Pulmonary defense against environmental injury depends on airway mucus, which traps inhaled toxins that are then cleared from the lungs by ciliary beating and cough. This review examines the normal and abnormal formation and clearance of mucus, as well as the therapy of mucus dysfunction.

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Airway mucus function and dysfunction.

Total serum immunoglobulin (Ig)E levels are genetically regulated, but the mechanism of inheritance is not well understood. Cytokines produced by T-helper (Th)1 and Th2 lymphocytes control IgE synthesis. Bacterial antigens may favor the development of Th1 cells from naive CD4-positive T cells through a CD14-dependent pathway. CD14 is constitutively expressed on the surface of monocytes and macrophages, and is also present in serum in a soluble form (sCD14). The CD14 gene maps to chromosome 5q31.1, a candidate region for loci regulating total serum IgE. We hypothesized that genetic variants in the CD14 gene could influence Th-cell differentiation and thus total serum IgE. We identified a C-to-T transition at base pair −159 from the major transcription start site (CD14/−159). Among 481 children recruited from a general population sample, frequency of allele C was 51.4%. TT homozygotes had significantly higher sCD14 levels than did carriers of both the CC and CT genotypes (P = 0.01). TT homozygotes also had ...

https://www.atsjournals.org/doi/pdf/10.1165/ajrcmb.20.5.3494

A Polymorphism* in the 5 ′ Flanking Region of the CD14 Gene Is Associated with Circulating Soluble CD14 Levels and with Total Serum Immunoglobulin E

Alcohol dependence is a leading cause of morbidity and premature death. Several lines of evidence suggest a substantial genetic component to the risk for alcoholism: sibs of alcoholic probands have a 3-8 fold increased risk of also developing alcoholism, and twin heritability estimates of 50-60% are reported by contemporary studies of twins. We report on the results of a six-center collaborative study to identify susceptibility loci for alcohol dependence. A genome-wide screen examined 291 markers in 987 individuals from 105 families. Two-point and multipoint nonparametric linkage analyses were performed to detect susceptibility loci for alcohol dependence. Multipoint methods provided the strongest suggestions of linkage with susceptibility loci for alcohol dependence on chromosomes 1 and 7, and more modest evidence for a locus on chromosome 2. In addition, there was suggestive evidence for a protective locus on chromosome 4 near the alcohol dehydrogenase genes, for which protective effects have been reported in Asian populations.

Genome‐wide search for genes affecting the risk for alcohol dependence

Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.

/pdf/muc5b-is-required-for-airway-defence-16k1tja8l7.pdf

Muc5b is required for airway defence

REVIEW ARTICLE Genomewide Scans of Complex Human Diseases: True Linkage Is Hard to Find

Asthma is an inflammatory airwaysdisease associated with intermittent respiratory symptoms, bronchial hyperresponsiveness (BHR) and reversible airflow obstruction and is phenotypically heterogeneous1,2. Patterns of clustering and segregation analyses in asthma families have suggested a genetic component to asthma3–6. Previous studies reported linkage of BHR and atopy to chromosomes 5q (refs 7–9), 6p (refs 10–12), 11q (refs 13–15), 14q (ref. 16), and 12q (ref. 17) using candidate gene approaches. However, the relative roles of these genes in the pathogenesis of asthma or atopy are difficult to assess outside of the context of a genome-wide search. One genome-wide search in atopic sib pairs has been reported18, however, only 12% of their subjects had asthma. We conducted a genome-wide search in 140 families with ≥2 asthmatic sibs, from three racial groups and report evidence for linkage to six novel regions: 5p15 (P= 0.0008) and 17p11.1–q11.2 (/> = 0.0015) in African Americans; 11p15 (P = 0.0089) and 19q13 (P = 0.0013) in Caucasians; 2q33 (P = 0.0005) and 21q21 (P = 0.0040) in Hispanics. Evidence for linkage was also detected in five regions previously reported to be linked to asthma-associated phenotypes: 5q23–31 (P = 0.0187), 6p21.3–23 (P = 0.0129), 12q14–24.2 (P = 0.0042), 13q21.3–qter (P = 0.0014), and 14q11.2–13 (P = 0.0062) in Caucasians and 12q14–24.2 (P = 0.0260) in Hispanics.

Rhonda Peterson

Papers

A genome-wide search for asthma susceptibility loci in ethnically diverse populations