Page 362 - Clinical Immunology_ Principles and Practice ( PDFDrive )

342 ParT TwO Host Defense Mechanisms and Inflammation

other drugs that inhibit COX-1. Although tissue mast cell burden around sites of parasitical infestation. Subsequent studies have
in AERD does not exceed that seen in aspirin-tolerant control demonstrated a role for mast cells in mouse models of helminth
patients with asthma, baseline levels of serum tryptase and urinary infection in the gut as well as in parasitical skin infections. 37
PGD 2 metabolites are higher, potentially reflecting a loss of Production of IL-4 and IL-13 by mast cells and basophils
homeostatic PGE 2 from the surrounding tissue. These values may play an important role in early parasitical infections, leading
increase markedly with aspirin challenges, and treatment with to IgE production, secretion of effector molecules, activation of
cromolyn or nedocromil blocks the characteristic reactions, smooth muscle cells, and increased mucus production, among
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1
supporting their mast cell dependency. Notably, a mouse model other effects. Furthermore, although expulsion of hookworm
suggests that mast cell activation in response to aspirin challenge during primary infection in mice depends on mast cells, basophils
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depends on IL-33 rather than the allergen. It is tempting to are necessary to expel hookworms during secondary infection,
1
speculate than innate cytokines could account for mast cell possibly because of activation by helminth-specific antibodies.
activation in other nonatopic disorders. Intestinal helminth infections typically elicit a T cell-dependent
There is growing evidence that basophils play a role in the expansion of mast cells and basophils in the involved mucosal
8
pathogenesis of asthma as well. Basophils are enriched in post- site. In that regard, mast cells and basophils can be viewed as
mortem human lung tissue from patients who have died as a components of the effector arm of adaptive immunity.
result of asthma as well as in bronchial biopsy specimens of Mast cells are important in the generation of immune
1,3
patients with asthma. In mouse models of allergic airway responses to bacterial pathogens. For example, mast cell deficient
inflammation, basophils have been shown to promote Th2 mice have increased mortality in a model of Escherichia coli–
3
cytokine responses and pathological airway inflammation. The induced peritonitis. Mast cells have shown protective roles in K.
specific functions of basophils relative to asthma are not yet pneumoniae lung infections and Pseudomonas skin infections in
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known, though it seems likely that they could contribute Th2 mice. Mice lacking mast cells as a result of loss-of-function Kit
cytokines and cysLTs. and SCF mutations are significantly more susceptible to lethal
gram-negative sepsis than are congenic mast cell–sufficient
Allergic Rhinitis controls. Reconstitution of the tissues with wild-type mast cells
Allergic rhinitis is an inflammatory disease of the nasal mucosa restores protective immunity. Both proteases and TNF-α are
that occurs as a reaction to airborne allergens (Chapter 41). linked to the protection from bacterial infections conveyed by
Increased numbers of activated MC T mast cells are found in the mast cells.
nasal epithelium of patients with allergic rhinitis, and these
numbers increase further with allergy provocation challenge or Mast Cells in Other Diseases
34
during seasonal disease exacerbations. Basophils are present Mast cells may play a role in other disease processes as well.
3
in nasal washes from patients with allergic rhinitis. In addition, Increased numbers of mast cells have long been noted in human
nasal challenges with allergens lead to the release of histamine atherosclerotic lesions compared with healthy control tissue.
and cysLTs, which are preformed mediators of both mast cells Mast cell functions within these plaques are not completely
and basophils. 34 understood, although mouse models suggest that atherosclerotic
changes are promoted by release of proinflammatory cytokines
Atopic Dermatitis by mast cells. Mouse models of autoimmunity, including
38
40
39
Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin autoantibody-mediated arthritis and multiple sclerosis, have
condition that is commonly diagnosed in young children and demonstrated a pathological role for mast cells. Skin mast cells
often precedes the development of allergic rhinitis and asthma are activated rapidly following thermal trauma, and the release
(Chapter 44). The pathogenesis of AD remains incompletely of mast cell proteases is crucial for development of the inflam-
understood but is likely multifactorial with contributions from matory response in burn lesions. 41
skin barrier dysfunction, innate and adaptive immune dysregula- Recent work in mice has shown that mast cells protect from
tion, and environmental and genetic factors. Increased numbers the detrimental effects of arthropod or reptile venoms via the
of mast cells can be seen in skin lesions from human AD and degradation of venom toxins by mast cell proteases. Furthermore,
mouse AD models, but their role in the pathophysiology of the acquired Th2 immune responses associated with IgE production
disease is not known. 34 can protect mice from challenge with potentially lethal doses of
Basophils have been identified in lesional skin of patients venoms from honeybee or the Russell viper. 42
with AD, but their precise role in human disease remains unclear.
In murine models of AD-like skin disease, significant TSLP- Mast Cell Roles in Normal Physiology
dependent basophilia has been noted in lesional skin. TSLP is In addition to their immune functions, mast cells are thought
also associated with human AD, so it is possible that TSLP-induced to have normal physiological functions as well. Data from mouse
basophil populations could play a role in human disease as well. 1,3 studies suggest a role for mast cells in intestinal barrier function
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and homeostatic intestinal epithelial migration. Human uterine
Mast Cells and Basophils in Immunity tissue has increased density of mast cells during pregnancy, where
44
Although mast cells are found throughout most tissues, they they may mediate contractility, in addition to contributing to
are notably located at interfaces with the environment, such as local immunity.
skin and the mucosal surfaces. This suggests a potential role in
pathogen recognition and host defense. Additionally, mast cells MASTOCYTOSIS AND OTHER
have the capacity to increase in numbers during mucosal inflam- MAST CELL DISORDERS
matory responses, suggesting that their effector capabilities can be
magnified to suit the context. The first associations of mast cells A variety of human disorders are associated with excessive
with host defense included observations of mast cells clustering numbers of mast cells, increased activation of mast cells, or both.