Page 448 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 30 Host Defenses to Protozoa 427

class I-restricted parasite-specific CD8 T cells and, to a lesser fly becomes infected by ingesting amastigotes during a blood
extent, CD4 T cells, via IFN-γ-induced NO-dependent killing meal. In the sand fly gut, the amastigotes differentiate into
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of intrahepatocyte parasites. Potentially protective immune infectious metacyclic promastigotes that infect the vertebrate
mechanisms against the preerythrocytic stage have largely been host during the next blood meal. The surface lipophospho-
identified by study of mice vaccinated with irradiated sporozoites glycan (LPG) plays a central role in the parasite’s entry and
and challenged with murine Plasmodium spp. Irradiated sporo- survival in host cells. Immunomodulatory factors present in
zoite challenge also protects humans and is being scaled up for the sand fly saliva may enhance the infectivity of the parasite.
vaccine trials. Antisporozoite immunity requires the presence Once introduced into skin, the promastigotes are phagocytosed
of high antibody titers and high numbers of T cells to block (through complement–complement receptor–mediated coiling
sporozoite invasion of the hepatocyte, which occurs in just a phagocytosis) by neutrophils, DCs, and macrophages, where
few cells within minutes of inoculation. they transform to amastigotes and replicate within the acidic
Both antibody-dependent and cell-mediated immune mecha- and hostile environment of the phagolysosome. Eventually,
nisms are active against the erythrocytic stage of infection. Both the phagocytes rupture and release amastigotes to infect other
B cells and CD4 T cells are required for complete clearance of macrophages or a sand fly.
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parasites. Adoptive transfer of human immune serum is protective
for naïve individuals. Antibodies directed against merozoite Innate Immunity
surface proteins can inhibit invasion. A significant proportion Much of what we know of immunity in leishmaniasis comes
of antibodies to infected erythrocytes are directed toward variant from studies of inbred mouse strains, which demonstrate a
antigens, such as PfEMP-1 on the surface of the RBC. Immu- genetically determined spectrum of innate and adaptive immune
noglobulin G1 (IgG1) and IgG3 isotype antibodies specific for responses that shape the outcome of infection. The innate immune
parasite antigens exported to the surface of the RBC play a role response to Leishmania is mediated by complement, NK cells,
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in naturally acquired immunity by opsonizing infected cells for cytokines, and phagocytes. The production of IL-12 early in
phagocytosis in the spleen. the course of infection by DCs leads to the early activation of
CD4 T cells are implicated in protection by experiments NK cells and the production of IFN-γ. Chemokines (IP-10, MCP-1,
showing that MHC class II–restricted antigen presentation is and lymphotactin), as well as LPG–TLR interaction, can also
required for reduction of parasitemia and pathology. Protective promote the early NK-cell activation. Activated NK cells have
cellular immune responses (CD4 and CD8 T-cell proliferation, been shown to be cytolytic for Leishmania-infected macrophages,
IFN-γ production, and NO synthesis) in the absence of detectable but NK cell–derived IFN-γ plays a more prominent role in host
antibody responses were identified in naïve volunteers, who were defense by activating macrophages to kill the intracellular parasite
protected by repeated exposure to low doses of blood-stage through the generation of reactive oxygen intermediates (ROIs)
parasites. In addition to promoting phagocytosis, CD4 T cells or reactive nitrogen intermediates (RNIs). Parasite-induced,
are required to help B cells, especially by the production of IL-21. MyD88-dependent signaling through TLR2, TLR3, and TLR4
One of the most important roles for CD4 T cells is the regulation contributes to macrophage activation and NO production.
of the intense inflammatory response through production of Activated polymorphonuclear leukocytes (PMNs) can kill parasites
antiinflammatory cytokines IL-10 and TGF-β. through oxidative mechanisms, but the role of neutrophils in
vivo depends on the timing of their recruitment and their
Evasion of Host Immunity interaction with other immune cells. An important study
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The malaria parasite uses several different mechanisms to evade demonstrated that infiltrating neutrophils promote sand fly–
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the host immune response. Sporozoites and merozoites evade transmitted infection, probably through modulation of macro-
circulating antibody by rapidly entering hepatocytes or RBCs, phage function following engulfment of apoptotic parasitized
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respectively. Some sporozoite proteins enter the hepatocyte nucleus neutrophils. Type 1 IFNs participate in the early induction of
and influence the expression of a number of host genes, thereby NO and control of parasite replication early in infection.
favoring parasite survival. Mature RBCs do not express MHC
molecules on their surface and so avoid recognition by T cells. Adaptive Immunity
The few parasite proteins that are expressed on the erythrocyte Within an endemic area there is acquisition of immunity in the
surface exist in multiple allelic forms to avoid quick recognition population over time. Retrospective epidemiological studies
by the adaptive immune system. Many of the immunodominant indicate that most individuals with prior (primary) infection
antigens in Plasmodium spp. are proteins having extensive repeat (subclinical or healed) are immune to a subsequent clinical
sequences that vary over time. The large number of bloodborne infection. Following primary infection, parasites persist for the
antigens induces a plasmablast response generating a short-lived life of the host and maintain long-term immunity.
burst of low-affinity antibodies. Although there is an increase There is extensive evidence from experimental models that
in atypical B cells, memory B cells and long-lived plasma cells cellular immune mechanisms mediate adaptive resistance to
are generated. It is unclear if poor immunity following a single Leishmania infection, and human studies have generally confirmed
infection is caused by ineffective, atypical B cells or misdirected this. Antileishmanial antibodies, which are produced at a low
antibody specificity. level in localized cutaneous leishmaniasis (LCL) and at a very
high level in visceral leishmaniasis (VL), play no role in protection.
Leishmania spp. The general mechanisms of cellular immunity in leishmaniasis
can be summarized (Fig. 30.2). Following infection in the skin,
Pathogenesis migratory dermal DCs phagocytose Leishmania and presumably
The intracellular Leishmania amastigote replicates within macro- transport the intracellular parasite to the regional lymph node,
phages in the vertebrate host, and the extracellular promastigote where they induce a T-cell response. Adaptive immunity is primar-
develops within the insect vector. The female phlebotomine sand ily mediated by parasite-induced production of IFN-γ by CD4