Page 463 - Clinical Immunology_ Principles and Practice ( PDFDrive )

442 ParT ThrEE Host Defenses to Infectious Agents

neutrophils resulted in greater worm burdens because of lack by vaccination with irradiated cercariae. This resistance is
of immunity in the lungs. Thus neutrophils appear to play an dependent on a Th1-mediated immune response consisting of
unexpected role in immunity to helminths that certainly merits macrophages and endothelial cells activated by IFN-γ and TNF-α,
further investigation. producing nitric oxide and Th1-associated antibodies—IgG2a
and IgG2b. In contrast, studies in rats and epidemiological studies
PROTECTIVE IMMUNITY AGAINST HELMINTHS in humans suggest Th2-mediated effector mechanisms involving
IgA and IgE antibodies as well as eosinophils are thought to be
The mechanism of protective immunity to helminths is dependent central to protective immunity. Protective immunity to filarial
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on the location of the helminth infection. Clearly, T cells are infections in mice is dependent primarily on Th2 responses in
central to resistance against helminths. For example, T cells are mice. Thus mice lacking IL-4, IL-4R, or Stat6 are all susceptible
essential in mediating the expulsion of GI nematodes. Mice to infection with Brugian parasites.
lacking T cells are defective in their ability to expel T. muris, but In tissue-invasive helminth infections, effector mechanisms
resistance can be reconstituted by transfer of T cells from normal involve multiple innate immune cells, with antibodies acting as
mice. In addition, CD4 T cells from infected mice can transfer initiators of immunity by activating Fc receptor expressing cells.
protective immunity to severe combined immunodeficiency Basophils, by their ability to produce high levels of IL-4, act as
(SCID) mice (lacking both B and T cells), indicating that CD4 effectors to promote helminth killing in secondary or challenge
T cells, not CD8 T cells, were important for protective immunity. infections. For example, basophils are important in immunity
Similarly, T cells were shown to be required for expulsion in N. to the skin invasive stages of intestinal helminths and, through
brasiliensis infection. Both nude mice (lacking T cells alone) and IL-4 release, promote the activation of macrophages that trap
SCID mice are susceptible to infection with Brugian parasites, larvae in an arginase-dependent manner. Although eosinophils
whereas mice that lack either CD4 T cells or CD8 T cells are are crucial players in producing IL-4 early in infection, they are
not. In schistosome-infected mice, T cells are essential in forming also amplifiers of immune responses, rather than being critical
host-protective granulomas around the eggs deposited in the mediators of primary immunity, since depletion of eosinophils
liver. does not alter the course of many helminth infections in murine
The role of cytokines in protective immunity has been models. The mechanism of protection mediated by eosinophils
extensively studied in murine models of both GI helminths and is thought to be by antibody-dependent, cell-mediated cytotoxicity,
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tissue-invasive helminths. In general, type 2 (Th2) cytokines as observed in S. mansoni studies in vitro or through release of
target epithelial cells, goblet cells, smooth muscle cells, and eosinophil granule contents. In addition, eosinophils play an
macrophages, which together coordinate parasite expulsion by important role in the protective immunity against primary
increasing fluid and mucus production, encapsulation and barrier infection with B. malayi and/or secondary infection with either
formation, epithelial cell turnover, smooth muscle cell contraction, T. spiralis or N. brasiliensis. The two most abundant granular
and production of anthelmintic effector molecules, such as proteins, major basic protein (MBP) and eosinophil peroxidase
RELM-β. The cytokines involved in both responses are IL-4, (EPO), are required for protective immunity against S. stercoralis
IL-5, IL-9, and IL-13. Most of the studies examining resistance and L. sigmodontis. Similarly, neutrophils can attack helminth
to intestinal helminths involve four parasitical GI nematode larvae in response to IL-4 and IL-5, but their importance in
infections of rodent models—T. spiralis, H. polygyrus bakeri, N. resistance to primary helminth infections is not known.
brasiliensis, and T. muris. These studies show that (i) CD4 T cells Antibodies play a major role in mediating protection to some
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are crucial for host protection; (ii) IL-4 is required for host but not all helminth infections. Antibody-mediated passive
protection and limiting host pathology; (iii) IL-13 can substitute immunity has been demonstrated in animal models for A.
for IL-4 in some but not all infections; (iv) IL-2 and IFN-γ inhibit caninum, Schistosoma species, Taenia species, Ascaris suum, S.
protective immunity; and (v) IL-4 and IL-13 have multiple effects ratti, T. muris, N. brasiliensis, and H. polygyrus bakeri. Passive
on the immune system and gut physiology leading generally to immunity has also been shown by using IgG monoclonal antibod-
protection. Type 2 cytokines mobilize a broad range of down- ies (mAbs) specific for Fasciola hepatica and S. mansoni; IgM
stream effector mechanisms. Epithelial cells in the gut, specifically (mAbs) specific for B. malayi; and IgG or IgA mAbs specific for
tuft cells, promote goblet cell differentiation, enhancement of T. spiralis. Again using genetically manipulated mouse models,
mucus secretion, and the production of RELM-β, an innate IgM has been shown to be crucial for host protection against B.
effector molecule with direct anthelmintic activity. Goblet cells malayi and to S. stercoralis. B1B cells, a subset of B cells that
can also secrete gel-forming mucins, which are major macro- secrete IgM, appear to be an important component of this
molecular components of the mucus barrier. Two of these mucins protective axis. Finally, antibodies have the capacity to trap tissue
have been shown to be critical in resistance to intestinal nematode migrating helminth larvae and prevent tissue damage by driving
infection—Muc2 and Muc5AC. IL-4Rα activation also leads an IL-4Rα–independent alternative differentiation of macro-
increased intestinal smooth muscle hypercontractility and phages, in a process dependent on CD11b and FcγR1.
accelerated epithelial turnover to promote an effector response In terms of protection, a major mechanism appears to be the
akin to an “epithelial escalator,” which, together with epithelial formation of multicellular, immune cell aggregates, called granu-
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secretions, helps expel intestinal helminths. Mucosal mast cells lomas, around incoming infectious larvae or eggs. In murine
release proteases that can degrade epithelial tight junctions, models of schistosomiasis and filariasis, granulomas are primarily
thereby increasing fluid flow as part of the “weep and sweep” composed of T cells (which help in the recruitment of other cell
response. AAMs in the gut can also entrap intestinal worms and types and mediate alternative activation of macrophages), B cells
cause death by compromising worm vitality. (particularly the B1 subset), and macrophages and eosinophils.
Although the role of Th2 cytokines in immunity to GI helminth Although the exact mechanism by which granulomas mediate
infection is well defined, their role in protective immunity to killing of the parasite remains unknown, it is clear that formation
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tissue-invasive helminths is not as clear. In murine models of of these structures is an important host defense mechanism. One
schistosomiasis, protective immune responses can be generated cell type that can mediate effector functions within granulomas