Asthma diagnosis and treatmentChitinases and chitinase-like proteins in TH2 inflammation and asthma
Section snippets
Biology of chitin and chitinases
Chitin is a polymer of N-acetylglucosamine that, after cellulose, is the second most abundant polysaccharide in nature. Although it does not have a mammalian counterpart, chitin is found in the walls of fungi; exoskeleton of crabs, shrimp, and insects; the microfilarial sheath of parasitic nematodes; and the lining of the digestive tracts of many insects.4, 5, 6, 7, 8, 9, 10, 11 These pathogens use chitin to protect the invader from the harsh conditions inside the animal or plant host. In these
Mammalian chitinase and chitinase-like genes
Until a few years ago, it was generally assumed that mammals lacked chitinases. Recent studies in human subjects and rodents, however, have identified a family of chitinase and chitinase-like (C-CL) genes in both species. Acidic mammalian chitinase (AMCase), chitotriosidase, oviductin, human cartilage glycoprotein-39 kd (HcGP-39)/YKL-40, and YKL-39 have been described in human subjects, whereas YM-1, YM-2, AMCase, oviductin, and breast regression protein 39 (BRP-39) have been described in mice.5
AMCase
AMCase was the second mammalian chitinase to be cloned. It is a 50-kd product of genes on mouse chromosome 3 and human chromosome 1 at p13.1-p21.3.5, 17 The enzyme is acid stable, with a pH optimum of 2.0, and has true chitinase bioactivity when tested with crab, fungal, and synthetic substrates. This enzyme might also have non–chitin-related biologic effector properties because an AMCase-like protein has been reported to possess fibroblast growth-promoting activity,18 and AMCase has been
BRP-39
BRP-39 was discovered in mouse breast cancer cells,19 and a variety of homologues (with different names) have been described in different species. They include human cartilage glycoprotein-39 kd (HcGP-39), human YKL-40, porcine 38-kd heparin-binding glycoprotein (GP38K), and bovine 39-kd whey protein. BRP-39 and HcGP-39/YKL-40 are 39-kd products of genes on chromosome 1 in the mouse and human subject, respectively, that do not have chitinase activity. A variety of lines of evidence, however,
Functions of mammalian C-CL proteins
One of the most pressing issues in chitinase biology relates to our almost complete lack of understanding of the functions of these strongly conserved (and therefore presumably biologically important) enzymes in human subjects.14 We are also lacking in our knowledge of the importance of chitinase degradation of chitin, glycosaminoglycans, and/or glycoproteins17 and the ability of some C-CL proteins to act as lectins and bind to heparin and heparan sulfate moieties26 in mediating their biologic
C-CL proteins in TH2- and IL-13–induced inflammation
Host immune responses to parasites include an early innate component designed to control or eliminate parasitic infestation and, over time, an adaptive response that controls the parasite in an antigen-specific fashion. The immune response to parasites is frequently TH2 dominated and is known to share key features with tissue allergy, including the increased production of IL-4, IL-5, IL-13, and IgE and prominent tissue eosinophilia. As a result, it is believed that TH2 inflammatory responses
AMCase in human asthma
The studies noted earlier demonstrate that AMCase is prominently expressed in lungs from antigen-sensitized and challenged and IL-13 transgenic mice. To begin to define the relevance of these findings to human TH2 inflammatory responses, in situ hybridization has been used to compare the expression of AMCase in lung biopsy samples from healthy subjects and patients with asthma. AMCase mRNA was not readily detected in lung tissues from the patients without known lung disease. In contrast, AMCase
The tip of the iceberg
There is mounting evidence that C-CL proteins are highly regulated and can contribute to tissue inflammatory and remodeling responses. This can be readily appreciated in studies of the novel chitinase AMCase that is stimulated in an IL-13–dependent, TH2-specific fashion in the murine lung where it plays an important role in TH2 inflammation and IL-13 effector pathway activation. In accordance with these findings, AMCase is also overexpressed in human asthma. These studies highlight the tip of
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Guest editor: William W. Busse, MD