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Published ahead of print on August 19, 2003, doi:10.1164/rccm.200306-737OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 1091-1094, (2003)
© 2003 American Thoracic Society

Rhinovirus-induced Interferon-{gamma} and Airway Responsiveness in Asthma

G. Daniel Brooks, Kim A. Buchta, Cheri A. Swenson, James E. Gern and William W. Busse

Section of Allergy, Departments of Medicine and Pediatrics, University of Wisconsin, Madison, Wisconsin

Correspondence and requests for reprints should be addressed to G. Daniel Brooks, M.D., K4/910, Clinical Science Center 9988, 600 Highland Avenue, Madison, WI 53792. E-mail: gdb{at}medicine.wisc.edu


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The majority of asthma exacerbations are caused by respiratory infections, with rhinovirus (RV) being the most common virus. Recent evidence has suggested that decreased generation of IFN-{gamma} is associated with more severe colds and delayed elimination of virus. Whether the generation of IFN-{gamma} also has any relationship to general features of asthma severity has yet to be determined. To evaluate this hypothesis, peripheral blood mononuclear cells from 19 subjects with atopy and asthma were incubated with RV16 for 6 days to determine IFN-{gamma} and interleukin (IL)-5 production; these responses were then compared with measurements of airflow obstruction and airway responsiveness. RV16-induced IFN-{gamma} production correlated significantly with the methacholine PD (r = 0.50, p = 0.03), and the ratio of RV16-induced IFN-{gamma}:IL-5 correlated with % predicted FEV1 (r = 0.53, p = 0.02). In contrast, there were no significant associations between measures of asthma severity and RV-induced IL-5. These findings suggest that a cytokine imbalance with a deficient Th1 response to RV, but not a Th2 response, is associated with measures of asthma severity and support the concept that impaired antiviral responses may be associated with asthma severity.

Key Words: asthma • rhinovirus • viruses • IFN type II

Asthma has often been associated with an abnormal pattern of cytokine responses to allergenic proteins, consisting of increased production of T helper (Th) type 2 cytokines (interleukin [IL]-4, IL-5, and IL-13) (1–3). Evidence, however, suggests that some subjects with asthma also have a defect in Th1 cytokine production, which includes reduced production of IFN-{gamma} or T-bet (a Th1 transcription factor) (4, 5). There are also indications that decreased IFN-{gamma} production may be related to asthma severity: reduced-function DNA polymorphisms in the promoter region of IL-12 (a Th1-stimulating cytokine) have been associated with symptoms of severe asthma (6), and reduced production of IFN-{gamma} in response to dust mite has been associated with symptoms of asthma severity and asthma persistence (7). Together, these findings suggest that reduced Th1 production is associated with asthma severity.

Rhinovirus (RV) infections induce Th1 responses (8, 9) and are the most common triggers of asthma exacerbations (10–13). Thus, the immune response to RV provides an attractive, and potentially informative, model to evaluate the role played by Th1 responses in asthma pathogenesis. Previous investigations suggest that subjects with atopy and asthma have reduced IFN-{gamma} production in response to RV compared with normal subjects (9). Furthermore, a reduced Th1 response to RV is associated with increased symptom scores and viral shedding during experimental RV infection, suggesting a relative vulnerability to respiratory illnesses among patients with asthma with reduced Th1 responses compared with other patients with asthma (8, 14). Together, these observations have led us to hypothesize that a defective Th1 response to RV could also be associated with clinical features of greater asthma severity. Some of the results of these studies have been reported previously in the form of an abstract (15).


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Population
Adult subjects with mild to moderate allergic asthma participated in the study (Table 1) . Inclusion criteria consisted of a physician diagnosis of asthma, together with coughing, wheezing, or shortness of breath and relief with use of bronchodilators. All subjects had a history of 12% reversibility in FEV1 after albuterol administration or methacholine provocative dose for a 20% decrease in FEV1 (PD20) less than 80 cumulative breath units. Spirometry and methacholine challenge were performed on each subject on entry to the study. Subjects with current inhaled corticosteroid use, a history of severe episodes of asthma, symptoms of an acute upper respiratory infection within the past 30 days, or serum-neutralizing antibody to RV16 were excluded. All subjects underwent skin prick testing to a panel of 12 common aeroallergens (14) and had at least one positive immediate skin test response. The experimental protocol was approved by the Health Sciences Human Subjects Committee at the University of Wisconsin, and informed consent was obtained from the study subjects before they were enrolled in the protocol.


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  		TABLE 1. Subject characteristics

 
Cell Cultures and Cytokine ELISAs
Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples as described previously (8). PBMCs (106 cells/1 ml) in Roswell Park Memorial Institute medium with 25% autologous plasma were incubated (37°C, 5% carbon dioxide) with phytohemagglutinin (PHA) (10 µg/ml), RV16 (107 plaque-forming units), RV1A (107 plaque-forming units), tetanus toxoid (3 µg/ml), polyinosinic-polycytidylic acid (polyIC) (10 µg/ml), or medium alone. The first six patients did not have RV1A used as a stimulus. After 2 days (PHA) or 6 days (other stimuli), the cells were pelleted and the supernates were frozen (-70°C). IFN-{gamma} was analyzed using a commercial ELISA kit (BD Pharmingen, San Diego, CA, catalog number 555,142) with a lower detection limit of 4.7 pg/ml. IL-5 was measured by ELISA as described previously (16), and the lower detection limit was 6 pg/ml. RVs (RV1A and RV16) were grown and titered in HeLa cells as described previously (17, 18). As a control for nonspecific stimulants in the viral suspension, PBMCs from six subjects were incubated for 48 hours with RV16 in the presence or in the absence of antiintercellular adhesion molecule-1 antibodies that block viral attachment to cells. Anti–intercellular adhesion molecule-1 antibodies significantly decreased IFN-{gamma} production (194 to 19 pg/ml).

Data Analysis
IFN-{gamma} levels and methacholine PD20 were analyzed after log transformation to normalize the distribution. The intraclass correlation coefficient was used to measure the reproducibility of IFN-{gamma} secretion by stimulated PBMCs. The paired t test was used to compare RV-induced IFN-{gamma} with controls with a Bonferroni correction for multiple comparisons, and Pearson's coefficient of correlation was used to measure correlations between IFN-{gamma} production by different stimuli and measures of pulmonary function. IL-5 did not follow a log-normal distribution because of the large number of samples with undetectable IL-5 levels. Wilcoxon's signed-rank test and Spearman's rank correlation coefficient were used for analyses of IL-5 and IFN-{gamma}:IL-5. If levels of IFN-{gamma} or IL-5 were below detection, they were arbitrarily assigned the values 2 and 3 pg/ml, respectively. Analyses were done with the aid of computer software (SigmaStat 2.03, SPSS Science, Chicago, IL). A p value less than 0.05 was considered significant.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subject Characteristics
Nineteen subjects (10 women, 9 men) with allergic asthma participated in the study (Table 1). Ages ranged from 18 to 56 years, with most subjects between 18 and 28 years of age. One subject had sensitization only to seasonal allergens, one subject had sensitization only to perennial allergens, and 17 subjects had sensitization to both. FEV1 measurements were consistent with mild to moderate obstruction (71–110% predicted). All the 19 subjects had symptoms of asthma, a positive skin test to at least one aeroallergen, and a previous methacholine PD20 in the asthmatic range (< 80 cumulative breath units). Five subjects had a methacholine PD20 in the normal range at the time of the study but were included in the study to evaluate a broader range of airway responsiveness.

RV-induced Cytokine Secretion
To determine patterns of virus-induced cytokine secretion, PBMCs were incubated with RV16, RV1A, polyIC, PHA, and tetanus toxoid. RV1A was chosen because it has molecular similarities to RV16, although the cellular receptor for RV1A is in the low-density lipoprotein family, and the receptor for RV16 is intercellular adhesion molecule-1 (19, 20). To determine whether IFN-{gamma} is stimulated by double-stranded RNA present during viral replication, polyIC was included. Tetanus toxoid and PHA were also included as known stimulators of IFN-{gamma} and to determine whether variation in IFN-{gamma} production between individuals was similar for virus, antigen, and mitogen.

RV16, RV1A, tetanus toxoid, polyIC, and PHA induced significant amounts of IFN-{gamma} in culture supernates compared with cells incubated in media alone (Table 2) . Tetanus toxoid and PHA stimulated significant amounts of IL-5 compared with media alone, but RV16 did not cause significant increases in IL-5 secretion. Cytokine production was also expressed as a ratio (IFN-{gamma}:IL-5) such that higher ratios would indicate relatively strong Th1 responses. RV16 and PHA induced an increase in the IFN-{gamma}:IL-5 ratio, whereas tetanus did not.


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  		TABLE 2. Cytokine production by peripheral blood mononuclear cells*

 
RV16-induced IFN-{gamma} was compared with RV1A-induced IFN-{gamma} to assess whether RV subtypes that use different cellular receptors would stimulate different quantities of IFN-{gamma}. IFN-{gamma} stimulation by the two subtypes of RV was strongly correlated (Figure 1) . There was no correlation between RV16-induced IFN-{gamma} and IFN-{gamma} induced by tetanus toxoid, polyIC, or PHA.



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  		Figure 1. Correlation between IFN-{gamma} induced by rhinovirus (RV) 16 (major group virus) and RV1A (minor group virus). Peripheral blood mononuclear cells (PBMCs) were incubated with RV16 or RV1A for 6 days, and culture supernatant fluids were analyzed for IFN-{gamma} (n = 13).

 
To determine whether an individual's IFN-{gamma} secretion was a relatively constant characteristic, 9 of the 19 subjects had PBMCs isolated twice, 1 week apart, and RV16-induced IFN-{gamma} was determined. The measurement of IFN-{gamma} between visits showed good reproducibility; the variability in IFN-{gamma} between subjects was significantly greater than the variability between measurements in the same subject (intraclass r = 0.71, 95% confidence interval [0.18, 0.93]).

RV-induced Cytokine Production and Measures of Asthma Severity
To determine whether virus-induced Th1 responses are inversely associated with measures of asthma severity, RV16-induced IFN-{gamma} and IL-5 were compared with airway responsiveness (methacholine PD20). Methacholine PD20 correlated significantly with RV16-induced IFN-{gamma} (Figure 2) but not with IFN-{gamma} induced by PHA, polyIC, tetanus toxoid, or RV1A.



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  		Figure 2. Association between RV16-induced IFN-{gamma} and methacholine PD20. PBMCs were incubated with RV16, and IFN-{gamma} responses were compared with methacholine reactivity for each individual subject (n = 19).

 
RV16 and RV1A are closely related at the molecular level (20). To explain why IFN-{gamma} induced by RV16, but not by RV1A, correlated with methacholine reactivity, we considered the fact that the subjects were all seronegative for RV16, whereas many of the subjects had detectable neutralizing antibody to RV1A. To determine whether this was a confounding factor, the six patients who were RV1A-seronegative were analyzed separately. In this subset analysis, there was a nonsignificant trend toward association between RV1A-induced IFN-{gamma} and methacholine PD20 (r = 0.68, p = 0.14).

Next, RV16-induced cytokine production was related to measures of airway obstruction (FEV1 [% predicted] and FEV1:FVC ratio). There was a trend toward a positive association between RV16-induced IFN-{gamma} and FEV1 (r = 0.38, p = 0.11), but no relationship between RV16-induced IFN-{gamma} and the FEV1:FVC ratio was noted. There was no relationship between IL-5 secretion induced by RV16, tetanus toxoid, or PHA and methacholine responsiveness, FEV1, or FEV1:FVC.

Finally, the ratio of RV16-induced IFN-{gamma}:IL-5 (a measure of Th1/Th2 balance) correlated with FEV1 (Figure 3) , and there was a trend toward a correlation with the FEV1:FVC ratio (r = 0.37, p = 0.11). RV16-induced IFN-{gamma}:IL-5 did not correlate with methacholine PD20.



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  		Figure 3. Correlation between RV16-induced IFN-{gamma}:interleukin (IL)-5 ratio and FEV1. The ratio of RV16-induced IFN-{gamma} to RV-induced IL-5 was compared with baseline FEV1 (n = 19).

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although RV infections are the most common cause of asthma exacerbations (10–13), little is known about how RV-induced immune responses relate to the severity of the disease. We have made several observations in this regard. First, PBMC cultures with RV induce a significant amount of IFN-{gamma} but only a small amount of IL-5, and this finding is consistent with previously reported observations of a predominant Th1-like immune response to RV (8, 9, 21). Second, Th1 responses to RV, as measured by IFN-{gamma} or IFN-{gamma}:IL-5 ratio, correlate with methacholine PD20 and FEV1, respectively, but there was no relationship between RV-induced IL-5 and these measures of asthma severity. The relationship between RV-induced IFN:IL-5 ratio and FEV1 also appears to be related more to a deficient Th1 response than to an exuberant Th2 response because minimal IL-5 is produced and it does not correlate with FEV1. Finally, the association between measures of asthma severity and IFN-{gamma} production was specific to RV because no relationship was found with IFN-{gamma} induced either by tetanus toxoid or mitogen. This finding complements the previous observation that clinical symptoms of asthma severity are associated with reduced house dust mite–induced IFN-{gamma} but not PHA-induced IFN-{gamma} (7). Together, these findings suggest that, in asthma, a defect in Th1 response is not limited to allergens but may also extend to viruses.

The lack of statistically significant correlation between RV1A-induced IFN-{gamma} and asthma severity could be due to the limited power of this analysis (n = 13, power < 0.80) or to the confounding effects of neutralizing antibody and earlier exposure. The subgroup analysis indicated that the relationship between RV1A and methacholine PD20 was closer after individuals with positive RV1A titers were excluded. It is plausible that RV1A-specific IgG antibodies could effect antigen presentation through Class II pathways or could have downregulatory effects through Fc-{gamma}RIIb receptors (22), both of which may influence in vitro IFN-{gamma} production.

Why do some subjects reproducibly make less IFN-{gamma} in response to RV? It is possible that previous exposure to multiple RV infections promotes increased IFN-{gamma} responses to epitopes that are shared among different serotypes of RV (21). By extension, people who have experienced fewer colds may have lower IFN-{gamma} responses. Alternatively, genetic pathways have been identified that modify Th1 responses to intracellular infections (23), and some subjects may have polymorphisms that cause lower production of IFN-{gamma} in response to virus. Finally, some individuals may have a more general defect in IFN-{gamma} production; this condition has previously been related to childhood atopic disease and wheezing during lower respiratory tract infections (24, 25).

Although there are several possible explanations for the correlation between RV-induced IFN-{gamma} and measures of asthma severity, the true nature of this relationship is not yet known. One possibility is that previous respiratory infections have acted to increase RV-induced IFN-{gamma} production while also acting through separate unknown mechanisms to decrease asthma severity. There is evidence that exposure to respiratory infections protects individuals from symptoms of asthma. For example, children who have had more viral infections when they were young have fewer respiratory illnesses and episodes of wheezing when they are adolescents (24, 26). Another possibility is that individuals with more effective immune responses to RV, surrogated by elevated IFN-{gamma} generation to this virus, will have a degree of protection against future RV infections (8). RV infections have been shown to spread to the lower airway (27, 28), and protection against RV infections could prevent subsequent injury to the lower airways.

Previous research into mechanisms of immune dysregulation in asthma has largely focused on excessive Th2 responses to allergen. Our findings, when considered with other recent reports, suggest that deficient Th1 responses to viruses and allergens are also a potentially relevant immune characteristic of asthma. Defining the precise mechanisms that determine the association between reduced Th1 responses and markers of increased asthma severity is likely to lead to a greater understanding of the natural history of asthma, declining lung function, and the role played by viral infections in this regard and is a focus of ongoing investigation.


   FOOTNOTES
 
Supported by National Institutes of Health grants AI50500, AI07635, and by MO1 RR03186.

Conflict of Interest Statement: G.D.B. has no declared conflict of interest; K.A.B. has no declared conflict of interest; C.A.S. has no declared conflict of interest; J.E.G. has no declared conflict of interest; W.W.B. has no declared conflict of interest.

Received in original form June 4, 2003; accepted in final form August 18, 2003


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