HLA-C and Killer Cell Immunoglobulin-like Receptor
Genes in Idiopathic Bronchiectasis
Rosemary J. Boyton, John Smith, Rosemary Ward, Meinir Jones, Lorraine Ozerovitch, Robert Wilson,
Marlene Rose, John Trowsdale, and Daniel M. Altmann
Lung Immunology Group, Department of Biological Sciences and National Heart and Lung Institute, Faculty of Medicine, South Kensington
Campus; Department of Occupational and Environmental Medicine, National Heart and Lung Institute, Brompton Campus; and Human
Disease Immunogenetics Group, Department of Infectious Diseases, Hammersmith Campus, Imperial College; Host Defense Unit, Department
of Respiratory Medicine, Royal Brompton and Harefield National Health Service Trust, London; Heart Science Centre, Harefield Hospital,
Imperial College, Harefield; and Immunology Division, Department of Pathology, University of Cambridge, Cambridge, United Kingdom
Rationale: In idiopathic bronchiectasis, lung inflammation and
ble role for natural killer (NK) cells is suggested by the observation
Objective: Because the HLA-C locus and killer cell immunoglobulin-
like receptors (KIRs) are of key importance for NK cell recognition,
we analyzed HLA-C/KIR combinations by genotyping patients with
ectasis and 101 control subjects was analyzed by polymerase chain
reaction with sequence-specific primers. High-resolution HLA-C
genotyping was performed in addition to KIR analysis.
gosity are associated with the presence of bronchiectasis. Analysis
of the relationship between HLA-C and KIR genes suggests a shift
to activatory NK cell function.
Conclusion: This is the first demonstration of genetic susceptibility in
gosity, and the interplay between HLA-C and KIR genes, argue for a
role for NK cells in the progressive lung damage seen in this disease.
This will require further investigation using functional studies.
Keywords: bronchiectasis; HLA-C; humans; immunity; killer cell
Idiopathic bronchiectasis is a lung disease in which a dysregu-
lated inflammatory response and recurrent bacterial infection
result in progressive lung damage. Bronchiectasis in general can
be defined as a common structural end point that can be reached
by several pathological routes ranging from foreign body obstruc-
tion to postinfectious damage (Mycobacterium tuberculosis), ge-
netic defects (cystic fibrosis), abnormal host defense (ciliary dys-
kinesia and hypogammaglobulinemia), and autoimmune disease
(systemic lupus erythematosus, rheumatoid arthritis, and ulcera-
defined group of patients in whom there is bilateral, predomi-
nantly lower lobe diseaseassociated with sinusitis, no underlying
(Received in original form January 26, 2005; accepted in final form October 26, 2005)
Supported by grants from the Royal Brompton and Harefield NHS Trust Clinical
Research Committee, the Welton Foundation, and the Medical Research Council,
United Kingdom. R.J.B. is supported by a Medical Research Council Clinician
Correspondence and requests for reprints should be addressed to Rosemary
Boyton, M.D., Lung Immunology Group, Department of Biological Sciences/Na-
tional Heart and Lung Institute, Sir Alexander Fleming Building, South Kensington
Campus, Faculty of Medicine, Imperial College, London SW7 2AZ, UK. E-mail:
Am J Respir Crit Care Med
Originally Published in Press as DOI: 10.1164/rccm.200501-124OC on October 27, 2005
Internet address: www.atsjournals.org
Vol 173. pp 327–333, 2006
disease mechanism has been identified to date. In fact, the diag-
nosis can be made only after all known causes of bronchiectasis
have been excluded.
Patients with bronchiectasis are commonly infected with bac-
terial pathogens such as Haemophilus influenzae, Streptococcus
pneumoniae, and Pseudomonas and show persistent neutrophil
trafficking (2, 3). It is thought that colonization of the lower
respiratory tract by microorganisms causes a chronic inflamma-
tory response characterized by neutrophil migration into the air-
ways andsecretion of tissue-damaging oxidants and enzymes such
as neutrophil elastase and myeloperoxidase with impaired mucus
clearance (4, 5). Although evidence clearly indicates a dysregu-
anism is unknown. Both innate and adaptive responses are impli-
cated. There is evidence indicating the presence of interleukin 6
T cells, and macrophages in the lungs of patients (6–8).
Natural killer (NK) cells rapidly accumulate in lung paren-
chyma during inflammation, recruiting other cell types including
neutrophils and T cells (9–11). They play a critical role in early
host protection againstS.pneumoniae infectionandotherpatho-
gens including M. tuberculosis (12, 13). Phenotypic differences
in NK cells have been shown in mouse strains susceptible and
resistant to chronic lung infection with Pseudomonas aeruginosa
(14). CD1d knockout mice show reduced lung eradication of
P. aeruginosa (15). Chemokine-mediated recruitment of NK
losis (16). These are all infectious pathogens that are often seen
in bronchiectasis. In addition, NK cells have been implicated by
the development of familial bronchiectasis in individuals with
mutations in TAP (transporter associated with antigen pro-
cessing) genes (17). These individuals have impaired class I ex-
pression and consequent dysfunction of NK cells that may con-
tribute to progressive lung damage (18, 19).
In light of these data, investigation of NK cell regulation
through HLA-C/killer cell immunoglobulin-like receptor (KIR)
gene analysis in individuals with idiopathic bronchiectasis could
be an important step in the elucidation of mechanisms underlying
disease susceptibility. NK cells are involved in the surveillance of
pathogens through the interaction of receptors expressed by NK
cells with major histocompatibility complex (MHC) class I mole-
of NK cell activation (20, 21). NK cells interact with HLA class I
ligands through receptors such as KIR. Particularly relevant to
NK recognition by KIRs are polymorphic HLA-C molecules.
Structurally and functionally there are two KIR groups: stimula-
tory KIRs bind directly to HLA-C, but experimental evidence
suggests that this might be the case. It has been proposed that
the binding of HLA-C to activating KIR 2DS1 and KIR 2DS2 is
328AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 1732006
weaker than to their inhibitory counterparts KIR 2DL1 and KIR
2DL2/3 (21, 23–26). KIR haplotypes, on chromosome 19q13.4,
are highly polymorphic but can broadly be classified as A or B
(21). Similarly, HLA-C alleles can be divided into group 1 or
group 2 depending on whether there is an asparagine or lysine
present at position 80 of the ?1 domain (20, 27). The two HLA-C
groups act as ligands that bind different KIRs, thespecificitybeing
determined by a single amino acid residue at position 44 of the
KIR 2D domain (20, 27). Through the interaction with inhibitory
KIRs, HLA-C molecules are able to modulate NK cell function.
This ligand–receptor pairingis thusunusual in theimmune system
insofar as inheritance of different combinations of these polymor-
phic germ line sequences in populations imparts differential con-
nectivity to NK cell activation, with different effector cell out-
We analyzed HLA-C/KIR combinations in individuals with
idiopathic bronchiectasis. We identified an increase in the preva-
sis, which may result in increased probability of mismatches
between KIR and HLA-C ligand with the potential to alter NK
cell regulation and function.
Subjects with Bronchiectasis and Control Subjects
The study group consisted of 96 unrelated individuals (mean age, 55 ?
informed consent. Peripheral blood samples were collected from pa-
tients attending the Host Defense Unit at Royal Brompton Hospital
(London, UK). Patients seen in this unit are clinically phenotyped
according to a detailed protocol of investigations. A diagnosis of idio-
pathic bronchiectasis is made, where there is predominantly bilateral
lower lobe bronchiectasis and chronic rhinosinusitis, on the basis of
clinical examination, pulmonary function tests, and high-resolution
computed tomography. All patients undergo chest and sinus radiogra-
phy, high-resolution thin-section computed tomography scan, respira-
tory function tests, and blood investigations including levels of IgG,
IgM, IgA, IgE, and IgG subclasses, and testing for rare immunodefi-
ciencies in selected patients where clinically indicated, Aspergillus radio-
immunosorbent test and precipitins, rheumatoid factor, anti-nuclear
antibodies, and ?1-antiproteinase. Sputum is sent for microscopy, cul-
ture, and sensitivities, smear, and culture for acid-fast bacilli. Skin tests
are performed for Aspergillus, and a sweat test proceeding to cystic
fibrosis genotyping if abnormal. Cystic fibrosis transmembrane regula-
tor genotyping is conducted to detect the following mutations: ?F508,
G551D, G542X, 621?1G ? T, R553X, 1717-G ? A, W1282X, N1303K,
R117H, R1162X, R334W, and 3849?10kbC ? T. These account for
Nasal mucociliary clearance and exhaled nasal nitric oxide are mea-
sured, proceeding to full cilia studies where indicated. In selected
patients, fiberoptic bronchoscopy, barium swallow, respiratory muscle
function tests, semen analysis, and tests for associated conditions
are also conducted if clinically indicated. Consequently, patients with
known underlying causes ofbronchiectasis suchas cystic fibrosis, immu-
noglobulin deficiency, and primary ciliary dyskinesia were excluded
before a diagnosis of idiopathic bronchiectasis was made. Control sub-
jects consisted of 101 U.K. heart/lung transplant organ donors (mean
age, 24.8 ? 1.4 yr; 73% male). The majority of control subjects died
unexpectedly after a road traffic accident, head injury, or cerebrovascu-
lar event. The study was approved by the Royal Brompton, Harefield,
and National Heart and Lung Institute Ethics Committee. The two
groups were matched for ethnicity. We acknowledge that they are not
fully matched for age and sex (due to the preponderance of females
in the patient group). We know of no bias imposed by sex on HLA-C
gene frequencies. Relative ages of sample groups can be a confounding
factor for a disease in which the most severely affected individuals die
at a young age. There is no evidence of such an effect in this disease,
where onset is generally in the twenties and thirties.
Genomic DNA was extracted from peripheral blood by a high-salt
technique. HLA typing of HLA-C alleles was performed by poly-
merase chain reaction with sequence-specific primers (PCR-SSP), using
a cycler plate system (Protrans; Quest Biomedical, Shirley, UK). High-
resolution HLA-C analysis was similarly performed with typing plates
according to the manufacturer’s instructions.
KIR Gene Analysis
Genomic DNA from individuals was typed for the presence or absence
of the KIR genes 2DL2, 2DL3, 2DS1, and 2DS2, using two separate
PCR amplifications with primers specific for each locus (PCR-SSP) as
previously described (28). Internal control primers for a 796-bp frag-
ment of the third intron of the DRB1 gene were included in each PCR.
The PCR conditions used were as follows: 10 min at 96?C (HotStart
Taq; Qiagen Ltd., West Sussex, UK), followed by 3 cycles of 96?C for
24 s, 67?C for 45 s, and 72?C for 30 s; 25 cycles of 96?C for 25 s, 64?C
for 45 s, and 72?C for 30 s; 4 cycles of 96?C for 25 s, 55?C for 60 s, and
72?C for 120 s; and a final extension of 72?C for 10 min.
Allele and genotype frequency was determined by direct counting.
ysis (31). The odds ratio (OR) and 95% confidence interval (CI) were
calculated. Allele and genotype frequency comparisons were made by
?2or Fisher’s exact test. p Values less than or equal to 0.01 were re-
garded as significant and those less thanor equal to 0.001 were regarded
as highly significant.
Individuals with Idiopathic Bronchiectasis Show an Increased
Frequency of HLA-Cw*03, whereas the Frequency of
HLA-Cw*06 Is Reduced
Ninety-six unrelated patients with idiopathic bronchiectasis and
101 control subjects were studied. The frequencies of HLA-C
alleles in individuals with bronchiectasis compared with control
subjects are shown in Table 1. HLA-Cw*03 was more common
in subjects with bronchiectasis compared with control subjects.
HLA-Cw*03 was identified in 19.8% of patients, but in only
9.9% of the control subjects (OR, 2.25; 95% CI, 1.25–4.02; p ?
0.006). In contrast, HLA-Cw*06 was identified in 4.2% of pa-
tients and 14.4% of control subjects (OR, 0.26; 95% CI, 0.12–
0.58; p ? 0.0005; Figure 1A). The Cw*03 allele was associated
with a 2.25-fold increased risk of bronchiectasis and the Cw*06
allele with a 0.26-fold reduced risk.
Increased Frequency of HLA-C Group 1 Alleles in Individuals
with Idiopathic Bronchiectasis
Dimorphisms in the HLA-C ?1 domain that are characterized
by Ser-77/Asn-80 and Asn-77/Lys-80define serologically distinct
HLA-C groups termed HLA-C group 1 and HLA-C group 2, re-
spectively (20, 27). HLA-C alleles are defined in terms of group
1 and 2 (Table 2). HLA-C group 1 was more common in subjects
with bronchiectasis compared with control subjects. HLA-C
group 1 was present in 66% of patients with bronchiectasis com-
paredwith 51% incontrolsubjects (OR, 1.88; 95%CI, 1.25–2.82;
p ? 0.002; Figure 1B). Furthermore, a trend toward significance
is seen when HLA-Cw*03 and HLA-Cw*06 alleles are not in-
cluded in the analysis, excluding the possibility that these alleles
are singularly driving the group 1/group 2 effect (Figure 1C).
HLA-C Group 1 Homozygosity in Idiopathic Bronchiectasis
gous for HLA-C group 1 (Figure 2A) compared with one-quarter
of the control subjects (OR, 2.56; 95% CI, 1.41–4.64; p ? 0.002).
HLA-Cgroups 1and 2actasligandsforKIR2Dsand itisthrough
Boyton, Smith, Ward, et al.: HLA-C and KIR in Bronchiectasis329
TABLE 1. HLA-C ALLELE FREQUENCY IN SUBJECTS WITH IDIOPATHIC BRONCHIECTASIS AND IN
Allele Allelic SubtypeOR 95% CIp Value
Definition of abbreviations: 95% CI ? 95% confidence interval; ND ? not determined; OR ? odds ratio.
Data on allelic frequencies yielding statistically significant results are indicated in boldface.
* n ? 96 individuals studied.
†n ? 101 individuals studied.
this interaction that HLA-C molecules protect healthy cells from
NK cell–mediated cytolysis. KIR 2DL1 and 2DS1 interact with
group 2,whereas KIR 2DL2, 2DL3, and 2DS2 interact with group
1 (Table 2). The specificity for the HLA-C type is defined by a
single amino acid substitution at KIR 2D position 44 (21, 27).
Figure 1. Frequency
HLA-C alleles and group 1 and
2 motifs in subjects with idio-
pathic bronchiectasis and con-
trol subjects. (A) HLA-Cw*03
quency in patients (n ? 192;
blackbars) andcontrol subjects
(n ? 202; gray bars). (B) HLA-C
group 1 and 2 motif frequency
and control subjects (n ? 200;
gray bars). (C) HLA-C group 1
and 2 motif frequency in pa-
tients (black bars) and control
subjects (gray bars), excluding
HLA-Cw*03 and HLA-Cw*06
from the analysis. HLA-C group
1: patients, n ? 154; control
subjects, n ? 180. HLA-C
group 2: patients, n ? 184;
control subjects, n ? 171. n ?
number of alleles.
Relationship between HLA-C and KIR Haplotype
The overall KIR gene frequency for 2DL2, 2DL3, 2DS1, and
2DS2 was not significantly different in patients with idiopathic
bronchiectasis compared with control subjects (Table 3).
330AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 1732006
TABLE 2. HLA-C GROUP 1/GROUP 2 MOTIFS AND THEIR
CORRESPONDING HLA-C ALLELES AND KILLER CELL
Position Corresponding HLA-C AllelesCorresponding KIR
1 Asn-80 Cw*01 (02, 03)
Cw*03 (02, 03, 041)
Cw*07 (01, 02, 03, 04, 05, 06)
Cw*08 (01, 02, 03)
Cw*12 (021, 022, 03, 06)
Cw*14 (002, 03)
Cw*16 (01, 03, 041)
Cw*02 (021, 022, 023, 024)
Cw*12 (041, 042, 05)
Cw*15 (02, 03, 04, 051, 052)
Cw*17 (01, 02)
Cw*18 (01, 02)
2DL2, 2DL3, 2DS2
2 Lys-80 2DL1, 2DS1
Definition of abbreviation: KIR ? killer cell immunoglobulin-like receptor.
Individuals only expressing HLA-C group 1 on targets will
overall have fewer NK cells under inhibitory receptor control
due to the missing inhibitory receptor ligand. This would allow
stimulatory KIRs greater impact on NK cell function, enhancing
activation (29). We examined the impact of HLA-C group 1
homozygosity in the presence of 2DS1 and/or 2DS2 and found
that genotypes with stimulatory KIR expressing only HLA-C
group 1were significantlyoverrepresented inidiopathic bronchi-
ectasis (33% in patients and 16% in control subjects; OR, 2.733;
95% CI, 1.31–5.70; p ? 0.006; Figure 2B).
Figure 2. HLA-C group 1 homozygosity confers in-
creased susceptibility to idiopathic bronchiectasis.
Black bars, patients; gray bars, control subjects, for
all panels. (A) HLA-C group 1 and 2 motif genotype
and disease susceptibility. Patients, n ? 96; control
subjects n ? 99. (B) HLA-C group 1 homozygosity
in the presence and absence of 2DS1 and/or 2DS2
killer cell immunoglobulin-like receptors (KIRs) and
disease susceptibility. Patients, n ? 90; control sub-
jects,n?84.(C)HLA-Cgroup 1and 2heterozygos-
ity in the presence and absence of 2DS1 and/or
2DS2 KIRs and disease protection. Patients, n ? 93;
control subjects, n ? 85. n ? number of individuals
TABLE 3. KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR
GENE FREQUENCY IN SUBJECTS WITH BRONCHIECTASIS
AND IN CONTROL SUBJECTS
Frequency ofIndividualsPositivefor EachKIR Gene
Bronchiectasis Control Subjects
GeneNo. (%)n*No. (%)n*OR p Value
Definition of abbreviations: KIR ? killer cell immunoglobulin-like receptor; OR ?
* Number of individuals studied.
We then explored the relationship between the presence and
absence of the activating KIR 2DS1 and 2DS2 in individuals
expressing both group 1 and group 2 HLA-C. We determined
gotes with 2DS1 and 2DS2. By the criteria defined in the model
describedby Nelsonandcolleagues (29),thepresenceofHLA-C
group 1/2 heterozygosity along with KIR 2DS1 and 2DS2 is
expected to lie at the most “inhibitory” end of the NK cell acti-
vation gradient. This genotype was significantly underrepre-
sented in individuals with bronchiectasis (Figure 2C, upper pair
of bars; 19% in control subjects compared with 5% in patients;
OR, 0.25; 95% CI, 0.09–0.70; p ? 0.005).
About one-quarter of the patients with idiopathic bronchiec-
tasis were homozygous for the AA*01 KIR haplotype (defined
in this study as the presence of 2DL3 and the absence of 2DL2,
2DS1, and 2DS2; Figure 3A). The relationship between HLA-C
group 1 homozygosity and KIR group AA*01 homozygosity in
Boyton, Smith, Ward, et al.: HLA-C and KIR in Bronchiectasis 331
Figure 3. KIR and HLA-C group genotype in idio-
pathic bronchiectasis (A) compared with control
subjects (B). Black bars, HLA-C group 1/HLA-C
group 1; gray bars, HLA-C group 1/HLA-C group 2;
white bars, HLA-C group 2/HLA-C group 2. n ?
type is defined as the presence of 2DL3 and the
absence of 2DL2, 2DS1, and 2DS2.
individuals with idiopathic bronchiectasis and control subjects
group 1 homozygosity in idiopathic bronchiectasis that allows a
greater proportion of potential mismatches between KIRs and
HLA-C ligands present, which may result in altered NK cell
In idiopathic bronchiectasis chronic bacterial infection and in-
inantly lower lobe bronchiectasis is one of the clinical features
of TAP deficiency syndrome (individuals with a mutation in the
TAP gene),whichcan also encompasschronicsinusitis, necrotiz-
ing granulomatous skin lesions, and recurrent bacterial pneumo-
nia (18, 19, 32). Mutations preventing expression of either or
sion of HLA class Imolecules and, as a consequence, expansions
of NK and ?? T cells with increased cytolytic activity are seen
(18, 19, 32–35). Although this rare group of patients represents
a special case of bronchiectasis, the data indicate that bronchiec-
tasis may be associated with dysregulated NK cell function.
The hypothetical framework for our study was thus that idio-
etiology, may involve a genetic susceptibility to inappropriate
or dysregulated NK cell surveillance of bacterial infection in the
lung. The functional impact on NK cell killing of KIR/HLA-C
interactions is often analyzed with respect to susceptibility to
viruses or tumors, in which mechanisms subverting adaptive
immunity through class I down-regulation are a common feature
of pathogenesis, leading to a presumed importance of NK cell
surveillance. However, bacterial genomes contain, in addition
to the well-documented TLR-mediated capacity to up-regulate
MHC, gene products capable of specific interference with MHC
actions are dependent on combinations of variable KIR and
HLA class I gene products. Because the two loci segregate inde-
pendently, NK cells can express KIRs for which there is no
known HLA ligand present. As different receptor–ligand inter-
actions mayresult inaltered NKcell–mediated immunity against
pathogens, it is proposed that the relationship between these
genes may be important in a disease such as bronchiectasis,
where chronic bacterial infection and progressive lung damage
may be the result of a dysregulated immune response to infec-
tious pathogens and/or self-antigens.
To gain insights into whether NK cell function may be more
broadly significant in this disease, the key polymorphic ligand/
receptor HLA-C and KIR 2D genes were analyzed. We found
HLA-Cw*03 to be present more commonly in individuals with
idiopathic bronchiectasis, and HLA-Cw*06 less so. The Cw*03
allele was associated with a 2.25-fold increased risk, and the
Cw*06 allele with a 0.26-fold reduced risk, of bronchiectasis.
More generally, HLA-C group 1 motifs were more common in
bronchiectasis, whereas group 2 motifs were less so. HLA-C
group 1 homozygosity was associated with markedly increased
susceptibility to bronchiectasis. This is noteworthy because a
homozygosity effect of this type is not easily reconciled with a
simple immune response gene effect whereby a particular HLA
class I allele is required for adaptive response to an epitope
from a particular pathogen. It is highly reminiscent of several
other NK cell disease models, whereby individuals (homozy-
gotes) who are missing ligands for inhibitory receptors will have
fewer NK cells under inhibitory control (28–30). An absence of
inhibitory receptors KIR 2DL1 and 2DL2/3, in the presence
of the respective homologous activating KIR 2DS1 and 2DS2
receptors, has been associated with the HLA-Cw*0602–
associated inflammatory disease psoriatic arthritis (28–30). The
bronchiectasis group contained a significantly increased number
of individuals expressing only HLA-C group 1 with 2DS1 and/or
2DS2 stimulatory KIRs: this would be considered at the “top
end” of the activation spectrum for NK cells. At present, such
interpretations depend on a model encompassing many un-
knowns including the relative affinities of inhibitory and activat-
ing KIRs, competitive binding, influence of peptide binding and
clonotypic expressionofreceptors. Nevertheless, theimplication
that will need to be pursued through functional experiments is
that an element of the pathogenesis in this disease relates to
excessiveactivationofNKcells.Antigenic peptidescanbe either
permissive or prohibitive to KIR recognition of HLA class I
(21, 25, 37–39). This has led to the proposal that a basal set of
peptides presentedby healthy cells containspermissivepeptides,
tuned just above the threshold that permits inhibition of NK
cells. However, subtle changes in the peptide pool, resulting
from, for example, infection, might trigger NK activation (21,
25). This may be particularly relevant for HLA-C molecules, as
they are expressed at one-tenth to one-third of the level of
HLA-A and HLA-B and are therefore closer to the threshold
necessary for NK cell inhibition (39, 40). Using activating KIR
tetramer–binding studies, formal dependence on the nature of
HLA-C–presented peptides has been demonstrated (25). Fur-
thermore, virally infected cells showed enhanced binding for
both stimulatory and inhibitory KIRs (25). The precise, physio-
logical ligands for the activating KIRs are poorly defined. It has
been elucidated that binding of HLA-C to activating KIR 2DS1
and 2DS2 would be weaker than to their inhibitory counterparts
KIR 2DL1 and 2DL2/3 (23–25). KIR tetramer–binding studies
suggest that activating and inhibitory receptors recognize the
same set of HLA class I molecules, differing in their binding
affinities, such that the stimulatory KIR is not always sufficient
to trigger an NK cell response to ligand. This allows fine control
during cellular activation (25). There is support for the notion
that non-HLA molecules (such as foreign or microbial antigens,
aberrantly expressed normal cell surface proteins, or complexes
of pathogen-derived peptides bound to MHC class I molecules)
may behave as ligands for activating KIRs (28). Furthermore,
the presence of an activating KIR (KIR 3DS1) gene along with
specific HLA alleles encoding Bw4–80I has an epistatic protec-
tive effect on AIDS progression (41).
332 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 1732006
On the basis of gene content, two distinct primary sets of
haplotypes have been determined for KIR genes, termed A and
B (22). Haplotype A has seven loci: 2DL1, 2DL3, 2DL4, 2DS4,
relevant difference between A and B haplotypes is the presence
of stimulatory KIR genes. Haplotype B contains various combi-
nations of 2DS1, 2DS2, 2DS3, 2DS5, 3DS1, and 2DS4, whereas
haplotype A contains only a single stimulatory KIR gene, 2DS4.
The 2DS4 gene has a null allele with a population frequency of
about 84% (42). Therefore, most individuals who are homozy-
gous for haplotype A may express no activating KIR (43). The
frequency of the two major haplotype groups, A and B, is differ-
ent across ethnic groups (44–51). For example, the A haplotype
allele frequency for Japanese populations is as high as 75% and
for Australian aborigines aslow as15% (52,53). It is noteworthy
that the prevalence of childhood bronchiectasis among Austra-
lian aborigines is extremely high at 14.7 per 1,000, a rate that is
40-fold greater than in nonindigenous Australian populations
(0.35 per 1,000) (52). Furthermore, a chronic, HLA class I–
associated lung disease similar to bronchiectasis, diffuse pan-
bronchiolitis, is relatively common in Japanese populations (53).
Thus, in two ethnic groups with increased probability of polar-
ized HLA classI/KIR combinations, an unusuallyhigh incidence
of bronchiectasis-like disease is described. About one-quarter
of the patients in this study were homozygous for the KIR A
haplotype (defined in this study as the presence of 2DL3 and the
absence of2DL2, 2DS1, and 2DS2). The increased prevalence of
HLA-C group 1 allotype homozygosity in bronchiectasis allows
a greater proportion of potential mismatches between KIRs and
HLA-C ligands, which may impact NK cell regulation.
The present studyis the first to establish genetic susceptibility
in idiopathic bronchiectasis: the association with HLA-C group
1 homozygosity, and the interplay between HLA-C/KIR genes,
taken together with findings in TAP deficiency syndrome, are
consistent with a role for NK cells in disease pathology. More
specifically, the data suggest a rolefor excessive or inappropriate
NK cell activation. Certainly, for this chronic progressive lung
disease, for which there is no clear mechanistic hypothesis, the
findings suggest that experiments on NK cell function may be
informative. More generally, the findings reveal a new level of
complexity to our understanding of the relationship between
HLA class I and KIR genes and the impact that this has on
disease susceptibility. In evolutionary terms it seems that, to
benefit from the genetic diversity of this system that allows the
generation of an efficient and effective immune response to
environmental pathogens, there is a cost: mismatches can occur
at an individual or population level, ending in disease through
an inappropriately regulated immune response.
Conflict of Interest Statement: None of the authors have a financial relationship
with a commercial entity that has an interest in the subject of this manuscript.
Acknowledgment: Theauthorsthank ProfessorsMalcolmGreen,AnthonyNewman-
Taylor, Tim Evans, Peter Cole, and Maggie Dallman for continued support and
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