Age-related changes in immune function: Effect on airway inflammation

Mechanisms of allergic diseases

Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donna Vercelli, MD

Age-related changes in immune function: Effect on airwayinflammation

Paula J. Busse, MD,a and Sameer K. Mathur, MD, PhDb New York, NY, and Madison, Wis

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Credit can now be obtained, free for a limited time, by reading the review

articles in this issue. Please note the following instructions.

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mitted online at www.jacionline.org. Fax or other copies will not be accepted.

Date of Original Release: October 2010. Credit may be obtained for

these courses until September 30, 2012.

Copyright Statement: Copyright � 2010-2012. All rights reserved.

Overall Purpose/Goal: To provide excellent reviews on key aspects of

allergic disease to those who research, treat, or manage allergic disease.

Target Audience: Physicians and researchers within the field of allergic

disease.

Accreditation/Provider Statements and Credit Designation: The

American Academy of Allergy, Asthma & Immunology (AAAAI) is ac-

credited by the Accreditation Council for Continuing Medical Education

(ACCME) to provide continuing medical education for physicians. The

AAAAI designates these educational activities for a maximum of 1 AMA

PRA Category 1 Credit�. Physicians should only claim credit commensu-

rate with the extent of their participation in the activity.

List of Design CommitteeMembers: Fellows-in-Training BobMiyake,

MD, Shruti Wilson, MD, Betty Liu, MD, and Program Director Mary Beth

Fasano, MD, MSPH

Activity Objectives

1. To understand the role of immunosenescence in asthma in older adults.

2. To identify age-related changes in innate immunity that might affect

asthma in the elderly.

3. To identify age-related changes in the adaptive immune system that

might contribute to the pathogenesis of late-onset asthma.

Recognition of Commercial Support: This CME activity has not

received external commercial support.

Disclosure of Significant Relationships with Relevant Commercial

Companies/Organizations: P. J. Busse has received research support

from the National Institutes of Health and the American Academy of Al-

lergy, Asthma & Immunology. S. K. Mathur has received research support

from theAmericanAcademyofAllergy,Asthma&Immunology/T. Franklin

Williams Scholars Program and the John A. Hartford Foundation and is

vice chair of the American Academy of Allergy, Asthma & Immunology’s

Asthma and Allergic Diseases in the Elderly Committee.

Immunosenescence is defined as changes in the innate andadaptive immune response associated with increased age. Theclinical consequences of immunosenescence include increasedsusceptibility to infection, malignancy and autoimmunity,decreased response to vaccination, and impaired wound healing.However, there are several immune alterations that mightfacilitate persistence of asthma into late adulthood ordevelopment of asthma after the age of 50 to 60 years. Asthma inolder patients is not uncommon, and this is a growing populationas the average lifespan increases. Specific innate changes that

From athe Division of Clinical Immunology, Department of Medicine, Mount Sinai

School of Medicine, New York, and bthe Department of Medicine, Section of Allergy,

Pulmonary and Critical Care, University of Wisconsin School of Medicine and Public

Health, William S. Middleton VA Hospital, Madison.

Disclosure of potential conflict of interest: P. J. Busse has received research support from

the National Institutes of Health and the American Academy of Allergy, Asthma &

Immunology. S. K.Mathur has received research support from the American Academy

of Allergy, Asthma & Immunology/T. Franklin Williams Scholars Program and the

John A. Hartford Foundation and is vice chair of the American Academy of Allergy,

Asthma & Immunology’s Asthma and Allergic Diseases in the Elderly Committee.

Received for publication June 8, 2010; revised July 30, 2010; accepted for publication

August 5, 2010.

Reprint requests: Paula J. Busse, MD, Division of Clinical Immunology, Department of

Medicine, Mount Sinai School ofMedicine, 1425Madison Avenue, Room 11-20, New

York, NY 10029. E-mail: [email protected].

0091-6749/$36.00

� 2010 American Academy of Allergy, Asthma & Immunology

doi:10.1016/j.jaci.2010.08.011

Terms in boldface and italics are defined in the glossary on page 691.

690

might affect severity of asthma in older patients or be involved inthe development of late-onset asthma include impairedmucociliary clearance and changes in airway neutrophil,eosinophil, and mast cell numbers and function. Additionally,age-related altered antigen presentation and decreased specificantibody responses might increase the risk of respiratory tractinfections. Respiratory tract infections exacerbate asthma inolder patients and possibly play a role in the pathogenesis oflate-onset asthma. Furthermore, cytokine profiles might bemodified with aging, with some investigators suggesting a trendtoward TH2 cytokine expression. This review examines specificinnate and adaptive immune responses affected by aging thatmight affect the inflammatory response in older adults withasthma. (J Allergy Clin Immunol 2010;126:690-9.)

Key words: Asthma, atopy, aging, elderly, immune function,immunosenescence

Research from animalmodels and human subjects suggests thatwith increasing age, there are several important changes in theinnate and adaptive immune responses, a phenomenon termed‘‘immunosenescence.’’ Immunosenescence most likely plays arole in the increased susceptibility to infections and increasedrates of malignancies and autoimmune diseases in the elderly.Older subjects with fewer features of immunosenescence mighthave a prolonged lifespan.1 Conversely, specific features ofimmunosenescence, including impaired T-cell proliferation,

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VOLUME 126, NUMBER 4

BUSSE AND MATHUR 691

Abbreviations used

AM: A

GLOS

a-GalC

N-FORM

N-form

cytic c

activity

GM-CS

eosinop

IL-6: IL-

inhibits

MYELO

CELLS

IFN-a a

can be

NATUR

such as

but hav

and ca

activati

PERIOD

stainsm

The Ed

irway macrophage

BALF: B
ronchoalveolar lavage fluid
Foxp3: F
orkhead box protein 3
mDC: M
yeloid dendritic cell
NK: N
atural killer
ROS: R
eactive oxygen species
TCR: T
-cell receptor
TLR: T
oll-like receptor
Treg: R
egulatory T
increased CD81 cytotoxic/suppressor cell numbers, and de-creased CD41 T-cell and CD191 B-cell numbers, are associatedwith increased morbidity and mortality.2 Another finding ofimmunosenescence is the presence of chronic systemic inflamma-tion, which is referred to as ‘‘inflamm-aging’’ and characterizedby increased serum IL-6 and TNF-a levels and clinically bymore ‘‘frail’’ subjects.3

Altered immune response with aging might affect thepathophysiology of asthma in older patients. Although asthma istypically considered a disease of early childhood, asthma in olderpatients is not uncommon; it has been reported that between 4% and13% of the population older than 65 years have a diagnosis ofcurrent asthma.4-8 However, this number is likely to be an underes-timate because asthma in the elderly is underdiagnosed.5,9,10

Asthma in older adults can be classified as long-standing/childhood-onset asthma, childhood-onset asthma that becamequiescent and returned later in life, or late-onset asthma. There isno strict age definition that classifies late-onset asthma. Older pa-tients with asthma have a high rate of morbidity and mortality,11,12

possibly because of undertreatment5,9 and comorbid conditions.13,14

However, it might also be due to immunosenescence.This review will focus on changes in the immune system with

age, specifically targeting those that might influence asthma(Table I). There are several features that are well characterized,

SARY

er: An activating ligand for NKT cells that are CD1d restricted.

YL-METHIONYL-LEUCYL-PHENYLALANINE (fMLP): fMLP is an

ylated peptide. fMLP functions as a chemoattractant for phago-

ells that also induces degranulation. TNF-a enhances fMLP

. The fMLP receptor has significant homology to the IL-8 receptor.

F: GM-CSF promotes survival, proliferation, and chemotaxis of

hils, neutrophils, and mast cells.

6 is released by dendritic cells, primes for TH2 effector cells, and

the suppressive functions of CD41CD251 Treg cells.

ID DENDRITIC CELLS (mDCs), PLASMACYTOID DENDRITIC

(pDCs): pDCs do not express CD11c and express high levels of

fter viral stimulation of TLR7 and TLR9.mDCs express CD11c and

activated by LPS to produce IL-12 and induce TH1 development.

AL KILLER T (NKT) CELLS: NKT cells share features of T cells,

expression of abTCR, and NK cells, such as CD16 and CD56,

e limited diversity, recognize glycolipids in the context of CD1,

n express significant amounts of IL-4, GM-CSF, and IFN-g on

on.

IC ACID–SCHIFF (PAS): PAS stain is used to detect glycogen and

ucous positive cells (eg, in the epitheliumof asthmatic patients).

itors wish to acknowledge Seema Aceves, MD, PhD, for preparing th

whereas for others, there are conflicting reports. This might bedue to differences in experimental protocols or to inclusion ofsubjects with comorbidities that could affect immunologic func-tion. As a result, much of the research on immunosenescencehas been performed by using aged murine models.

AGE-RELATED CHANGES IN INNATE IMMUNITY

Epithelial cellsThe respiratory epithelium is composed of ciliated and secre-

tory cells and is an important component of the innate immunesystem. Ciliated cells propel inhaled antigens and irritants trappedin mucus produced by goblet cells proximally up the tracheo-bronchial tree by means of mucociliary clearance. Additionally,the airway epithelial cells produce nitric oxide and secrete severalcytokines, particularly type I and III interferons, growth factors(eg,GM-CSF), IgA, and several antimicrobial proteins. There arenotable changes in the airway epithelium in patients with asthma,including disruptions of the epithelial cell tight junctions,increased susceptibility to apoptotic effects of oxidants, and im-paired production of IFN-b and IFN-a, which promote epithelialdamage and increase the susceptibility to viral infections.15

Lung epithelial cell senescence might contribute to the path-ogenesis of late-onset asthma or to persistence of asthma into lateryears. Nasal epithelial tissue collected from nonsmoking healthysubjects (ages 11-90 years) without respiratory tract diseasedemonstrated a significantly decreased ciliary beat frequency andclearance with age accompanied by microtubular disarrange-ments.16 Svartengren et al17 reported a decreased clearance of la-beled Teflon particles deposited in smaller airways in older (agerange, 19-81 years) healthy subjects. The effect of age onmucosalcell hyperplasia andmucous hypersecretion is not well studied. Ina study of 51 patients undergoing endoscopy, the mean number offundic mucous cells peaked in the 41- to 50-year-old group, re-mained increased in the 51- to 60-year-old group (comparedwith those <40 years old), and was lowest in the greater than

TOLL-LIKE RECEPTORS (TLRs): TLRs are important mediators of innate

immunity. TLR1bindsbacterial lipopeptidesandusesMyD88-dependent

signaling. TLR2 binds glycolipids, lipoteichoic acid, and fungal zymosan

andusesMyD88-dependent signaling. TLR3binds double-strandedRNA

from viruses and uses MyD88-independent signaling.

TNF-a: Also known as ‘‘cachectin,’’ TNF-a is produced primarily by

monocytes/macrophages and functions similarly to IL-1, causing in-

creased vascular activation and acute-phase reactants. TNF-a is also

produced by TH17 cells, and plays a role in promoting autoimmunity.

TNF blockers, including etanercept (Enbrel), infliximab (Remicade),

and adalimumab (Humira), are used for autoimmune diseases, includ-

ing rheumatoid arthritis, psoriasis/psoriatic arthritis, and Crohn disease.

TRIGGERING RECEPTOR EXPRESSED ONMYELOID CELLS 1 (TREM-1):

TREM-1 is upregulated by LPS and increases secretion of IL-8, TNF-a,

and neutrophil degranulation, thereby amplifying inflammation.

TYPE I INTERFERON, TYPE III INTERFERON: Type 1 interferons (a, b, v)

aremade principally bymyeloid cells, aswell as by activated epithelium,

and are secreted in large amounts in response to viral infections. IFN-a

and IFN-b have clinical utility in treating hypereosinophilic syndrome

and multiple sclerosis. Type III interferons (l) include IL-28 and IL-29,

which can downregulate IL-13.

e glossary.

TABLE I. Summary of immunosenescence features

Cell type Changes with aging

Neutrophils Reduced phagocytosis

Reduced ROS production

NK cells Increased numbers

Reduced cytotoxicity

NKT cells Reduced numbers

Reduced proliferation

Monocytes/macrophages Reduced phagocytosis

Reduced cytokine and chemokine secretion

Reduced generation of nitric oxide and

superoxide

Eosinophils Reduced degranulation

Reduced superoxide production

Dendritic cells Reduced phagocytosis and pinocytosis

Increased IL-6 and TNF-a production

Diminished TLR expression and function

T cells Reduced response and proliferation

Reduced CD28 expression

Accumulation of CD81CD281 T cells

Reduced TCR diversity

Reduced signal transduction

B cells Production of low-affinity antibodies

Increased oligoclonal expansion

Reduced surface MHC class II molecule

expression


OCTOBER 2010

692 BUSSE AND MATHUR

60-year-old group.18 In aged (18-month) BALB/c mice sensitizedand challenged intratracheally to ovalbumin, airway mucousmetaplasia measured by means of periodic acid–Schiff (PAS)staining and mRNA expression for the mucin-producingMUC5AC gene were increased compared with that seen in youn-ger (6-week) antigen-treated mice.19 The effect of increased ageon vascular cell adhesion molecule and intercellular adhesionmolecule expression on airway epithelial cells has not been inves-tigated. This is an important question because these markers areinvolved in cell trafficking and intercellular adhesion molecule1 is a receptor for rhinovirus. In agedmice these adhesionmarkersare increased in the endothelium and in hepatic macrophages.20,21

Viral respiratory tract infectionsmight be an initiating event in thepathogenesis of late-onset asthma.22

NeutrophilsAlthough neutrophil numbers in the peripheral circulation do not

vary with age, there is evidence that their chemotaxis and phago-cytotic properties and generation of superoxidemight change. Bothimpaired and normal chemotaxis has been reported to occur withaging.23,24 Although invitro peripheral neutrophil production of su-peroxide in response toN-formyl-methionyl-leucyl-phenylalaninewas not reduced in healthy older subjects (mean age, 68.2 years)compared with healthy young adults (mean age, 25.9 years), phag-ocytosis offluorescein isothiocyanate–labeledEscherichia coliwasdecreased. The authors concluded that the decreased phagocytic in-dex in the older subjects was secondary to an age-related decreasein surface CD16 expression that is necessary for Fc-mediated phag-ocytosis.25 However, other groups have reported a diminished res-piratory burst and protection from apoptosis from PMNs collectedin older healthy subjects on engagement of the surface triggeringreceptor expressed on myeloid cells 1 receptor26 or N-formyl-methionyl-leucyl-phenylalanine but a similar production of

reactive oxygen species (ROS) with phorbol 12-myristate 13-ace-tate stimulation.27 Thus the capacity to produce ROS might be in-tact, but specific signaling pathways to evoke ROS productionmight be deficient in the elderly. In addition, it has been observedthatGM-CSF–, IL-2–, or LPS-treated neutrophils from the elderlywere less protected from apoptosis than neutrophils from youngersubjects.28 Collectively, these observations suggest neutrophilsmight be less abundant in acute inflammatory responses becauseof greater apoptosis, and those present might have diminishedantipathogen activity, resulting in more frequent and more severerespiratory tract infections.The effect of aging on the airway neutrophil, specifically in

asthmatic subjects, is not as well characterized. The aging processhas been shown to be associated with increased lung inflammationwithout concomitant lung disease. Bronchoalveolar lavage fluid(BALF) from subjects aged 19 to 83 years lacking a history ofallergies, pulmonary disease, or gastroesophageal reflux showedan increase in BALF neutrophils and CD41 T cells with age,29,30

whichmight differ fromperipheral blood changes (ie, CD41T-cellcounts might decrease with age). Patients older than 55 years ofage with asthma (n5 14) demonstrating reversibility on spirome-try with less than a 5 pack-year history of tobacco use had greatersputum neutrophil counts than younger patients with asthma.31

Thirteen of the 14 older patients evaluated were atopic, whichwas defined as having at least 1 positive skin prick test responseto an aeroallergen. Furthermore, the increased airway neutrophiliacorresponds to increased levels of sputum neutrophil mediators,including matrix metalloproteinase 9, neutrophil elastase, andIL-8, in older asthmatic subjects, resembling changes seen in pa-tientswith neutrophil-predominant severe asthma.32 Thus it is pos-sible that the increased airspace neutrophil numbers contribute togreater severity of asthma in the elderly.

Natural killer cellsNatural killer (NK) cells are cytotoxic cells that play an

important role in antiviral host defense. In a study of 82subjects (age range, 30-99 years), the numbers of NK cells(CD32CD161CD561) increasedwith aging; however, the cytotox-icity of these cells,measured based on 51Cr release, diminished on aper-cell basis with aging.33 In contrast to NK cells, natural killer T(NKT) cell (CD31CD161CD561) numbers have been shown todecrease in elderly subjects.34,35 Furthermore, proliferation in re-sponse to IL-2 anda-GalCer, a specific ligand for CD1d on invari-ant NKT cells, is diminished in older subjects.36 There is emerginginterest in the involvement of NK and NKT cells in the pathophys-iology of asthma.37-39 The clinical effect of a decrease in the func-tion, numbers, or both of these cells with aging has not beenestablished in asthmatic subjects. However, given their role in path-ogen clearance, especially viruses, it is possible that virus-inducedexacerbations of asthma might be more severe in the elderly.

Macrophages and monocytesMacrophage and monocytes are phagocytic cells that express

Toll-like receptors (TLRs), which recognize pathogen-associatedmolecular patterns. With aging, there might be decreased surfaceexpression and altered downstream TLR-mediated signaling, in-creasing the risk of respiratory tract infections. Macrophages de-rived from in vitro differentiation of monocytes had decreasedexpression of TLR3 mRNA and intracellular protein in older




subjects.40 Monocytes stimulated through the TLR1/2 heterodi-meric receptor generated fewer IL-6– and TNF-a–producing cellsin older subjects.41 Additionally, the production of ROS, which isimportant for killing of invading bacteria, might be altered. In al-veoar macrophages isolated from rats, fewer cells produced ROSon LPS stimulation in senescent animals, although there was asuggestion of more ROS per cell.42 The total in vitro LPS-induced production of nitric oxide was also significantly dimin-ished in macrophages from senescent animals.The ability of the aged airway macrophage (AM) to release

arachidonic acid and secrete leukotrienes has been evaluated inthe context of respiratory tract infections. In aged rats there wasno significant difference between release of these factors afterAM culture withKlebsiella pneumoniae in aged and young rats.43

However, decreased urinary levels of the anti-inflammatoryarachidonic acid byproduct lipoxin A4, which antagonizes theproinflammatory functions of leukotriene D4, were noted in olderhealthy subjects.44 Although not specifically examining leukotri-ene production by AMs, the levels of leukotriene C4 were notsignificantly higher in BALF cells or peripheral blood stimulatedwith Ca ionophore A23197 collected from atopic asthmaticsubjects older than 60 years compared with those 20 to 59 yearsof age.45 Therefore it is possible that regulation of leukotrienesmight be altered with aging.

Mast cellsMast cells are widely distributed throughout many tissues,

including blood vessels, the central nervous system, smoothmuscle, and epithelium. In many asthma phenotypes mast cellsare important in the early-phase bronchoconstriction and inductionof subsequent inflammatory cell influx. The effect of age on mastcell numbers and function has been studied in some other humandiseases besides asthma and murine models and depends on thetissue source and species. In the human brainmast cell numbers inthe ventricular choroid plexus were decreased in older patientsdying of non–central nervous system or cardiovascular causes.46

Similarly, dermal mast cell numbers decreased with age in humansubjects.47 Numbers of mast cells in the lamina propria of jejunalbiopsy specimens collected from subjects older than 70 years withgastrointestinal symptoms but without immunologic, allergic,infectious, neoplastic cause were similar to those from healthycontrol subjects (age range, 20-50 years).48 In contrast, vein sam-ples removed in aortocoronary bypass or varicose vein surgerydemonstrated greater numbers of mast cell numbers in older pa-tients.49 Young (6-week) and aged (3-12 months) C57BL/6 micehad similar dermal mast cell numbers.50 Liver mast cell numbersincreased to a greater extent after acute liver injury in young (2and 6 months) compared with aged (12 and 19 months) rats.51

The effect of age on mast cell degranulation is unclear. Eartissue mast cell degranulation and edema after prostaglandin Einjection was significantly increased in aged (>6 months) com-pared with young (2 month) mice. However, both aged andyoung mice had similar edema and mast cell degranulation inear tissue after IgE-dependent passive sensitization.50 The au-thors concluded that age modulates mast cells through non-FcR pathways. In addition, peritoneal mast cells obtained fromaged (72-94 weeks) compared with younger (6-8 weeks)C57BL/6 mice had a decrease in FcgRIIB/III (negative regula-tor) expression and a higher nonspecific IgG-mediated degranu-lation after incubation with 2.4G2.52

EosinophilsCurrently, there is very little reported on the age-associated

changes in eosinophil numbers and function. However, it appearsthat aged eosinophils might have altered effector functions and beless important in airway hyperresponsiveness. Although antigen-sensitized and antigen-challenged aged mice had greater BALFeosinophilia in comparison with younger mice, airway hyper-responsiveness was lower in the former.19 In a study examiningage-related changes in eosinophil function, it was found that pe-ripheral eosinophils from asthmatic subjects (age range, 55-80years) exhibited decreased degranulation in response to IL-5stimulation and a trend for decreased superoxide productionwhen compared with cells from patients 20 to 40 years ofage.31 However, a comparison of another in vitro eosinophil effec-tor function, leukotriene C4 production, revealed no differencebetween older and younger asthmatic subjects.53 Furthermore,older asthmatic subjects with evidence of atopy continue toexhibit sputum eosinophil numbers comparable with those seenin younger asthmatic subjects.31 In a study comparing subjectsolder than 64 years with either chronic obstructive pulmonarydisease (n5 28) or asthma (n5 21), as defined bymedical historyand a lack of smoking history, who also had fixed airway obstruc-tion (FEV1/forced vital capacity ratio <70% after bronchodilatoruse), those with asthma had significantly increased blood andsputum eosinophil counts and eosinophilic cationic proteinlevels.54 In addition, chronic respiratory symptoms and airwayhyperresponsiveness to methacholine challenge were associatedwith increased peripheral blood eosinophil counts in malesubjects (mean age, 60 years) enrolled in the Normative AgingStudy.55 Thus eosinophils might be less functional in the elderlybut continue to be associated with asthma.

AGE-RELATED CHANGES IN ADAPTIVE IMMUNITY

Dendritic cellsDendritic cells lie at the interface between the innate and

adaptive immune responses and are categorized as plasmacytoiddendritic cells or myeloid dendritic cells (mDCs). Experimen-tally, monocytes can be differentiated in vitro to an mDC-likephenotype. The monocyte derived dendritic cells from older sub-jects exhibited decreased phagocytosis of carboxyfluorescein suc-cinimidyl ester-labeled apoptotic T cells and decreasedpinocytosis of fluorescein isothiocyanate–labeled dextran.56

A recent study demonstrated decreased TLR function of plasma-cytoid dendritic cells and mDCs from older (age >_65 years) com-pared with younger (age range, 21-30 years) volunteers. Defectsin dendritic cell function correlated with a poor antibody responseto influenza immunization in the older subjects. The effect of den-dritic cell age-related changes in asthma is not clear. However, it ispossible that diminished function impairs a robust adaptive im-mune response, leaving the inciting antigen or pathogen to evokefurther innate responses.

T cellsThymic involution. Thymic involution is a well-

characterized feature of immunosenescence. After approximately1 year of life in human subjects, the thymopoietic space, whichcontains thymocytes and supporting thymic epithelial cells, isreplaced with fatty tissue. By 70 years of age, the thymopoieticspace is reduced to approximately 10% of the total thymus.57


OCTOBER 2010


There are several consequences of thymic involution. First, T-cellreceptor (TCR) diversity decreases from approximately 2 3 107

different TCR b-chains before 60 years of age to 200,000 after 70years of age.58 Decreased TCR diversity in aged (>18 months)C57BL/6 mice after infection with influenza virus A epitopes de-creased viral clearance.59 Thymic output of naive cells(CD41CD45RO1) also diminishes by greater than 95% afterthe age of 70 years.58 As a result, in murine models naiveCD41 T cells maintained a longer lifespan, with increasedresistance to apoptosis but decreased response to antigen.60 Ad-ditionally, in aged mice recent thymic emigrants produced by theaged thymus secreted less IL-2 and showed decreased prolifera-tion, weak expression of early activation markers, and decreasedintracellular Ca21 levels after TCR stimulation.61,62 Despitedefects in recent thymic emigrants from aged mice, new CD41

T cells generated from aged bone marrow stem cells, when trans-planted into young hosts, function normally and generate normalmemory responses.63 In addition to the diminishing thymic out-put of naive cells, the maintenance of the naive T-cell pool withaging might be compromised. Although it is controversialwhether IL-7 levels decrease with age, it is clear that IL-7 is crit-ical for naive and memory T-cell maintenance and survival. IL-7increased telomerase activity in naive peripheral CD41 T cellsof healthy aged adults, protecting against telomere loss andapoptosis.64

Increased memory T cells. Although thymic output ofnaive cells decreases with aging, the total numbers of T cellsremain relatively constant because of the survival of memorycells. The increased survival of memory CD41 T cells was re-ported to be due to changes in the aged mouse’s microenviron-ment.65 Numbers of memory CD81 T cells might be increasedbecause of chronic viral stimulation.66 Despite prolonged sur-vival, memory CD41 and CD81 T cells from aged mice mighthave poor antigen response.67,68 In human subjects defective ef-fector CD41 T cell responses after influenza vaccination werenoted in healthy subjects older than 65 years.69

Alterations in cytokine profile. Aging has been associ-ated with a chronic proinflammatory state characterized byincreased IL-1, IL-6, and TNF-a levels, which might predictmorbidity and mortality in the elderly.70,71 However, the effectof increased age on the balance between type I and type II cyto-kine lymphocyte expression is difficult to determine because itcan be altered by many factors, including the presence of comor-bid diseases. Although some studies suggest increased IFN-gsecretion by activated peripheral CD41 and CD81 cells,72 sev-eral others have shown a shift toward type 2 cytokine production.In a study of healthy subjects in 3 different age groups (21-30years, 80-81 years, and 100-103 years), flow cytometry wasused to evaluate both CD41 and CD81 T-cell populations withrespect to intracellular IL-4 (TH2) and IFN-g (TH1) expressionon phorbol 12-myristate 13-acetate stimulation.73 When the ratioof IFN-g/IL-4–producing cells was examined, there were noage-related differences in the CD41 T cells; however, the IFN-g/IL-4 ratio in the CD81 T cells was lower in both the olderage groups, suggesting an age-related shift from TH1 to TH2cytokine profiles. The cytokine secretion of IFN-g and bothIL-4 and IL-10 (TH2) was measured after a-GalCer stimulationof NKT cells isolated from younger and older subjects.35 Theratios of IFN-g/IL-4 and IFN-g/IL-10 were both significantlydecreased in the older subjects, suggesting a transition to agreater TH2 response with aging.

Decreased T-cell signaling. One of the essential functionsof T cells is the recognition of specific antigen in the context of anantigen-presenting cell followed by proliferation and cytokinesecretion. The aging of T cells in human subjects typicallycorresponds to a loss of CD28 expression, an accessory moleculefor TCR signaling. The consequences of the CD28 loss includedecreased IL-2 secretion and increased apoptosis on activa-tion.74,75 An in vitro loss of CD28 can be achieved with repeatedantigen stimulation.76 Furthermore, type I interferons (IFN-a andIFN-b) and TNF-a can also decrease CD28 expression.77,78

Therefore the loss of CD28 is thought to reflect a lifetime ofantigen or pathogen exposure.TH17 cells. TH17 cells are a subgroup of T cells that secrete

IL-17A, IL-17F, IL-22, and TNF-a. TH17 cells are differentiatedfrom naive T cells in the presence of IL-6 (increased expressionassociated with aging, see above) and TGF-b, which upregulatesthe transcription factors retinoid acid–related orphan nuclear hor-mone receptor gt and signal transducer and activator oftranscription 3.79 TH17 cells are maintained by IL-23. Severalmurine models of allergic asthma have suggested that IL-17Aand IL-17F are important in airway inflammation, particularlyneutrophilia80,81; enhance TH2-associated eosinophila82; andincrease airway hyperresponsiveness and airway MUC-5ACexpression.83,84 IL-17A and IL-17F are expressed in the airwaysof asthmatic patients.85,86 In addition to playing a role in antigeninduction of airway inflammation, the IL-23–TH17 axis is impor-tant for host response to respiratory tract bacterial infection andpotentially viral infection.87 Therefore it is possible that TH17cells might be involved in the exacerbation of asthma or inthe pathogenesis of late-onset asthma after respiratory tractinfection.The effect of aging on TH17 cells has been recently investigated,

and most work suggests increased IL-17 expression with aging.Aged (18-20 months) C57BL/6 and BALB/c mice infected withherpes simplex virus 2 or murine cytomegalovirus produced higherlevels of serum IL-17A accompanied by an increase in liver neutro-phil accumulationandmortality comparedwith infectedyoung (2-4months) andmiddle-aged (8-10months)mice.88 Conversely, IL-17neutralization or neutrophil depletion reduced liver damage andprevented death in these models of viral infection. Aged (16-18months) DBA/2 or BALB/c mice infected with the gram-negativebacteria Brucella abortus had significantly increased IL-17 andIL-6 splenocyte expression comparedwith similarly infectedyoung(2-3 months) mice who displayed TH1 expression.89 Additionally,aged (18-23months) CBA (H2k) and C57BL/6 mice demonstratedincreased IL-17 spleen cell production after stimulationwith irradi-ated donor spleen cells compared with strain-matched young (2-4months) mice.90 The role of TH17 cells in the pathogenesis oflate-onset asthma in a murine model or in older human subjectswith asthma has not been reported.Treg cells. Regulatory T (Treg) cells suppress several effector

functions of T-cell subsets, including TH1, TH2, and TH17. Tregcells might protect against autoimmune diseases, such as multiplesclerosis and diabetes, but excessive numbers and function mightlead to increased susceptibility to infection and cancer. Treg cellsfound in the lung are in the CD41CD25hi population. NaturalTreg cells are derived from the thymus, express the transcriptionfactor forkhead box protein 3 (Foxp3), and mediate suppressionprimarily through cell contact. Peripheral antigen-induced adap-tive Treg cells are either Foxp31 or Foxp32, and their major sup-pressive action is mediated through IL-10 and TGF-b. The




precise role of natural Treg cells and antigen-induced adaptiveTreg cells in asthma is not clearly established, but most studiesin murine models of asthma and in human subjects suggest a pro-tective role.91-93 Additionally, antigen tolerance inmurinemodelsof asthma induced by means of inhalation or low-dose oral feed-ing of allergen to young mice has been shown to suppress severalfeatures of allergic asthma and might involve Treg cells.94-96

The effect of age on the Treg cell pool number and function isless clear. Numbers of cord blood CD41CD25hi cells are in-creased at 2.3% to 9.5% of total CD41 T cells (suggested to sup-port fetal development of the immune system), decreasewithin thefirst 36months of life, and then remain stable in young andmiddle-aged healthy adults.97 In older patients the change in Treg cellnumbers is less investigated, and studies in human subjects havebeen limited to peripheral blood. Some investigators have shownan increase in CD41CD251 and CD41Foxp31 T cells98,99 inhealthy elderly subjects comparedwith those seen in younger sub-jects, whereas other groups have found no significant differencesin numbers of CD41Foxp31 T cells.100 The proportion and num-bers of CD41Foxp31 cells have been shown to be increased inlymphoid organs but not in lungs and blood of aged (>20 months)C57BL/6 mice compared with younger mice.99,101 Earlier studiessuggested that the suppressive activity of Treg cells decreaseswithincreasing age,102 but more recent studies have suggested that it ispreserved or even enhanced.98,100,101

The importance of Treg cells in airway inflammation in olderpatients with asthma has not been widely investigated. However,aged mice fed low-dose ovalbumin before antigen sensitizationand challenge had decreased airway hyperresponsiveness,antigen-specific serum IgE levels, BALF eosinophilia, and mu-cous hypersecretion compared with those seen in age-matchednontolerant mice. Additionally, the percentage of lung tissueCD41CD251Foxp31 cells was increased in antigen-tolerantaged mice. (Busse PJ, manuscript in preparation).

B cellsThe potential to generate new naiveB cells might diminishwith

age. In a study of 662 bone marrow biopsy specimens fromsubjects ranging in age from2months to 92 years, a decrease in thenumbers of B-cell precursors was observed.103 In mice there is atransition from naive B cells to ‘‘antigen-experienced’’ B cells.104

However, in mice the ability to produce antibody remains intactwith aging,105 but the quality of antibody produced hasdecreased affinity and avidity for antigen.106 This observation islikely due to deficient somatic hypermutation, which is responsi-ble for enhancement of antibody specificity for antigen.107 How-ever, there are also defects on aged T cells, which might alsoaccount for altered immunoglobulin production. Transfer ofaged, stimulated murine CD41 T cells into young hosts resultedin diminished B-cell activation, lower levels of antigen-specificIgG, and decreased expansion of the lymph nodegerminal centers.These alterations were secondary to reduced CD154 (CD40 lig-and) expression.108 Therefore the age-related decrease in the di-versity and quality of antibody, particularly in the setting of newantigen exposure, might affect the ability to clear pathogens andprovide protection against a repeat exposure to the pathogen.

ALLERGEN SENSITIZATION IN OLDER ADULTSApproximately 80% of young children in the United States with

asthma are allergen sensitized, and atopy in this age group increases

disease morbidity.109,110 The role of allergen-specific sensitizationin the pathophysiology and severity of disease seen in older patientsis not well understood. It is generally accepted that total IgE levelsdecreasewith increasing age. Several cross-sectional studies of ran-domly selected subjects from the Tucson Epidemiological Studyand the National Health and Nutrition Examination Survey(NHANES 2005-2006) have demonstrated that total serum IgElevels peak by 20 years of age and are lowest after 70 years.111,112

However, some studies have not supported this trend.113,114 Studiesalso suggest that younger populations tend to have a higher preva-lence of allergen-specific IgE sensitization than older groups.113,115

The decrease in total IgE and allergen-specific IgE levels with in-creasing agemight bedue toboth age and cohort effects.The effectsof increased age on alterations in total and allergen-specific IgEpro-ductionaremost likelydue to several factors of immunosenescence,including alterations in cytokine profiles and changes in B-cell an-tibody production, and are described elsewhere in the text. A cohorteffect is due to the observation that there has beenan increasedprev-alence of atopic diseases over time, possibly because of environ-mental factors. Therefore more recent birth cohorts might havehigher rates of allergen sensitization because of environmental con-ditions present at the time of birth and in early childhood and notcompletely because of younger age. There have been several longi-tudinal studies from cohorts of randomly selected subjects fromTuscon,115Nottingham,116 andCopenhagen117 and in theEuropeanCommunity Respiratory Heath Survey118 that support a cohort ef-fect along with an aging effect to explain differences in IgE levelsamong age groups.For many years, asthma in older patients was characterized as

nonatopic or intrinsic.119 However, over the past 2 decades, therehave been a few reports looking at older patients with asthma thathave demonstrated that atopy is not uncommon in this group. Thereported percentage of older patients with atopic versus nonatopicasthma varies and might depend on the characteristics of the pop-ulation studied. Studies in nonminority populations suggest that28% to 74% of older adults with asthma (not classified basedon age of onset) are sensitized to at least 1 antigen.4,120-122 Addi-tionally, it appears that there is a higher rate of allergen sensitiza-tion in older patients with asthma compared with age-matchedcontrol subjects.4,121

Two studies have specifically looked at antigen sensitizationrates in older asthmatic subjects from inner-city populations.Rogers et al123 demonstrated, in a study of 45 patients older than65 years of age recruited from an asthma clinic in New York City,that 60% had at least 1 detectable allergen-specific IgE level(including outdoor allergens), and 47% were sensitized to cock-roach. Among these patients, cockroach sensitization was associ-ated with more severe asthma, as measured by airflow limitationand hyperinflation. However, this study did not compare rates ofsensitization of elderly versus younger asthmatic subjects.The second study looked at adult inner-city patients with

moderate-to-severe persistent asthma and found that 41% of thoseolder than 60 years were sensitized to at least 1 antigen, whereas73% between 18 and 35 years of agewere sensitized.124 The mostcommon aeroallergen to which older patients are sensitized is notconsistent among reports and has been cat,122 dust mites,121,124

and cockroach.123Whether the differences in specific antigen sen-sitization are due to socioeconomic status, geographic location, orenvironmental exposures is not well established. Additionally, therole of allergen exposure in asthma pathogenesis and severity insensitized older patients is not completely understood.

FIG 1. Role of immunosenescence on features of asthma. This diagram

highlights the potential mechanism and clinical effect of immunosenes-

cence on long-term asthma, late-onset asthma, and asthma exacerbations

in the elderly.


OCTOBER 2010


Some studies have suggested that antigen sensitization mightplay a role in late-onset asthma.125,126 In the Normative AgingStudy men with airway hyperresponsiveness after 49 years ofagewere more likely to be sensitized to cat (23.9% vs 4.4%) com-pared with age-matched control subjects.125 However, sensitiza-tion to other indoor allergens (dust mite and mouse) were notsignificantly different. Nearly 50% of the 40 patients in the Tuc-son Epidemiological Study of obstructive lung diseases who hadasthma after the age of 60 years had positive skin prick testresponses to at least 1 antigen compared with 26% of the age-matched control population without asthma.4 In a study of 21patients with asthma onset after 65 years of age, 81% had positiveskin prick test responses to at least 1 allergen compared with agroup of 14 patients with asthma younger than 65 years inwhom 57% were allergen sensitized.126 A French study recruited1,485 patients (mean age, 73 years) with a diagnosis of asthmafrom a total of 379 lung specialists to examine disease character-istics. Of those with asthma after 65 years of age, 14.7% weresensitized to at least 1 antigen, as determined by means of skinprick testing, whereas 60.1% of thosewith asthma before 21 yearsof age were antigen sensitized.120

CLINICAL IMPLICATIONS AND SUMMARYOlder patients with asthma pose special considerations in

their treatment, and clinical management is addressed in detailelsewhere (see the article by Reid in this issue).127 Treatment iscomplicated by comorbid conditions, side effects of medica-tions, and potential physical impairments decreasing effectivedrug delivery (ie, difficulty administering an inhaler becauseof arthritis). Additionally, asthma in this population is frequentlysevere, and increased age might affect cellular responses tocorticosteroids, leukotriene inhibitors, anticholinergic agents,b-agonists, or anti-IgE. There have been limited numbers ofstudies specifically addressing the role of asthma medicationson airway inflammation and asthma outcomes in older patients.Additionally, whether the asthma is long standing or late onsetmost likely also plays a role in medication response. Corticoste-roids work in some, but not all, older patients. A large databasereview of patients 65 years old hospitalized at least once forasthma and followed 12 months after discharge demonstrated

that those given inhaled corticosteroids had a 29% reductionin asthma readmission and a 39% reduction in all-cause mortal-ity.128,129 However, some older patients with asthma might havea component of fixed airway obstruction.130 The National Insti-tutes of Health’s National Asthma Education and PreventionProgram sponsored a working group report on the topic ofasthma in the elderly in 1996 that recommended that olderpatients be administered a 2-week trial of oral corticosteroids(0.3-0.5 mg/kg) and have repeat lung function after the courseto assess for possible benefit.131 Although a reduction in anti-inflammatory lipoxin A4 with aging has been reported,44 theimprovement in asthma with leukotriene receptor antagonistsappears to be more beneficial in younger patients. Zafirlukastdecreased asthma symptoms regardless of age but had its great-est effects on adolescents and adults and did not change lungfunction in older patients.132,133

In September 2008, the National Institutes of Health’s NationalInstitute on Aging and the National Heart, Lung, and BloodInstitute cosponsored a conference with experts on asthma inolder patients. Existing data from animal models and humanstudies was reviewed, and it was concluded that inflammationassociated with asthma in the elderly differs from that seen inyounger asthmatic subjects. Age-related changes in immunefunction have been observed for components of the innate andadaptive immune responses. These changes might have implica-tions for the clinical features of long-term asthma and late-onsetasthma, as well as asthma exacerbations (Fig 1). Furthermore,with the expected increase in elderly populations, includingelderly asthmatic subjects, there is an urgent need to study thesepersons with particular attention to the differences in inflamma-tory mechanisms and responses to therapy.

Key concepts

d Age-related changes in immune function have been ob-served for components of the innate immune response, in-cluding epithelial cells, neutrophils, monocytes,macrophages, mast cells, and eosinophils.

d Age-related changes in immune function have also beenobserved for components of the adaptive immune re-sponse, including dendritic cells, T cells, Treg cells, andB cells.

d The age-related changes in immune function in humanasthmatic subjects and the corresponding clinical conse-quences have yet to be fully characterized.

d Asthma in older subjects is not uncommon and can eitherdevelop in childhood or later in life, when it is termedlate-onset asthma.

d Current pharmacologic interventions and those in devel-opment for the management of asthma are increasinglyfocused on specific inflammatory pathways. Thereforean understanding of age-related changes in inflammatoryresponses will be essential to establish rational ap-proaches to the treatment of asthma in the elderly.

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Age-related changes in immune function: Effect on airway inflammation

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