American Lung Association Asthma Clinical Research Centers: Asthma in the Elderly
(AIE): Challenges and Opportunities
Immunology of the Aging Lung and Asthma
Linda Rogers, MD FCCP
Although we have gained a significant understanding about age-related changes in
systemic immune function, also known as immunosenescence, less is known about
changes in immune function of the lung with age. The lung is the largest epithelial surface
in contact with the external environment and undergoes continuous exposure to
microorganisms and particulate matter. It works continuously to maintain the sterility of
lower airways by daily clearance of small microbial challenges and inhaled particles. The
innate immune system in the lung, which includes the epithelial barrier, dendritic cells,
macrophages, neutrophils, various effector proteins, and cytokines, is the first line of host
defense and does not rely on immune memory. In contrast, adaptive responses are
antigen specific and characterized by immune memory. Most of the B and T cells in the
lung are memory cells and can coordinate cellular and humoral responses to previously
encountered pathogens.
Both the innate and the adaptive branches of the immune system undergo
changes with advancing age. It is hypothesized that the burden of continuous exposure to
bacterial, viral, exogenous, and self antigens over a lifetime eventually leads to
diminishing adaptive responses associated with a lesser decline in innate immunity. As
adaptive immunity declines, there is a greater dependence on innate immunity to fill the
“gap” in adaptive immune function. In addition to this shift, sometimes referred to as
immune “remodeling”, aging has been associated with a low-grade, chronic upregulation
of the inflammatory response described by Franscheschi as “inflammaging”.
“Inflammaging” may be involved in the pathogenesis of common age-associated diseases
including atherosclerosis and neurodegenerative disorders.
Does immune remodeling and “inflammaging” occur in the lung? Meyer et al
looked at this question in a series of studies comparing immune responses in peripheral
blood and bronchoalveolar lavage (BAL) fluid from healthy subjects in graded age groups.
Older subjects were found to have an increase in total BAL cells, an increased
percentage of BAL lymphocytes, increased BAL CD4+ cells, increased BAL CD4/CD8
ratio, and increased activated CD4+/HLA-DR+ T cells compared to younger subjects. In a
subsequent study, his group also found an increase in neutrophils, BAL immunoglobulins,
increased PMA stimulated release of superoxide anion, and increased IL6 concentrations
in the oldest age group. Thus, evidence of low-grade inflammation was observed in the
lungs of healthy older subjects.
Much of what we know about immunosenescence has been delineated by study of
tissues that are easily accessed, including the peripheral blood, gut, and skin. Studies
have suggested that there are organ specific differences in immune function. Therefore,
although we have gained some understanding of systemic immunosenescence, this may
not accurately reflect age related changes in lung immunology. Very few studies have
looked at age related changes in inflammatory pathways in asthma in humans. Mathur et
al. demonstrated that the degree of airway eosinophilia in older subjects with asthma is
similar to that observed in younger subjects. Peripheral blood eosinophils of older
asthmatics showed impaired effector functions compared to younger subjects. He also
observed greater degrees of airway neutrophilia in older subjects compared with younger
subjects. The same group also showed impaired leukotriene responses from stimulated
cultured airway inflammatory cells in older subjects with asthma compared with younger
subjects with asthma, with no difference in leukotriene production by peripheral blood
mononuclear cells according to age
Many infectious and inflammatory lung diseases become more common with age.
What do we know about the natural history of the immune pathways involved in asthma
with age? Does immune remodeling affect the natural history of asthma? Is
“inflammaging” linked to age-related changes in lung matrix? Does immunosenescence
influence the natural history of asthma? The answers to these questions await the results
of more research on asthma in the elderly.
Suggested Additional Reading:
Hanania et al. Asthma in the elderly: Current understanding and future research needsa report of a National Institute on Aging (NIA) workshop. Journal of Allergy and Clinical
Immunology 2011; 128:S1-22.
Busse P, Mathur, SK. Age-related changes in immune function: Effect on airway
inflammation. J Allergy Clin Immunol 2010; 126:690-9.
Meyer, KC. The Role of Immunity and Inflammation in Lung Senescence and
Susceptibility to Infection in the Elderly. Semin Respir Crit Care Med 2010; 31:561-574.
Linton, PJ, Dorshkind, K. Age-related changes in lymphocyte development and function
Nature Immunology 2004; 5:133 – 139.
Franceschi C, Bonafe M, Valensin S. Human immunosenescence: the prevailing of
innate immunity, the failing of clonotypic immunity, and the filling of immunological
space. Vaccine 2000;18:1717–20.