N E W S A N D V I E W S

NATURE IMMUNOLOGY VOLUME 5 NUMBER 3 MARCH 2004 243

Asthma is a chronic disease of the lungscharacterized by reversible airway

obstruction and hyper-responsiveness and isassociated with pulmonary inflammation.Classically, asthma is thought to arise froman imbalance in T helper type 1 (TH1)-TH2immune regulation, resulting in increasedTH2 cytokines, interleukin 4 (IL-4), IL-5 andIL-13, as well as augmented immunoglobu-lin E (IgE) titers and lung eosinophilia. Thisimmune response is driven in large part byallergen-specific CD4+ T helper cells. Thefunction of the TH1 cytokines interferon-γ(IFN-γ) and IL-12 in the pathogenesis ofallergen-induced lung disease is less clear,but it is believed that these cytokines canantagonize the actions of the TH2-type inter-leukins and attenuate the pulmonaryinflammation seen with antigen exposure1.This TH1 versus TH2 model of immunedevelopment is a useful, if simplistic, para-digm for several disease processes. However,one aspect of asthma immunology that hasnever been adequately addressed by this par-adigm is the observation that exposure torespiratory viruses, which can engender arobust TH1 immune response, can initiateand promulgate the pulmonary inflamma-tion and airway obstruction seen in asthma2.In this issue of Nature Immunology, Dahl etal. directly address this important questionby examining how prior lung infection withinfluenza A virus affects subsequent devel-opment of immunity in a mouse model ofallergen-induced lung inflammation3.

Dahl and colleagues showed influenza Ainfection incites a robust IFN-γ response inthe lung, promoting the development ofdurable, TH1-polarizing dendritic cells(DCs). These DCs bolstered subsequentimmunity in a TH2-dependent mouse modelof allergen-induced lung inflammation,enhancing both TH1 and TH2 immunecytokines and immunoglobulin production.

These provocative data contribute to a grow-ing body of literature showing that interac-tions between the TH1 and TH2 immuneresponses are not solely antagonistic but canmodulate the integrative immune responsein vivo in a much more complex way (Fig. 1).The precise effects most likely rely on theexact timing, intensity and dose of cytokinesand antigen as well as how these interactionsalter T helper regulatory cells and cytokines.

An idea closely related to the TH1-TH2model of asthma development is the so-called ‘hygiene hypothesis’4. This theorystates that the rising incidence of allergicasthma is causally related to a decreasinginfectious burden in Westernized society.Factors associated with a lessening incidenceof asthma include increased early exposure toviral illnesses, endotoxin and mycobacterialinfections. Indeed, children attending day

care from an early age or raised with oldersiblings, and thus exposed to more viral res-piratory tract infections, are much less likelyto develop wheezing later in life5. The studyby Dahl et al. suggests that the inverse corre-lation between infectious burden and devel-opment of TH2 immunity, as outlined in thehygiene hypothesis, may be an overly sim-plistic model. The authors show that a preceding influenza infection does not ame-liorate, and in fact worsens, subsequent TH2immunity. Thus, the precise effect ofinfluenza on asthma severity may be depen-dent on the exact dose and timing of the viralburden in relation to the development of theTH2 immune response. Although not exam-ined by Dahl et al., different viral pathogens(such as respiratory syncytial virus) may alsoalter the lung immune response throughalternative pathways, including activation of

Richard J. Riese, Patricia W. Finn and Steven D.

Shapiro are in the Pulmonary and Critical Care

Division, Brigham and Women’s Hospital and

Harvard Medical School, Boston, Massachusetts

02115, USA.

e-mail: sshapiro@rics.bwh.harvard.edu

Influenza and asthma: adding to the respiratory burdenRichard J Riese, Patricia W Finn & Steven D Shapiro

Viral TH1 responses can positively regulate TH2 responses in a mouse model of allergen-induced lung inflammation.This helps explain why respiratory viral infections can exacerbate allergic TH2-type diseases.

DDay 0

Day 30

Influenza AA

FN-IF γ

IL-12

Immature DC

Lung DC

TH1-polarizing DC

Increasedpulmonary

inflammation

MHC class II

CD80 or CD86

CD28

40CD

CD40 CD40L

Allergen

TH2

TH1

CD4+ T cell

TCRpMHC

CD80or

CD86

K.R

.

Figure 1 Viral-induced TH1-dependent enhancement of allergic inflammation. On day zero, influenzaA infection in the mouse lung generates a vigorous IFN-γ response, producing stable, TH1-polarizingDCs. On day 30, these DCs are capable of enhancing a subsequent TH2-dependent immune responsein the lung, perhaps through production of IL-12. They are also capable of augmenting both TH1- andTH2-controlled immune responses in this model of allergen-induced lung inflammation. MHC, majorhistocompatibility complex; pMHC, peptide–major histocompatibility complex; TCR, T cell receptor.

©20

04 N

atur

e P

ublis

hing

Gro

up

http

://w

ww

.nat

ure.

com

/nat

urei

mm

unol

ogy

N E W S A N D V I E W S

244 VOLUME 5 NUMBER 3 MARCH 2004 NATURE IMMUNOLOGY

lung epithelial cells, leading to more diverseeffects on subsequent allergen sensitizationand activation2. In addition, genetic variabil-ity in the human population and other envi-ronmental influences could certainly beimportant in determining disease outcome.

What are the exact characteristics of theDCs driving this response in the lung andhow do they compare with the known DCsubsets? Mouse DCs derived from the spleenand lymph nodes are typically CD11chi andare CD8α+, CD4+ or double negative6. Thereis also an additional population of CD11clo

‘plasmacytoid’ DCs. These DC subsets havedistinct characteristics that include expres-sion of molecules that mediate T helper cellpolarization (TH1, TH2, T regulatory) andexpression of different Toll-like receptors torespond to discrete innate stimuli. DC subsetswithin the lung are less well delineated, mostlikely because of the large residential myeloidcell population found in this organ expressinga wide range of myeloid cell surface mark-ers7,8. Indeed, recent data indicate that somelung macrophages may express CD11chi, fur-ther complicating the picture8. Other investi-gators have identified a CD11c+CD11b+ DCsubset in the lung that has the capacity to cap-ture airborne antigens and persist for up to 1month while still retaining its ability to stimu-late CD4+ T cells9. Expression of cell surfacemarkers and function of lung DCs may alsodepend on tissue factors expressed within thelung airway or interstitium10. Identificationand characterization of DC subsets within

the lung remains an interesting arena for fur-ther investigation.

One intriguing facet to the data presentedby Dahl et al. is the stability of the DC phe-notype induced by influenza A, leading to anextended ability to enhance subsequentimmunity. These DCs seem to acquire a‘memory-like’ function in their ability tomodulate T cells and adaptive immunity.These exciting data add to a growing body ofliterature investigating DC functions beyondtheir ability to intiate the adaptive immuneresponse. Traditionally, DCs are character-ized by their ability to present antigen andactivate naive T cells in priming and initiat-ing the immune response and are thought tohave a relatively short lifespan. However,more recent evidence has demonstratedadditional functions for these professionalantigen-presenting cells in influencing thefunction and maturation or differentiationof different lymphocyte classes as well assubclasses of T helper cells11. Thus, DC sub-sets may acquire long-lasting phenotypesand act as sentinels while patrolling sec-ondary lymphoid organs and modulatingsubsequent immune development.

How do these data contribute to ourunderstanding of the pathophysiology ofasthma? The association between acuteinfluenza infection and exacerbation of pul-monary function in patients with chroniclung diseases, including asthma, is well docu-mented. The paper by Dahl et al. demon-strates that the consequences of acute

influenza infection last much longer than theinfection itself. This perpetuation and pro-longation of immune system dysfunction inthe lung indicates a potential mechanism bywhich viral infections may affect the develop-ment of lung inflammation and airwayobstruction seen in asthma. At the very least,this indicates that pulmonary inflammationand acute worsening of asthmatic symptomsmay be temporally removed from the acuteviral infection, if the patient is subsequentlyexposed to the offending allergen. At worst,these data could link viral-induced DC dif-ferentiation to the pathogenesis of asthmaitself12. Investigations examining the interac-tions between influenza (and other viral dis-eases) and chronic lung diseases areespecially relevant as we emerge from a par-ticularly virulent influenza season.

1. Erb, K., Holloway, J., Sobeck, A., Moll, H. & Le Gros,G. J. Exp. Med. 187, 561–569 (1998).

2. Holtzman, M. et al. Physiol. Rev. 82, 19–46 (2002).3. Dahl, M., Dabbagh, K., Liggitt, D., Kim, S. & Lewis,

D. Nat. Immunol. 5, 337–343 (2004).4. Liu, A. & Murphy, J. J. Allergy Clin. Immunol. 111,

471–478 (2003).5. Ball, T. et al. N. Engl. J. Med. 343, 538–543 (2000).6. Kapsenberg, M. Nat. Rev. Immunol. 3, 984–993

(2003).7. Legge, K. & Braciale, T. Immunity 18, 265–277

(2003).8. Gonzalez-Juarrero, M., Shim, T., Kipnis, A.,

Junqueira-Kipnis, A. & Orme, I. J. Immunol. 171,3128–3135 (2003).

9. Julia, V. et al. Immunity 16, 271–283 (2002).10. Stumbles, P., Upham, J. & Holt, P. APMIS 111,

741–755 (2003).11. Steinman, R. APMIS 111, 675–697 (2003).12. Cohen, L. & Castro, M. Semin. Respir. Infect. 18, 3–8

(2003).

©20

04 N

atur

e P

ublis

hing

Gro

up

http

://w

ww

.nat

ure.

com

/nat

urei

mm

unol

ogy