POSSIBLE DUAL EFFECT OF CD14 MOLECULE ON ATOPY

To the Editor :

Koppelman and colleagues have found that homozygotes for the C allele at base pair 159 in the CD14 gene promoter region had higher atopic status (1). This finding is essentially a confirmation of the study by Baldini and colleagues showing a dominant effect of the C allele on total IgE levels in a general population (2). The important question is, of course, how does this polymorphism affect atopic status? It has been suggested that this polymorphism may downregulate CD14 expression (1, 2), and the inverse correlation between IgE and soluble CD14 (sCD14) has been observed (3). Th1-favored helper T cell differentiation, which is enhanced by complexes of CD14 and bacterial cell wall components, may be augmented by higher expression of CD14, which may result in a reduction in IgE responses, and consequently, serum IgE levels. If sCD14 really contributes to a decrease in the serum levels of IgE, lower levels of sCD14 should be expected among children with atopic asthma. However, we have previously shown that the levels of sCD14 in asthmatic children were significantly higher than those in normal controls (4). Moreover, there was a complete lack of either negative or positive correlation between the levels of sCD14 and IgE (unpublished data). In this connection, the levels of sCD14 have been shown to increase in the bronchoalveolar fluids of asthmatic patients, and this increase may worsen airway inflammation through enhanced LPS stimulation (5, 6). These observations, together with our data, suggest that CD14 expression is relatively enhanced and contributes to the worsening of allergic inflammation.

How can we explain these apparently contradictory effects of CD14? One possible explanation would be that higher level of sCD14 in asthmatic patients is secondary to allergic inflammation. As sCD14 level is a marker of monocyte/macrophage activation (4), it is possible that it increases as a result of monocyte involvement in allergic airway inflammation. If this is the case, we could expect negative correlation between sCD14 and IgE in early infancy, the time before the onset of asthma. In other words, sCD14 may have a dual effect, i.e., inhibition of IgE production before and aggravation of allergic inflammation after the onset of asthma. Actually, the inverse correlation between sCD14 and IgE observed by Vercelli and colleagues (3) is based on the study with general population, not allergic subjects. Further studies are thus necessary to determine the exact role of CD14 in atopy.

Kyoto University, Kyoto, Japan

Takeshi Miyanomae, and Yasuhiro Inoue

South Kyoto National Hospital, Kyoto, Japan

1. Koppelman GH, Reijmerink NE, Stine OC, Howard TD, Whittaker PA, Meyers DA, Postma DS, Bleecker ER. Association of a promoter polymorphism of the CD14 gene and atopy. Am J Respir Crit Care Med 2001; 163: 965-969 [Abstract/Free Full Text].

2. Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, Martinez FD. A polymorphism in the 5' flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E.  Am J Respir Cell Mol Biol 1999; 20: 976-983 [Abstract/Free Full Text].

3. Vercelli D, Baldini M, Martinez F. The monocyte/IgE connection: may polymorphisms in the CD14 gene teach us about IgE regulation? Int Arch Allergy Immunol 2001; 124: 20-24 [Medline].

4. Kusunoki T, Wright SD, Inoue Y, Miyanomae T, Yoshida Y, Yondeda K. Serum levels of soluble CD14 in allergic inflammation. Allergol Int 1998; 47: 271-278 .

5. Alexis N, Eldridge M, Reed W, Bromberg P, Peden DB. CD14-dependent airway neutrophil response to inhaled LPS: role of atopy. J Allergy Clin Immunol 2001; 107: 31-35 [Medline].

6. Dubin W, Martin TR, Swoveland P, Leturcq DJ, Moriarty AM, Tobias PS, Bleecker ER, Goldblum SE, Hasday JD. Asthma and endotoxin: lipopolysaccharide-binding protein and soluble CD14 in bronchoalveolar compartment. Am J Physiol 1996; 270: L736-L744 [Abstract/Free Full Text].

From the Authors:

We thank Dr. Kusunoki for his response. In four studies, the 159 promoter polymorphism of the CD14 gene is associated with the severity (1, 2) or susceptibility to atopy (3, 4), but not with asthma (2, 4). Atopy was associated with the C allele in three studies (1), and with T allele in one study (2). It is unclear if these differences are caused by other single nucleotide polymorphisms (SNPs), which could be in linkage disequilibrium with CD14/159, or by different interactions of CD14 with its ligand lipopolysaccharide (LPS). Further study of all SNPs in the gene, as well as of the interaction of CD14 with low and high levels of LPS exposure are necessary to resolve this.

What is the mechanism through which CD14 might act in atopy? Vercelli and coworkers showed that IL-4-dependent synthesis of IgE in peripheral blood mononuclear cells was strongly upregulated by LPS, but downregulated in the presence of anti-CD14 (5). Activation of CD14 appears to upregulate IL-4-dependent IgE production, although the underlying mechanism has not been elucidated to date. Cytokines known to be important in the regulation of the Th1-Th2 balance, such as interleukin 12, are produced by monocytes after stimulation with LPS, and further investigation into the role of these cytokines is necessary. In addition, it needs to be shown which alleles are associated with the upregulation of CD14. The relevancy of the finding by Kusunoki and coworkers that the levels of soluble CD14 in asthmatic children are not higher than those in controls to our work is not clear. In order to determine the effect of a given polymorphism, individuals should be genotyped and levels determined for each genotypic group.

It has been suggested that allergic inflammation in asthma may be upregulated by LPS inhalation. Not only CD14, but also TLR-4, another receptor of LPS, could be important (6). We agree with Dr. Kusunoki that in the development of atopy and asthma, the timing of CD14 activation may be very important. It is unknown whether gene-gene interaction, or interactions with other environmental factors, such as allergen exposure, contribute to atopy or asthma. Studies in both patients and in the general population are needed to answer these questions. To us, this illustrates that genetic research needs to be followed by further studies delineating gene function and interactions of relevant genes with the environment. This will permit a better understanding of the complex origins of atopy and asthma.

University Hospital Groningen, Groningen, The Netherlands

Deborah A. Meyers, and Eugene R. Bleecker

Wake Forest University, Winston Salem, North Carolina

1. Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, Martinez FD. A polymorphism in the 5' flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E.  Am J Respir Cell Mol Biol 1999; 20: 976-983 .

2. Koppelman GH, Reijmerink NE, Stine OC, Howard TD, Whittaker PA, Meyers DA, Postma DS, Bleecker ER. Association of a promoter polymorphism of the CD14 gene and atopy. Am J Respir Crit Care Med 2001; 163: 965-969 .

3. Gao PS, Mao XQ, Baldini M, Roberts MH, Adra CN, Shirakawa T, Holt PG, Martinez FD, Hopkin JM. Serum total IgE levels and CD14 on chromosome 5q31. Clin Gen 1999; 56: 164-165 .

4. Ober C, Tsalenko A, Parry R, Cox NJ. A second-generation genomewide screen for asthma-susceptibility alleles in a founder population. Am J Hum Genet 2000; 67: 1154-1162 [Medline].

5. Vercelli D, Baldini M, Martinez F. The monocyte/IgE connection: may polymorphisms in the CD14 gene teach us about IgE regulation? Int Arch Allergy Immunol 2001; 124: 20-24 .

6. Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000; 25: 187-191 [Medline].