The Journal of Clinical Investigation http://www.jci.org Volume 122 Number 8 August 2012
Asthma as a chronic disease of the innate
and adaptive immune systems
responding to viruses and allergens
Michael J. Holtzman
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Cell Biology and Physiology,
Washington University School of Medicine, St. Louis, Missouri, USA.
Research on the pathogenesis of asthma has traditionally concentrated on environmental stimuli, genetic suscep-
tibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth
muscle) as critical steps leading to disease. The focus of this cascade has been the response to allergic stimuli. An
alternative scheme suggests that respiratory viruses and the consequent response of the innate immune system also
drives the development of asthma as well as related inflammatory diseases. This conceptual shift raises the possibil-
ity that sentinel cells such as airway epithelial cells, DCs, NKT cells, innate lymphoid cells, and macrophages also
represent critical components of asthma pathogenesis as well as new targets for therapeutic discovery. A particular
challenge will be to understand and balance the innate as well as the adaptive immune responses to defend the host
against acute infection as well as chronic inflammatory disease.
Introduction and perspective
A major goal of medical research is to define the cause and
develop the cure for chronic inflammatory disease, traditionally
by targeting the adaptive immune system. Convention has also
led to a bipartite classification of the adaptive immune system,
wherein Th1 cells mediate delayed-type hypersensitivity reactions
and selectively produce IL-2 and IFN-γ, and Th2 cells promote B
cell–dependent humoral immunity and produce IL-4, IL-5, and
IL-13 (1). In the case of asthma, the “Th2 hypothesis” proposes
that an upregulated Th2 and a downregulated Th1 response drive
the development of disease (Figure 1 and ref. 2). Newer research
suggests that increased activity of Th17 (IL-17–producing) cells
or Th9 (IL-9–responsive) cells as well as decreased suppressor
activity of Tregs (IL-10– and TGF-β–producing cells) represent
additional mechanisms for other subsets of T cells to contrib-
ute to asthma, perhaps in part by skewing the system toward an
increased Th2 response (3–5).
The focus on T cell contributions is derived at least in part from
studies of allergen challenge in mouse models of asthma and in
humans (6, 7). In both cases, allergen challenge is often optimized
for a Th2-dominant response. However, this approach may not
represent the full clinical spectrum of the disease. The majority
of asthmatics may be atopic, but only a minority of those with
atopy or atopic disease (including those reactive to inhaled aller-
gen) will ever develop asthma (8). The Th2 hypothesis is therefore
challenged to incorporate the possibility that other environmental
stimuli might also be essential for asthma pathogenesis. Indeed,
there is considerable clinical evidence that respiratory viral infec-
tion is also linked to the initial development of asthma as well as
exacerbations that might perpetuate the disease. Early clinical
work on the role of respiratory viruses in asthma focused on the
role of respiratory syncytial virus (RSV) infection in infancy. RSV
is the most common cause of serious respiratory illness in this age
group and in severe cases is associated with the subsequent devel-
opment of a prolonged wheezing illness that in some cases may
extend at least to adolescence (9–16). The role of severe RSV infec-
tion as a risk factor for asthma in adulthood is less certain but is
still under study. Meanwhile, more recent studies have identified
infection with human rhinovirus (HRV) as a predominant respi-
ratory pathogen associated with asthma later in life (11, 17–21).
Other work on influenza A virus (IAV) connects this infection to
asthma in children and adults (22–25). Despite extensive asso-
ciation of common types of respiratory viruses with asthma, the
available evidence does not yet establish viral infection as a cause
of asthma per se, but rather suggests that there may be common
susceptibilities to both viral infection and asthma (26). Indeed,
atopy itself may predispose toward more severe respiratory viral
infection and associated wheezing, particularly in the case of HRV
(21, 27). In fact, perhaps the strongest predictor of subsequent
asthma is the concordance of atopy and severe respiratory viral
infection, suggesting that virus-allergen interaction is at work in at
least some asthmatics (19, 21, 28, 29). The proof of a causal role for
virus infection in asthma must therefore depend on better experi-
mental models of the process and ultimately on effective antiviral
measures that serve to lessen the acute infectious illness as well as
the subsequent chronic inflammatory disease in humans.
In response to this issue, adherence to the Th2 hypothesis
invokes an additional hygiene hypothesis, wherein a lack of expo-
sure to viruses (and/or other inhaled and ingested environmental
“dirt” from bacteria and parasites) in modern society leads to an
overactive Th2 (allergic) and an underactive Th1 (antiviral) sys-
tem (30–32). However, even with this hypothetical addendum, the
Th2 hypothesis still misses key immune components of asthma
(33–35). For example, it is possible to define a positive rather than
a negative relationship between viral infection and experimental
as well as natural asthma. In addition, increased susceptibility to
respiratory viral infection might be detectable even at birth, and
perhaps most significantly, as a deficiency of the innate immune
system, independent of the T cell response (36). Moreover, from
Conflict of interest: The author has been a principal investigator for research grants
to Washington University from the NIH, Hoffmann-La Roche, and Forest Labs and
has received income from Hoffmann-La Roche and Forest Labs.
Citation for this article: J Clin Invest. 2012;122(8):2741–2748. doi:10.1172/JCI60325.
2748 The Journal of Clinical Investigation http://www.jci.org Volume 122 Number 8 August 2012
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