Page 995 - Williams Hematology ( PDFDrive )

970 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 63: Basophils, Mast Cells, and Related Disorders 971

cell in such models of “innate immunity” in mice may partly reflect peptides. Work in mice deficient in mast cells, IgE, or components of the
complement-dependent, toll-like receptor (TLR) 4-dependent, endo- FcεRI suggests that mast cells also can contribute to the IgE antibody-
thelin-1–dependent, or neurotensin-dependent activation of mast cells, and FcεRI-dependent enhanced resistance to challenge with potentially
inducing the release of mast cell–derived mediators, which, in turn, can lethal amounts of honeybee venom that is observed in animals after an
contribute to enhanced local recruitment or activation of neutrophils initial exposure to a sublethal amount of that venom. Indeed, it has
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and enhanced clearance of bacteria, or which may reduce harmful lev- been hypothesized that the ability to participate in innate and acquired
els of TNF-α. 63,64,83 Studies in mice indicate mast cells can phagocytose immune defenses against components of venoms and other toxins are
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bacteria, and mouse and human mast cells can produce antimicrobial important functions of mast cells and, in the case of acquired immunity,
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peptides (cathelicidin LL-37 in humans). However, mast cells also of IgE antibodies. 95,96,100
may contribute to survival during bacterial infection in mice by addi-
tional mechanisms, such as protease-dependent degradation of endo- GENETIC APPROACHES FOR ANALYZING
thelin-1, 85,86 neurotensin, and perhaps other endogenous peptides that
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are produced during infections and which contribute to the pathology BASOPHIL AND MAST CELL FUNCTION
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associated with the disorders. On the other hand, some mast cell func- Factors capable of inducing basophil infiltration, mast cell prolifer-
tions that may be expressed during bacterial infections in mice, such as ation, and/or basophil or mast cell activation are generated during
the ability of mast cells to degrade IL-6 via dipeptidyl peptidase 1 or a wide variety of immunologic or pathologic processes, including
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to produce IL-10 that suppresses host acquired immunity, may have immune responses to parasites. 1,5,30,49–51,55–57,77 As a result, speculation
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detrimental consequences. Thus, mast cells may have complex roles in is considerable that basophils and mast cells express critical roles
innate immune responses, with some actions promoting host defense in diverse biologic responses. On the other hand, the precise func-
and survival and others enhancing the pathology associated with the tions of basophils and mast cells in most of the biologic responses in
response. which the cells have been implicated are obscure. Studies of basophil
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function in guinea pigs and mice 55–57 have employed antibodies
Viral Infections to deplete basophils, and such approaches also have been used to
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Mast cell progenitors 90–92 and basophils can become infected with deplete mast cells in mice ; however, the antibodies used may also
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“M tropic” strains of HIV. Although mature mast cells appear to be influence other cell types. 5,55–57,63,64,79 Various mutant or transgenic
resistant to such infection, mast cells that matured from infected pro- mice that exhibit constitutive or inducible depletion of some or all
genitors while harboring latent infection exhibited enhanced viral rep- mast cell populations, as well as mast cell–deficient mice that have
lication upon stimulation with ligands for TLR2, TLR4, or TLR9, 91,92 or been selectively engrafted with wild-type or genetically altered mast
via an IgE-dependent mechanism. At least one HIV-derived protein, cells (so-called mast cell knockin mice), have been used in efforts to
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glycoprotein 120 (gp120), can induce mast cell or basophil mediator define and quantify the contributions of mast cells to many different
release (histamine and, in basophils, IL-4 and IL-13) by binding to and biologic responses. 63,64,79 Transgenic mice also are now available that
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crosslinking cell-surface-bound IgE. Many patients infected with HIV exhibit constitutive or inducible depletion of basophils, or that lack
develop high levels of IgE and can exhibit exacerbation of the symptoms certain mast cell–associated products either globally or in selected
and signs of their allergic disorders. However, the clinical significance cell populations. 5,55–57,63,64,79 As has been extensively reviewed, 5,54–56,74–76
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of such findings in HIV-infected patients remains to be determined. the availability of such models has the potential to advance substan-
Many potential secreted products of mast cells or basophils may have tially our understanding of the roles of mast cells and basophils in
effects that enhance (or suppress) host responses to a variety of viruses health and disease in mice, including ascertaining the importance of
or contribute to the pathology associated with the infections. How- strain background on some of the findings. In evaluating the results
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ever, the extent to which mast cells contribute to host defense or pathol- of such studies, one should keep in mind that such genetic mod-
ogy during viral infections is not clear. els can have various advantages and disadvantages, and that even
Venoms The venoms of many animals contain substances that can very strong evidence that mast cells or basophils have particular
activate mast cells via innate mechanisms and/or can induce specific IgE roles in mice does not prove that the cells have identical functions
responses to venom components. 95,96 Many humans have IgE antibodies in humans.
against components of honeybee or wasp venom, but only a small frac- No humans devoid of mast cells have been reported. In addi-
tion of such “venom-sensitized” individuals have a history of anaphy- tion, the clinical findings in the rare patients who express a deficiency
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laxis or other serious clinical response to such venoms. Work in mast of basophils are not easy to interpret. One patient with a profound
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cell–deficient, mast cell knockin, and mast cell protease-deficient mice basopenia experienced persistent and severe infestation with scabies,
indicates that mast cells can enhance the resistance of mice to diverse a finding that might be viewed as consistent with the role of basophils
animal venoms and/or their toxic components, including the venoms in resisting ectoparasites in humans. However, that patient also had eos-
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of three poisonous snakes, the honey bee, 96,98 the Gila monster, and inopenia, IgA deficiency, and multiple other clinical problems. A sec-
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two species of scorpions, as well as to sarafotoxin 6b, a major toxin in ond basophil-deficient patient had a history of recurrent bacterial and
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Israeli mole viper snake venom and helodermin, a toxin in Gila mon- viral infections. However, this patient also had a deficiency of eosin-
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ster venom. 99 ophils, hypogammaglobulinemia, abnormal suppressor T-cell function
Notably, carboxypeptidase A3 (CPA3) or mouse mast cell pro- in vitro, and a thymoma. 34
tease (mMCP-4, the functional counterpart in the mouse to human
chymase) appeared to account for much or all of the protective effects BLOOD BASOPHIL COUNT
against various venoms that were attributable to mast cells. 86,96,98,99 CPA3
and mMCP-4 can degrade both endogenous biologically active pep- The normal blood basophil count is difficult to define precisely, but
tides (endothelin-1 [ET-1] 86,96 and vasoactive intestinal polypeptide several studies place the normal range between approximately 14 to
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[VIP], respectively) and similar peptides present in animal venoms 20 and 80 to 90/μL (approximately 0.014 to 0.020 and 0.080 to 0.090
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(sarafotoxin 6b and helodermin, respectively), which are thought to act × 10 /L). 8–10,102 The blood basophil count reportedly varies by age,
in mammals via the same receptors that bind the similar endogenous gender (in one study but not in another ), and season. 104
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