American Lung Association Asthma Clinical Research Centers: Asthma in the Elderly (AIE)

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 responsedescribed 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.