Page 426 - Clinical Immunology_ Principles and Practice ( PDFDrive )

406 Part tHrEE Host Defenses to Infectious Agents

test for T. pallidum-specific IgG, T. pallidum hemagglutination or epithelial cells, resulting in the recruitment of different types
test (TPHA), fluorescent treponemal antibody-absorption test of innate immune cells and their activation. Each PRR recognizes
(FTA-ABS), and ELISA. a specific structure that is present in a group or groups of
microorganisms and that distinguishes them from the more
Treatment specific recognition of antigens by the T- and B-cell receptors.
Susceptibility to infection with T. pallidum is universal, although The recognition of patterns instead of specific antigens provides
only 30% of exposures with lesions teeming with the spirochete the innate immune system with a rapid way to respond to infecting
result in infection. Infection results in gradual development of organisms until the more specific response mediated by T and
immunity against T. pallidum and often against heterologous B cells develops.
treponemes as well. However, treatment with long-acting penicillin A distinct innate cellular infiltration profile has been observed
subverts the development of immunity against T. pallidum. in B. burgdorferi–infected tissues. Based on studies using mice,
Administration of 2.4 million units in a single intramuscular the inflamed heart appears to predominately comprise macro-
dose the day that the primary, secondary, or latent syphilis is phages, with smaller amounts of T and invariant natural killer
diagnosed is effective at killing the spirochetes. For people who T cells (iNKT cells). However, neutrophils are the primary innate
are allergic to penicillin, there are alternative treatments, such immune cell found in the joints. In this tissue, resident myeloid
as doxycycline. cells act as the initiators of type I interferon (IFN) production
upon encounter with B. burgdorferi, whereas endothelial cells
HOST DEFENSES TO B. burgdorferi and joint fibroblasts expressing adhesion/ activation markers
amplify the response and serve as the major source of disease-
KEY CONCEPtS promoting chemokines. This tissue-specific tropism complicates
our understanding of the host defense against the spirochete,
Protective Versus Pathological Responses to but this suggests that macrophages are more efficient at preventing
Borrelia burgdorferi successful colonization of B. burgdorferi because carditis is a less
frequent manifestation of Lyme disease. These early defense
The early immune response to B. burgdorferi is necessary to control
spirochetal burden; however, by itself, it is not sufficient to resolve responses also have a role in determining the type, strength, and
infection. duration of the more specific adaptive immune response, beyond
Phagocytosis is a key element of the innate immune response, which their direct bacterial-killing capability.
is involved in the elimination of the bacteria while also contributing
to the proinflammatory output of macrophages Early Pathogen Recognition
The T cell–mediated response appears to be involved in pathology arising The interaction of B. burgdorferi lipoproteins with complexes
from infection.
A T cell–independent B-cell response is sufficient to resolve infection formed by TLRs 1 and 2 initiates a series of signaling cascades
with B. burgdorferi. that results in the production of proinflammatory cytokines
(IL-1β, tumor necrosis factor [TNF], interleukin [IL]-12, and
IL-18, among others), chemokines (IL-8, monocyte chemoat-
B. burgdorferi virulence is attributed, in part, to the evolution tractant protein [MCP]-1, keratinocyte chemoattractant [KC]),
of the spirochete’s sophisticated tactics to evade killing mecha- metalloproteinases, adhesion molecules (E-selectin, vascular cell
nisms during all stages of the immune response: the first stage, adhesion molecule-1 [VCAM-1] and intercellular adhesion
9
beginning with transmission into the host via tick engorgement, molecule-1 [ICAM-1]), and type I IFNs. These interactions are
at which time the spirochete is exposed to serum complement critical for generating an effective spirochete-clearing inflam-
and cellular immunity; and the second and third stages, that is, matory response, as demonstrated by experiments using mice
hematogenous dissemination to and colonization of peripheral deficient for TLR1, TLR2, or their adaptor molecule, MyD88.
sites, at which time the host is producing specific antibodies. These mice had significant increases in B. burgdorferi burdens
Both the innate and adaptive immune responses elicited by B. after infection. Moreover, humans with decreased TLR1 expression
burgdorferi are discussed, with the supposition that these responses are hyporesponsive to the original OspA-based Lyme disease
are required for efficient bacterial clearance, while acknowledging vaccine, and macrophages from these subjects also have dimin-
that unnecessarily prolonged or intense responses may contribute ished inflammatory responses to the lipoprotein. Besides TLR1/
to pathology arising from infection. Indeed, predisposition to TLR2 complexes, other members of this family of receptors
infection could be the result of one or more monogenic traits participate in, and amplify, the inflammatory response to B.
that confer primary immunodeficiencies; whether or not this is burgdorferi. These include TLR5, TLR7, TLR8, and TLR9, which
the case remains to be determined, but human studies have recognize different bacterial constituents. Importantly, the
shown that responses to B. burgdorferi are diminished in individu- development of inflammatory arthritis in the absence of TLRs
als with specific mutations in or diminished expression of innate or MyD88 was the first suggestion that alternative pathways
immune cell receptors (nucleotide-binding oligomerization trigger the inflammatory response to the spirochete. Other PRRs
domain-2 [NOD2] and Toll-like receptor-1 [TLR1]). that have been shown to be involved in the response to the
spirochete include NOD-like receptors. For the full inflammatory
Innate Immune Responses response to take shape upon recognition of B. burgdorferi, most
The initial recognition of pathogens with cells of the host relies of the interactions of B. burgdorferi constituents and PRRs occur
on a complex interplay between pathogen recognition receptors within the phagolysosome. Therefore phagocytosis is a hallmark
(PRRs) and bacterial constituents, and this initiates a cascade of the innate immune cell recognition of the spirochete.
of responses leading to the upregulation of chemokines and The interaction of several cell types with the spirochetes also
cytokines, adhesion molecules, and other effector molecules involves several integrins belonging to the β 1 , β 2 , and β 3 groups.
(Chapter 3). This response is often initiated by endothelial and/ Integrins are involved in the adhesion of cells to a variety of