to T. pallidum antigens.
site of infection probably underlies the vigorous cell-mediated
immune response, as well as chancre appearance, which follows B Cell–Mediated Responses
antigen presentation to and differentiation and activation of Many functional activities of human syphilitic serum originate
CD4 T cells. from B-cell responses to T. pallidum. Infection with T. pallidum
invokes a humoral immune response early in the course of infec-
Phagocytic Cell Recruitment and Spirochetal Clearance tion, which strengthens as the number of recognizable antigens
It is not until after the recruitment of macrophages and their increases during the progression of infection. A polymorphic
activation via CD4 T cell–derived IFN-γ, that the majority of gene family of T. pallidum, T. pallidum repeat (tpr), has been
spirochetes are killed and resolution of syphilitic lesions occurs. recently identified as related to the major surface protein (msp)
27
Activated macrophages readily phagocytose antibody-opsonized genes of T. denticola. A single member of the tpr family, tprK,
treponemes through Fc receptor–mediated uptake. Recently, it serves as an antigen for opsonizing antibodies, suggesting
has been shown that MyD88 mediates the opsonophagocytosis that this protein is a surface antigen of T. pallidum. However,
of T. pallidum by macrophages without affecting the production there are only inferential indications that surface antigens of
of opsonic antibodies. As result, MyD88-deficent mice infected T. pallidum exist. So, although candidate T. pallidum surface
with T. pallidum showed a defect in bacterial clearance that proteins have been advanced on the basis of porin activity or
resulted in worse inflammation. These results reveal a previously homology with a surface protein of T. denticola, there is no direct
unsuspected link between MyD88 signaling and FcR-mediated evidence identifying specific surface antigens on T. pallidum.
phagocytosis. However, as with DCs, uptake via a direct PAMP– Furthermore, like most pathogenic organisms, T. pallidum has
PRR interaction does not occur readily, and because of treponemal evolved various mechanisms to escape host killing. TprK is an
antigenic variation, not all spirochetes will be eliminated via immunogen with seven discrete variable regions differing among
27
opsonophagocytosis despite the vigorous inflammatory response. isolates of the spirochete. In fact, the antibody response to T.
The relatively few remaining spirochetes are able to cause per- pallidum is directed against these variable regions, which leads to
sistent infection. immune selection of new TprK variants; thus antigenic variation
is involved in the reinfection of hosts despite robust immune
Complement responses. 27,28
The immunoprotection afforded by human syphilitic serum is,
in large part, a result of the activation of the complement cascade Translational Research
by bactericidal antibodies and spontaneous hydrolysis of C3. ON tHE HOrIZON
Thus like B. burgdorferi, T. pallidum activates the CP and AP of
the complement cascade, and there is a considerable amount of Efficient diagnostic methods that are required to rapidly identify infection
evidence for an important role of these pathways in syphilitic and procure antimicrobial treatments
lesion resolution during human infection with treponemes. In Development of new generation vaccines for Lyme disease, including
contrast to B. burgdorferi, there is no evidence indicating that those that target the tick vector and that can prevent other tick-borne
infections
T. pallidum has evolved mechanisms to evade complement- Attention to communities at risk for contracting syphilis with investments
dependent killing, suggesting that these complement pathways in prophylaxis and efficient treatments
have a larger role in controlling treponemal infection than in
the case of B. burgdorferi.
During experimental syphilis, immunization with purified The challenge in the next 5–10 years is to develop effective
outer membrane vesicles (OMVs) isolated from T. pallidum diagnostic methods for both Lyme disease and syphilis and to
23
results in complement-dependent bactericidal activity. More devise new preventive measures. For Lyme disease, advances in
recently, immunization with OMVs led to the isolation of a genetic manipulation, as well as other means to study structure/