|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EK,
ZSLAV
KOLEK,
EN
WEIGL,  |
ABSTRACT |
|---|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Genes for the chemokine receptors CCR5 and CCR2 are characterized by polymorphisms resulting in a nonfunctional receptor expression. Ligands for CCR2 and CCR5 (chemokines monocyte chemotactic protein-1 [MCP-1] and RANTES) are implicated in the pathogenesis
of sarcoidosis. We have, therefore, analyzed polymorphisms of CCR5
(32-bp deletion in CCR5 gene [
32]) and of CCR2 (replacement of
valine by isoleucine in CCR2 gene [64I]) in 66 Czech patients with
sarcoidosis in comparison with a representative sample of Czech
normal population. The frequencies of CCR532 and CCR2-64I polymorphisms in patients with sarcoidosis were different from that in
control subjects. CCR532 allelic frequency was significantly increased in patients. By contrast, the CCR2-64I allele was more frequent in control subjects; however, the difference did not attain
significance. Interestingly, the CCR532 allele was associated with
clinically more apparent disease: it was present in 39.1% of patients requiring corticosteroids but only in 16.7% patients who did
not need therapeutic intervention (odds ratio [OR] = 2.9). When
patients requiring corticosteroids were compared with control
subjects, the differences in the CCR532 frequencies were enhanced (p < 0.01). In conclusion, the observed association of
CCR532 and CCR2-64I with sarcoidosis implicates a role for these
polymorphisms in disease susceptibility and protection.
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Sarcoidosis is a multisystem disorder of unknown origin most
frequently affecting the lungs, where it typically appears as CD4+ T-lymphocyte and macrophage alveolitis (1). Interplay
between chemotactic cytokines (chemokines), and their receptors is considered to be crucial for transmigration of lymphocytes and monocytes from the circulation to the bronchoalveolar space (2). CC chemokines RANTES (regulated upon
activation, normal T-cell expressed and secreted; CCL5), monocyte chemotactic protein-1 (MCP-1; CCL2), and macrophage
inflammatory protein-1
(MIP-1; CCL3) have been implicated
in this process (3).
Two of the receptor molecules, which may bind the aforementioned chemokines, namely CC chemokine receptor
(CCR) 5 and CCR2, are characterized by gene polymorphisms. A 32-bp deletion in the CCR5 gene (CCR532) results in a nonfunctional surface receptor molecule unable to
bind its chemokine ligands RANTES, MIP-1, and MIP-1
(7). A substitution mutation (replacement of valine by isoleucine in the transmembrane region) has been described in the
CCR2 gene (CCR2-64I) (8); CCR2 is a receptor for MCP-1 and also its homologues MCP-2 to MCP-5 (7). Both CCR mutations have been implicated in the pathogenesis of human immunodeficiency virus (HIV) infection, and the presence of the
mutated allele or alleles confers varying degree of anti-HIV
protection that is reflected in slower disease progression (9).
To investigate if these polymorphisms in "candidate" che-mokine receptor genes are relevant for the development of alveolitis in sarcoidosis, we have investigated the distribution of the wild-type and mutant alleles of CCR2 and CCR5 in Czech patients with sarcoidosis in comparison with healthy control subjects. Further, to explore if these polymorphisms may affect the clinical course of the disease, we have analyzed the association of particular genotypes with two groups of patients: those requiring corticosteroids for control of disease activity and those who do not need corticosteroids.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Study Population
Chemokine receptor polymorphisms were determined in 66 patients with sarcoidosis and in 386 control subjects (Table 1). The control group consisted of unrelated healthy subjects, participants of the Czech Bone Marrow Donor Registry (CNRDD), who agreed to the anonymous usage of their DNA for research purposes. Absence of lung disease in the control subjects was checked during their registration for the Registry by health questionnaire and interview. In patients, the diagnosis of sarcoidosis was based on typical clinical features together with granulomas on histopathologic examination. The diagnosis was further supported by a lymphocytic, CD4+ bronchoalveolar lavage. The blood for DNA extraction was obtained at the first day of presentation and after a period of 2 yr, the course of the disease was reviewed.
|
The patients were subdivided according to the need for cortico-steroid treatment into two groups: patients who received treatment (n = 46) and patients in whom treatment was not necessary, i.e., the disease resolved spontaneously (n = 18); in two patients data on therapy were unavailable. The treatment scheme did not differ from that recommended in the International Statement on Sarcoidosis (10): Treatment with steroids was indicated according to an accepted protocol: (1) all patients with chest X-ray Stage III disease at presentation; (2) patients with progressing and/or symptomatic Stage II disease; and (3) patients with persistent Stage I or II disease. Patients with persistent disease were treated after at least 6 mo of disease observation.
The study was performed with the approval of the ethics committee of the Medical Faculty and University Hospital Olomouc.
CCR Genotyping and Statistical Analysis
Assessment of chemokine receptor polymorphism. DNA was extracted
using a standard salting out procedure. CCR5 and CCR2 wild-type and mutant alleles were typed by polymerase chain reaction using sequence-specific primers (PCR-SSP); for primer sequences, see Table
2. For characterization of the CCR2 polymorphism, two amplification reactions were used: the first with primers specific for the wild-type allele sequence, the second with primers specific for the sequence of the
mutant allele. In the case of a homozygous wild-type individual, the
product was observed only in the first reaction; in the case of a homozygous mutant individual the product was detected only in the second reaction. When the typed proband was heterozygous (CCR2,
CCR2-64I), the products were detected in both the CCR2-specific and CCR2-64I-specific reactions. The composition of PCR reaction-mix, cycling protocol, and electrophoresis conditions was adopted
from "phototyping" methodology (11). The CCR5 polymorphism was
characterized as previously described (12) by one amplification reaction with primers flanking the region containing the 32-bp deletion.
The wild-type allele was detected as a 182-bp fragment; the CCR532 allele was detected as a 150-bp fragment. In a heterozygous individual, both fragments were detected.
|
Statistics. Comparisons were made between allelic (gene) and phenotype frequencies in the disease and control populations; the term "phenotype frequency" (i.e., carriage rate) gives the number of individuals carrying one (or two) copies of a particular allele on one or both (maternal and paternal) chromosomes. Comparisons were also made between patients with different clinical courses (patients requiring treatment or patients with spontaneous resolution of the disease without treatment). The data sets were compared using a standard 2 × 2 chi-square analysis by SIGTEST, a computer-based program that uses a Woolf-Haldane correction in cases of small numbers (13). This program has a facility for the calculation of chi-square statistics, the significance value, and the relative risk (odds ratio [OR]). The control populations were tested for conformity to the Hardy-Weinberg equilibrium using a 2 × 2 chi-square test between observed and expected numbers.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
The Czech (control and patient) populations were found to be
in Hardy-Weinberg equilibrium with regard to the distribution of CCR2 and CCR5 genotypes (p > 0.05). Phenotype and
gene frequencies for CCR2 and CCR5 polymorphisms are
summarized in Table 3. The frequencies of CCR2-64I in patients were different from control subjects (see Table 3) although these differences did not attain statistical significance.
By contrast, the allelic and phenotype frequency of CCR532
was significantly higher in patients than in control subjects (p = 0.02 and p = 0.03, respectively). The frequency of homozygous mutant (CCR532) individuals was 1.5% (1/66) in the
patient group and 0.3% in the control group (1/386); no homozygotes with CCR2-64I were detected in either control individuals or patients.
|
When the patients were divided according to the necessity
for treatment, more pronounced differences in CCR532 frequency emerged. In the group of 46 patients requiring treatment
there were 18 (39.1%) CCR532-positive individuals by comparison with three of 18 patients (16.7%) with spontaneous disease resolution (OR = 2.9; p = 0.1); phenotype frequency of
CCR532 in the normal population is 21.2% (Figure 1).
|
Importantly, when only the patients requiring treatment
were included in the analysis (based on the fact that they have
more pronounced disease), the differences between the allelic
and phenotype frequencies of CCR532 in the normal population and patients with sarcoidosis became highly significant
(allelic frequency, p = 0.005; phenotype frequency, p = 0.007).
Also, the relative risk of sarcoidosis for the subjects with
CCR532 allele increased from 1.9 to 2.4 (95% confidence interval [CI]: 1.3 to 4.5).
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
This study has shown an association between chemokine receptor polymorphisms and pulmonary sarcoidosis. Primary
analysis (comparison of sarcoidosis as a whole with the controls)
has shown a decrease of the CCR2-64I allele, and a significant
increase in the frequency of the CCR32 allele. Disease subset analysis of those patients requiring therapy compared with
those with spontaneous resolution of sarcoidosis showed that
the presence of the mutant CCR532 allele was confined to
the more pronounced clinical course of the disease. Subjects
with the mutant CCR5 allele were three times more prone to
require treatment than those without the allele, i.e., the presence
of the mutant CCR5 allele carried an increased relative risk
(OR = 2.9) of the need for treatment. Furthermore, if the cases
with a more benign clinical course (those not requiring treatment) were excluded from the analysis, the difference between CCR532 allelic and phenotype frequencies in patients with
sarcoidosis and control subjects became highly significant.
The results are therefore consistent with the hypothesis
that polymorphisms in CCR2 and CCR5 receptors for the
chemokines MCP-1 and RANTES (themselves implicated in
the pathogenesis of sarcoidosis) may affect the development
of this disease. In this regard, our patient population was representative of sarcoidosis with respect to the male:female ratio,
age range, and clinical course of the disease. Second, because
of different frequencies of CCR532 allele around the world
(14) only unrelated Czech patients and unrelated Czech control subjects who were white were included in the study to ensure that it is not confounded by ethnic mixing. Third, technical
problems in our analysis or data generation are unlikely as the
allele and genotype frequencies of both polymorphisms do not
deviate from what would be expected to occur randomly in the
population according to Hardy-Weinberg equilibrium (15). Further, the adequacy of the genotyping approach is evidenced by the agreement between the published CCR2-64I (16) and
CCR532 (14) frequencies and our results.
Our study is not the first investigation of chemokine receptors and their polymorphisms in sarcoidosis. Agostini and coworkers (17) found increased cell surface expression of CXCR3 (receptor for chemokines such as gamma interferon inducible protein-10 [IP-10]) on T cells from sarcoid lung. Recently, Hizawa and coworkers (18) have reported a significantly decreased frequency of the CCR2-64I allele in Japanese patients with sarcoidosis. Our results agree with those obtained in the Japanese population (18) and imply that a possible protective effect of the CCR2-64I polymorphism is present also in the white population, though less markedly. There have, however, been no reports to date concerning CCR5 expression or CCR5 gene polymorphisms in sarcoidosis. We can, therefore only speculate about the mechanism by which these CC chemokine receptor polymorphisms differentially contribute to susceptibility to sarcoidosis.
In sarcoidosis, an oligoclonal T helper cell, type 1 (Th1)
T-cell-mediated immune response elicited by unknown antigen leads to an accumulation of activated Th1 T cells at sites
of inflammation and contributes to the development of delayed type hypersensitivity (DTH) granulomas (1, 2, 19). Interestingly, T-cell lines from a CCR5-deficient individual
(CCR532 homozygote) contained high numbers of Th1 cytokine (interferon gamma [IFN-
], interleukin-2 [IL-2]) positive cells (20), and also T cells of the CCR5-deficient mice
showed increased production of IFN- and had an enhanced DTH reaction with increased CD4+ infiltration (21). By contrast, in CCR2-deficient mice an impaired DTH response and
decreased production of Th1-type cytokines was observed
(22). These findings allow the speculation that in individuals
carrying the CCR532 allele, there is an increased predisposition to a Th1-type immune response and subsequent granuloma formation, whereas in the individuals with CCR2-64I
Th1 reactivity is attenuated. This interpretation may be challenged by the recent findings of impaired Th2 cytokine-mediated lung granulomas elicited by schistosomal antigen in
CCR2-deficient mice (23). However, according to Kunkel and
coworkers (24), a switch to Th2-type T cells may occur in patients with sarcoidosis evolving toward lung fibrosis. On the
other hand, our hypothesis, that CCR532 polymorphism favors a Th1-type immune response is supported by the observation of a decreased frequency of CCR5 deletion mutation in
asthma, a typical Th2 disease (25).
The presence of a 32-bp deletion in the CCR5 loci on both
chromosomes results in a nonfunctional surface receptor molecule unable to bind its chemokine ligands RANTES, MIP-1
and MIP-1 (7). All but one of our CCR32-positive patients
was heterozygote. It is known that heterozygosity in CCR532
results in a 50% decrease of CCR5 molecule expression on the
cell surface (26), and, therefore, we have to ask whether the
deletion mutation and its gene dosage have a real impact on
cell recruitment. In the situation of partially or fully nonfunctional CCR5, monocytes and T cells could migrate to the sarcoid
lung using alternative pathways. For example, the chemokine
RANTES, a CCR5 ligand implicated in lymphocyte migration in sarcoidosis (3, 4), may exert its chemotactic effects by compensatory binding to other receptors such as CCR1 or CCR3, or both. Alternatively, cellular influx into sarcoid alveoli may be encouraged by other chemokines such as IP-10, which
binds to the CXCR3 receptor (17). CXCR3, together with
CCR5, characterizes cell subsets associated with Th1-type inflammatory reactions (27, 28) and importantly, cellular expression
of CXCR3 is upregulated in sarcoid patients (17).
The existence of compensatory mechanisms of cell migration suggests that the pathogenetic role of the CCR532 in
sarcoidosis may not be related to impaired cell migration. Alternatively, a stronger and prolonged immune response may
develop in CCR532-positive individuals with sarcoidosis as a
result of altered signaling through CCR5. This concept is supported by the results of gene targeting studies, which have recently indicated a novel role for CCR5 in modulating T-cell
function. Signaling through CCR5 might function as part of a
negative regulatory cycle of T-cell activation (21) and it was
suggested that there might be a cross-talk between T-cell receptor and chemokine signaling pathways (29).
CCR2 and CCR5 genes are (together with CCR1 and 3) located on chromosome 3p21.3, within a gene cluster of 350 kb
(30). Genome-wide screening has implicated the CCR5 region, defined by the marker DS3S1573, in the susceptibility to
Crohn's disease (31), which shares some pathogenetic features
(Th1 granulomatous inflammation and alveolitis) with sarcoidosis and may occur within families (32, 33). Therefore, another explanation of the observed association of CCR5 and
CCR2 polymorphisms with sarcoidosis is, as already suggested
by Hizawa and coworkers (18), the possibility of the existence
of linkage disequilibrium with other as yet unknown genes in
the CCR cluster. The candidates include CCR5 promoter alleles, some of which have been recently associated with HIV-1 disease progression (34). Alternatively, the observed relationship between presence of CCR532 and the need for corticosteroid treatment suggests that CCR5 may control the expression of other receptors with pharmacologic function.
In conclusion, we have shown that Czech patients with sarcoidosis have profiles of CCR2 and CCR5 polymorphisms distinct from the normal population; that these chemokine receptor
polymorphisms play an as yet undefined role in the development
of sarcoidosis; and that CCR532 is related to clinically more
apparent disease. CC chemokine receptor polymorphisms should,
therefore, be added to the current spectrum of immunogenetic
factors known to be involved in the pathogenesis of this multifactorial disease. Further work is required to characterize the
functional relevance of these polymorphisms.
| |
Footnotes |
|---|
Correspondence and requests for reprints should be addressed to Dr. Martin
Pet
ek, Department of Immunology, PalackýUniversity, I. P. Pavlova str. 6, CZ-775 20 Olomouc, Czech Republic. E-mail: petrekm{at}fnol.cz
(Received in original form January 7, 2000 and in revised form March 17, 2000).
This work was presented in part at the 6th Meeting of the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG), Kumamoto, Japan, November 8-13, 1999.
Acknowledgments:
Ms. M. Luke
ová helped with DNA extraction. The
primer sequences for the CCR5 typing were provided by Dr. N. R. Landau, Aaron Diamond AIDS Research Center, New York (Ref. 12). The authors thank Dr. S. Komenda for his contribution to the statistical analysis.
Supported in part by the Czech government research program (MSMT: J14/ 98.151100002) and by British Society for Immunology and ICN Pharmaceuticals traveling fellowship to M.P.
| |
References |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Newman, L. S.,
C. S. Rose, and
L. A. Maier.
1997.
Medical progress: sarcoidosis.
N. Engl. J. Med.
336:
1224-1234
2. Keane, M. P., T. J. Standiford, and R. M. Strieter. 1997. Chemokines are important cytokines in the pathogenesis of interstitial lung disease. Eur. Respir. J. 10: 1199-1202 [Medline].
3. Petrek, M., P. Pantelidis, A. M. Southcott, P. Lympany, P. Safranek, C. M. Black, V. Kolek, E. Weigl, and R. M. du Bois. 1997. The source and role of RANTES in interstitial lung disease. Eur. Respir. J. 10: 1207-1216 [Abstract].
4. Iida, K., J. Kadota, K. Kawakami, Y. Matsubara, R. Shirai, and S. Kohno. 1997. Analysis of T cell subsets and beta chemokines in patients with pulmonary sarcoidosis. Thorax 52: 431-437 [Abstract].
5. Semenzato, G.. 1998. Chemotactic cytokines: from molecular level to clinical use. Sarcoidosis Vasc. Diffuse Lung Dis. 15: 131-133 . [Medline]
6. Standiford, T. J., M. W. Rolfe, S. L. Kunkel, J. P. Lynch III, M. D. Burdick, A. R. Gilbert, M. B. Orringer, R. I. Whyte, and R. M. Strieter. 1993. Macrophage inflammatory protein-1alpha expression in interstitial lung disease. J. Immunol. 151: 2852-2863 [Abstract].
7. Mantovani, A.. 1999. The chemokine system: redundancy for robust outputs. Immunol. Today 20: 254-257 [Medline].
8. Kostrikis, L., Y. Huang, J. P. Moore, S. Wolinski, L. Zhang, Y. Guo, L. Deutsch, J. Phair, A. U. Neumann, and D. D. Ho. 1998. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Nature Med. 4: 350-353 [Medline].
9. Michael, N. L.. 1999. Host genetic influences on HIV-1 pathogenesis. Curr. Opin. Immunol. 11: 466-474 [Medline].
10.
Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World
Association of Sarcoidosis and Other Granulomatous Disorders
(WASOG) adopted by the ATS Board of Directors and by the ERS
Executive Committee, February .
1999.
Am. J. Respir. Crit. Care Med.
160:
736-755
11. Bunce, M., C. M. O'Neill, M. C. N. M. Barnardo, P. Krausa, M. J. Browning, P. J. Morris, and K. I. Welsh. 1995. Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 and DQB1 by PCR with 144 primers utilizing sequence-specific primers (PCR-SSP). Tissue Antigens 46: 355-367 [Medline].
12.
Drábek, J., and
M. Petek.
1998.
32 bp deletion in CCR-5 gene and human immunodeficiency virus epidemic in the Czech Republic.
Acta
Virol.
42:
121-122
[Medline].
13.
Avila, J. J.,
P. A. Lympany,
P. Pantelidis,
K. I. Welsh,
C. M. Black, and
R. M. du Bois.
1999.
Fibronectin gene polymorphisms associated with
fibrosing alveolitis in systemic sclerosis.
Am. J. Respir. Cell Mol. Biol.
20:
106-112
14. Liu, R., W. A. Paxton, S. Choe, D. Ceradini, S. R. Martin, R. Horuk, M. E. MacDonald, H. Stuhlmann, R. A. Koup, and N. R. Landau. 1996. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86: 367-377 [Medline].
15. Todd, J. A. 1999. Interpretation of results from genetic studies of multifactorial diseases. Lancet 354(Suppl. 1):15-16.
16. Su, B., L. Jin, F. Hu, J. Xiao, J. Luo, D. Lu, W. Zhang, J. Chu, R. Du, Z. Geng, X. Qiu, J. Xue, J. Tan, S. J. O'Brien, and R. Chakraborty. 1999. Distribution of two HIV-1-resistant polymorphisms (SDF1-3'A and CCR2-64I) in East Asian and world populations and its implication in AIDS epidemiology. Am. J. Hum. Genet. 65: 1047-1053 [Medline].
17.
Agostini, C.,
M. Cassatella,
R. Zambello,
L. Trentin,
S. Gasperini,
A. Perin,
F. Piazza,
M. Siviero,
M. Facco,
M. Dziejman,
M. Chilosi,
S. Qin,
A. D. Luster, and
G. Semenzato.
1998.
Involvement of the IP-10
chemokine in sarcoid granulomatous reactions.
J. Immunol.
161:
6413-6420
18.
Hizawa, N.,
E. Yamaguchi,
K. Furuya,
E. Jinushi,
A. Ito, and
Y. Kawakami.
1999.
The role of the C-C chemokine receptor 2 gene polymorphism
V64I (CCR2-64I) in sarcoidosis in a Japanese population.
Am. J. Respir.
Crit. Care Med.
159:
2021-2023
19. Müller-Quernheim, J.. 1998. Sarcoidosis: immunopathogenetic concepts and their clinical application. Eur. Respir. J. 12: 716-739 [Abstract].
20. Odum, N., S. Bregenholt, K. W. Eriksen, S. Skov, L. P. Ryder, K. Bendtzen, R. J. Van Neerven, A. Svejgaard, and P. Garred. 1999. The CC-chemokine receptor 5 (CCR5) is a marker of, but not essential for the development of human Th1 cells. Tissue Antigens 54: 572-577 [Medline].
21.
Zhou, Y.,
T. Kurihara,
R. P. Ryseck,
Y. Yang,
C. Ryan,
J. Loy,
G. Warr, and
R. Bravo.
1998.
Impaired macrophage function and enhanced T
cell-dependent immune response in mice lacking CCR5, the mouse
homologue of the major HIV-1 coreceptor.
J. Immunol.
160:
4018-4025
22. Boring, L., J. Gosling, S. W. Chensue, S. L. Kunkel, R. V. Farese Jr., H. E. Broxmeyer, and I. F. Charo. 1997. Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. J. Clin. Invest. 100: 2552-2561 [Medline].
23.
Warmington, K. S.,
L. Boring,
J. H. Ruth,
J. Sonstein,
C. M. Hogaboam,
J. L. Curtis,
S. L. Kunkel,
I. R. Charo, and
S. W. Chensue.
1999.
Effect
of C-C chemokine receptor 2 (CCR2) knockout on type-2 (schistosomal antigen-elicited) pulmonary granuloma formation: analysis of cellular recruitment and cytokine responses.
Am. J. Pathol.
154:
1407-1416
24. Kunkel, S. L., N. W. Lukacs, R. M. Strieter, and S. W. Chensue. 1996. Th1 and Th2 responses regulate experimental lung granuloma development. Sarcoidosis Vasc. Diffuse Lung Dis. 13: 120-128 . [Medline]
25. Hall, I. P., A. Wheatley, G. Christie, C. McDougall, R. Hubbard, and P. J. Helms. 1999. Association of CCR5 delta32 with reduced risk of asthma. Lancet 354: 1264-1265 [Medline].
26. Landau, N. R.. 1999. Recent advances in AIDS research: genetics, molecular biology and immunology. Curr. Opin. Immunol. 11: 449-450 [Medline].
27. Qin, S., J. B. Rottman, P. Myers, N. Kassam, M. Weinblatt, M. Loetscher, A. E. Koch, B. Moser, and C. R. Mackay. 1998. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J. Clin. Invest. 101: 746-754 [Medline].
28. Loetscher, P., M. Uguccioni, L. Bordoli, M. Baggiolini, B. Moser, C. Chizzolini, and J. M. Dayer. 1998. CCR5 is characteristic of Th1 lymphocytes. Nature 391: 344-345 [Medline].
29.
Sato, N.,
W. A. Kuziel,
P. C. Melby,
R. L. Reddick,
V. Kostecki,
W. Zhao,
N. Maeda,
S. K. Ahuja, and
S. S. Ahuja.
1999.
Defects in the
generation of IFN-gamma are overcome to control infection with
Leishmania donovani in CC chemokine receptor (CCR) 5-, macrophage
inflammatory protein-1 alpha-, or CCR2-deficient mice.
J. Immunol.
163:
5519-5525
30. Samson, M., P. Soularue, G. Vassart, and M. Parmentier. 1996. The genes encoding the human CC-chemokine receptors CC-CKR1 to CC-CKR5 CMKBR1-CMKBR5) are clustered in the p21.3-p24 region of chromosome 3. Genomics 36: 522-526 [Medline].
31. Satsangi, J., M. Parkes, E. Louis, L. Hashimoto, N. Kato, K. Welsh, J. D. Terwilliger, G. M. Lathrop, J. I. Bell, and D. P. Jewell. 1996. Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nature Genet. 14: 199-202 [Medline].
32. James, D. G.. 1995. Granuloma formation signifies a Th1 cell profile. Sarcoidosis 12: 95-97 [Medline].
33. Kolek, V. 1998. Sarcoidosis: Known and Unknown [in Czech]. Grada Publishing, Prague. 31, 51.
34. Tang, J., C. Rivers, E. Karita, C. Costello, S. Allen, P. N. Fultz, E. E. Schoenbaum, and R. A. Kaslow. 1999. Allelic variants of human beta-chemokine receptor 5 (CCR5) promoter: evolutionary relationships and predictable associations with HIV-1 disease progression. Genes Immunity 1: 20-27 .
This article has been cited by other articles:
 |
|
 |
|
  P. J. Holst, C. Orskov, K. Qvortrup, J. P. Christensen, and A. R. Thomsen CCR5 and CXCR3 Are Dispensable for Liver Infiltration, but CCR5 Protects against Virus-Induced T-Cell-Mediated Hepatic Steatosis J. Virol., September 15, 2007; 81(18): 10101 - 10112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Iannuzzi Thomas A. Neff Lecture. Advances in the Genetics of Sarcoidosis Proceedings of the ATS, August 15, 2007; 4(5): 457 - 460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Iannuzzi and B. A. Rybicki Genetics of Sarcoidosis: Candidate Genes and Genome Scans Proceedings of the ATS, January 1, 2007; 4(1): 108 - 116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. G.-J. Ooi, G. Galatowicz, V. L. Calder, and S. L. Lightman Cytokines and Chemokines in Uveitis - Is there a Correlation with Clinical Phenotype? Clin. Med. Res., December 1, 2006; 4(4): 294 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. B. Rasmussen, S. Timm, A. G. Wang, K. Soeby, H. Lublin, M. Fenger, R. Hemmingsen, and T. Werge Association Between the CCR5 32-bp Deletion Allele and Late Onset of Schizophrenia Am J Psychiatry, March 1, 2006; 163(3): 507 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Wysocki, Q. Jiang, A. Panoskaltsis-Mortari, P. A. Taylor, K. P. McKinnon, L. Su, B. R. Blazar, and J. S. Serody Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease Blood, November 1, 2005; 106(9): 3300 - 3307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Spagnolo, E. A. Renzoni, A. U. Wells, S. J. Copley, S. R. Desai, H. Sato, J. C. Grutters, A. Abdallah, A. Taegtmeyer, R. M. du Bois, et al. C-C Chemokine Receptor 5 Gene Variants in Relation to Lung Disease in Sarcoidosis Am. J. Respir. Crit. Care Med., September 15, 2005; 172(6): 721 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Valentonyte, J. Hampe, P. J. P. Croucher, J. Muller-Quernheim, E. Schwinger, S. Schreiber, and M. Schurmann Study of C-C Chemokine Receptor 2 Alleles in Sarcoidosis, with Emphasis on Family-based Analysis Am. J. Respir. Crit. Care Med., May 15, 2005; 171(10): 1136 - 1141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ahlenstiel, R. P. Woitas, J. Rockstroh, and U. Spengler CC-chemokine receptor 5 (CCR5) in hepatitis C--at the crossroads of the antiviral immune response? J. Antimicrob. Chemother., June 1, 2004; 53(6): 895 - 898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Spagnolo, E. A. Renzoni, A. U. Wells, H. Sato, J. C. Grutters, P. Sestini, A. Abdallah, E. Gramiccioni, H. J. T. Ruven, R. M. du Bois, et al. C-C Chemokine Receptor 2 and Sarcoidosis: Association with Lofgren's Syndrome Am. J. Respir. Crit. Care Med., November 15, 2003; 168(10): 1162 - 1166. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kaminski, J. A. Belperio, P. B. Bitterman, L. Chen, S. W. Chensue, A. M.K. Choi, S. Dacic, J. H. Dauber, R. M. du Bois, J. J. Enghild, et al. Idiopathic Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): S1 - 105. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Morohashi, T. Takada, K. Omori, E. Suzuki, and F. Gejyo Vascular Endothelial Growth Factor Gene Polymorphisms in Japanese Patients With Sarcoidosis Chest, May 1, 2003; 123(5): 1520 - 1526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. du Bois The Genetic Predisposition to Interstitial Lung Disease : Functional Relevance Chest, March 1, 2002; 121(2007): 14S - 20S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. CAPELLI, A. DI STEFANO, M. LUSUARDI, I. GNEMMI, and C. F. DONNER Increased Macrophage Inflammatory Protein-1alpha and Macrophage Inflammatory Protein-1beta Levels in Bronchoalveolar Lavage Fluid of Patients Affected by Different Stages of Pulmonary Sarcoidosis Am. J. Respir. Crit. Care Med., January 15, 2002; 165(2): 236 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. TOBIN Tuberculosis, Lung Infections, and Interstitial Lung Disease in AJRCCM 2000 Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): 1774 - 1788. [Full Text] [PDF]
|
|
|
|
|
|
M. J. Tobin Taxonomy of AJRCCM, a New Series, and a Medley of Metaphors Am. J. Respir. Crit. Care Med., October 15, 2001; 164(8): 1333 - 1335. [Full Text] [PDF]
|
|
|
|
|
|
R. M. du Bois Sarcoidosis: Do Our Genes Really Matter? Am. J. Respir. Crit. Care Med., September 1, 2001; 164(5): 725 - 726. [Full Text] [PDF]
|
|
|
|
|
|
M. SCHURMANN, P. REICHEL, B. MULLER-MYHSOK, M. SCHLAAK, J. MULLER-QUERNHEIM, and E. SCHWINGER Results from a Genome-wide Search for Predisposing Genes in Sarcoidosis Am. J. Respir. Crit. Care Med., September 1, 2001; 164(5): 840 - 846. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Proc. Am. Thorac. Soc. | Am. J. Respir. Cell Mol. Biol. |