A role for Leukotriene B4 in the induction of airway hyper-responsiveness was explored through the use of transgenic mice deficient in the BLT1 receptor for LTB4 . Ovalbumin challenge of sensitized wild-type mice resulted in the usual features of experimental asthma, including goblet cell hyperplasia, hyper-responsiveness to inhaled methacholine and elevated BAL fluid concentrations of the Th2 cytokine IL-13. In contrast, BLT1 –/– mice (i.e. genetically modified mice lacking the gene coding for the BLT1 receptor) exhibited significantly lower responses. BLT1 –/– mice also exhibited lower numbers of IL-13-positive T lymphocytes of both the helper (CD4 T Cells) and cytotoxic/suppressor (CD8 + ) types. (more…)

Treg cells or regulatory T cells constitute a large population of cellular infiltrate in atopic/allergic inflammation and a dysregulated immune response appears to be an important pathogenetic factor. Cardinal events during allergic inflammation can be classified as activation, organ-selective homing, survival and reactivation, and effector functions of immune system cells. T cells are activated by aeroallergens, food antigens, autoantigens, and bacterial exotoxins superantigens in allergic inflammation. They are under the influence of the skin, lung, or nose-related chemokine network and show organ-selective homing. (more…)

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A general pattern of factors influencing development of asthma seems to be emerging, including family allergy history/ asthma genetics, smoking, diet, obesity, and inactivity, all of which seem to influence the development of asthma and disease outcomes (Table bellow).

Many clinical or area studies have reported substantially higher rates of asthma prevalence, hospitalization, and mortality among racial and ethnic minorities. However, asthma is also most common among low socioeconomic groups, regardless of race. While black children have higher rates of asthma than white children, most studies have found that black race is not a significant correlate of asthma after controlling for location of residence and socioeconomic status (SES). The basis for the effects of poverty and urban residence on asthma prevalence is not known. One potential asthma factor is allergen exposure and allergen sensitization are common in urban environments. Black children in inner city Atlanta are exposed to high levels of dust mites and cockroach allergen, and a high proportion of the children with asthma were sensitized to these allergens. Litonjua and colleagues also concluded that a large proportion of racial/ethnic differences in asthma prevalence can be explained by factors related to income, area of residence, and level of education.

Asthma Factors that Influence Disease Development and Severity

Income is a determinant of access to health care, and frequently, the quantity and quality of health care available. Persons who have low income, regardless of race or ethnicity, are more likely to be uninsured, to encounter delays or be denied care, to rely on hospital clinics in emergency departments for health services, and to receive substandard care. The usual socioeconomic indicators, education and personal or household income, serve only as surrogates for more complicated correlates of individuals within populations and multiple asthma factors that can impact both on prevalence of asthma and adverse outcomes from the disease.

Studies from Germany comparing the populations of East and West Germany have shown the prevalence of hay fever and asthma as significantly higher in West German children, suggesting that asthma environmental factors explain the difference in prevalence in these ethnically similar populations. Early exposure to infections (as with being in a day-care environment early in life) or exposure to endotoxin (as with growing up on a farm with close exposure to the farm animals) are associated with a decreased prevalence of asthma. In contrast, growing up in an urban environment or generally with an increased standard of living are associated with an increased prevalence of asthma. Such correlates are also present for atopic disorders other than asthma. In fact, Strachan, who noted that prevalence of hay fever was inversely related to family size, was the first to recognize the importance of early exposures on atopic disease. In the USA, asthma is more prevalent in African-Americans and Puerto Ricans. These findings are not explained by the observations on the role of social class in European studies. Given the ethnic differences between African-Americans and whites, these studies may represent gene-by-environment interaction producing varied phenotypic outcomes.

Perhaps the most exciting recent advance in the cytokine signaling field has been the elucidation of the Jak/Stat pathway. The Janus kinase (Jak) family consists of four known enzymes (Jak1, Jak2, Jak3, and Tyk2), each of which associates specifically with the cytoplasmic tails of one or more cytokine receptor subunits. For example, IL-2R associates with both Jak1 and Jak3, which bind its α and γ subunits, respectively. Cytokine binding brings the receptor subunits together and allows the associated Jak proteins to phosphorylate and activate one another. The primary substrates of the activated Jaks are a family of transcription factors called the Stat (for signal transducers and activators of transcription) proteins. The Stat proteins contain SH2 domains and so are recruited to the vicinity of an activated receptor when its kinases become active. (more…)

The body’s innate resistance to many pathogens is provided by enzymes and other proteins in the blood and tissue fluids. These proteins are the effectors (ie, the active agents) of humoral innate immunity, and they have features in common with one another that are also characteristics of the innate immune system as a whole. First, these proteins are continually expressed throughout life, regardless of whether or not their protective effects are needed at a given moment. Second, although many of these proteins can be produced in higher quantities in times of need, their intrinsic properties (eg, substrate specificity and ige binding affinity) never change: The characteristics of these proteins have been shaped by evolution, are genetically determined, and are fixed at birth, so that they do not vary during an individual’s lifetime. (more…)

Hematopoietic progenitors depend on a variety of cytokines to control their growth and differentiation. These include several different types of colony-stimulating factor (CSFs) and interleukins that each act on specific cell types to promote or inhibit particular types of responses. Detailed discussions of individual cytokines are presented in Chapter 10; for the present, we focus on general principles of cytokine action as illustrated in their effects on hematopoiesis. (more…)

Our understanding of hematopoiesis has advanced greatly in recent years with the isolation and characterization of hematopoietic stem cells (HSCs) and the identification of many of the factors that influence the production and differentiation of lineage-committed progenitors (Figure 1 bellow). HSCs are defined by their abilities to self-renew throughout life and to give rise to committed progenitors that can differentiate along all of the possible hematopoietic lineages. They were first purified from mice as a tiny sub-population of marrow cells that could completely reconstitute the hematopoietic systems of other mice, whose own marrows had been destroyed by inherited mutations or by radiation. (more…)

Normally present at very low levels in plasma, antibodies of the immunoglobulin E (IgE) isotype were first discovered in 1967, decades after the description of IgA, IgG, and IM. IgE antibodies are produced primarily by plasma cells in mucosal-associated lymphoid tissue and their levels are uniformly elevated in patients suffering from atopic conditions like allergic rhinitis, asthma and atopic dermatitis. Production of allergen-specific IgE in atopic individuals is driven both by a genetic predisposition to the synthesis of this isotype as well as by environmental factors, including chronic allergen exposure. (more…)

Asthma is characterized by Th2-dominant cytokine profiles. The risk of developing asthma is lower in children attending day care in the first year of life. Therefore, this study was conducted to assess the interaction between day-care attendance, T-cell cytokine profiles and atopic phenotypes in early childhood. Children (n = 208) in the Childhood Onset of Asthma (COAST) study were genotyped for 72 polymorphisms in 45 immune response genes. The COAST cohort was selected on the basis of a high risk of asthma. Measurements of IFN-y (Th1), IL-5 and IL-13 (Th2), and IL-10 (Treg) were made at birth and at age 1 year and the children were stratified by day-care attendance. Wheeze and atopic dermatitis phenotypes were documented in the first year. (more…)

Increasing evidence demonstrates that cytokines of Th1 and Th2 cells play important roles in allergic disorders. This study examined polymorphisms in the IL-12B gene, a primary inducer of the development of Th1 cells with downregulation of the Th2 cytokines. The exons, splice sites and portions of the 5” and 3” flanking regions of the IL-12B gene were sequenced and 13 polymorphisms identified. A case–control study of Japanese children (297 cases) with asthma stratified by asthma-related phenotypes was conducted on a subset of three of these SNPs. The functional effects of the identified polymorphisms were examined using luciferase and RNA stability assays. (more…)