Page 428 - Clinical Immunology_ Principles and Practice ( PDFDrive )

408 Part tHrEE Host Defenses to Infectious Agents

molecule on the outer membrane that can inactivate MAC and with a ligand-binding lipoprotein known as decorin-binding
14
prevent complement-mediated lysis. It has been speculated that protein A (DbpA). A deficiency in decorin reduces the incidence
most borreliae are able to evade complement-mediated lysis, of Lyme arthritis in mice, suggesting that the interaction of DbpA
and recently, a novel protein expressed by B. hermsii (a relapsing with the extracellular matrix provides a protective niche for B.
fever spirochete) has been discovered that affords protection to burgdorferi, preventing humoral-mediated bacterial killing. Once
15
spirochete by inactivating C3b. More recently, it has been shown the spirochete is in the joints and the heart, its clearance may
that B. burgdorferi expresses a protein, BBK32, on its surface, be more dependent on cellular responses (e.g., macrophages in
which prevents activation of the CP by blocking activation of the heart) than on antibodies. In fact, the lack of IFNγ-mediated
the C1 complement complex. 16 activation of macrophages has profound consequences on murine
cardiac inflammation, even in the presence of strong antibody
Adaptive Immune Responses responses. Furthermore, the bacterial clearance potential of
T Cell–Mediated Responses infected mouse sera administered in newly infected mice is lost
Upon antigen presentation by macrophages, dendritic cells (DCs), when administered 4–8 days after infection, potentially the result
or B cells, naïve CD4 T cells are activated and differentiate into of the colonization of tissues into which antibodies are less able
effector T cells. Effector CD4 T cells are classified on the basis to penetrate.
of their cytokine production profile, which determines their B. burgdorferi can also avoid clearance by antibodies through
mode of action and downstream effects, and include Th1 (IFN- antigenic diversity. B. burgdorferi differentially expresses outer
γ-producing), T-helper [Th]2 (IL-4, IL-5, IL-13), Th17 (IL-17), membrane antigens under pressure from the immune response,
or regulatory T cells (Tregs; IL-10) (Chapter 16). Interaction of which might contribute to the ability of the spirochetes to persist
B. burgdorferi antigen with TLRs induces the production of IL-12, in the host. A mechanism that is potentially essential for spiro-
which drives the differentiation of CD4 T cells into Th1 effector chetal immune escape is the recombination that takes place at
18
cells. Th1 cells are regulators of the cell-mediated inflammatory the vls locus, located near the right telomere of the linear plasmid
reactions, which are characterized by macrophage activation, lp28-1. B. burgdorferi is also able to evade antibody responses
including phagocytosis, or the induction of opsonizing IgG during transmission from the tick by attachment to the tick
antibodies. Although IFNγ and Th1 CD4 T cells have been shown salivary protein, Salp15, which interacts with the lipoprotein,
to be protective during cardiac inflammation with B. burgdorferi, OspC, and protects the spirochete from antibody-mediated
joint inflammation is independent of this effector cell type in killing. 19
mice. However, in patients with Lyme disease, Th1 cells dominate
in the synovial fluid, and the severity of arthritis directly correlates HOST DEFENSES TO T. pallidum
17
with increased levels of Th1 cells in the synovium. Whether
neutrophilic infiltration during joint infection with the spirochete KEY CONCEPtS
is influenced by Th effector cells that more directly affect this
cell type, such as Th17 cells (through the production of IL-17) Protective Versus Pathological Responses to
remains to be elucidated. treponema pallidum
B Cell–Mediated Responses The role of the early innate response to T. pallidum is still poorly understood
because immunogenic cell surface proteins able to activate pattern
Antibodies are specific and powerful effector molecules of the recognition receptors remain to be found.
adaptive immune response (Chapter 15). Once antibodies bind It is likely that the cell-mediated immune response to T. pallidum is
to their specific foreign antigen, they confer protection to the involved in the development of pathology following infection with the
host by using a variety of effector mechanisms: antibodies spirochete. Likewise, this response seems to be involved in the resolu-
tion of infection with T. pallidum.
contribute to adaptive immunity by neutralizing microbes or The protection that the humoral response affords to the host is unclear.
their products, activation of complement, and opsonization, Furthermore, no definite antigens have been isolated from the spiro-
which leads to phagocytosis of microorganisms. The activation chete because of the inability to cultivate this organism in vitro.
of B cells and their differentiation into antibody-secreting plasma
cells often requires an interaction with Th cells, and this interac-
tion controls isotype switching as well as somatic hypermutation. T. pallidum is known colloquially as the “stealth pathogen”
However, in response to B. burgdorferi, T cell–independent because of its denuded outer membrane, which comprises mostly
humoral responses also confer protection to the host. Thus mice nonimmunogenic transmembrane proteins, whereas the highly
deficient in T cells, CD40L, and MHC class II infected with B. immunogenic lipoproteins are contained within the periplasmic
20
burgdorferi mount a protective antibody response, which, upon space. This molecular architecture, coupled with the ability to
passive serum transfer, affords protection to severe combined generate antigenic variants, is responsible for the treponeme’s
immune deficient (SCID) mice from homologous challenge. remarkable ability to cause persistent infection with relatively
21
However, mice that lack both B and T cells developed severe few organisms. We have yet to elucidate many of the specific
arthritis and carditis in response to infection with B. immunological phenomena that occur as a result of infection with
burgdorferi. the treponeme and that are inherent to the clinical manifestations
The role of antibodies in controlling B. burgdorferi infection of the disease. Our limited understanding of immunological
may be more important during the hematogenous dissemination phenomena during infection mainly results from our inability
phase, when they are easily accessible, than after the spirochetes to culture these organisms in vitro and to reproducibly infect
have colonized tissues. B. burgdorferi is able to evade the humoral an animal model. Consequently, our understanding of the
response by interacting with the extracellular matrix of the immune responses to this pathogen is not nearly as detailed as
mammalian host via attachment to decorin, a major component our knowledge of those elicited in response to infection with
of the extracellular matrix. B. burgdorferi attaches to decorin B. burgdorferi.