consider genetic testing in the evaluation of sarcoidosis? Certain granulomatous responses have been shown to reffect genetic traits. Chronic beryllium disease ...
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 168 2003
The gastric toxicity of conventional nonsteroidal anti-inflammatory drugs involves their inhibition of gastroprotective prostaglandin E2 and hepatocyte growth factor synthesis (16). In parallel fashion, is it possible that the coincidental administration of nonsteroidal drugs (or corticosteroids) during the lung’s response to injury (perhaps a viral syndrome?) might provide a milieu conducive to fibroproliferation? It sounds far-fetched. Then again, so did the notion that hormone replacement therapy might promote cardiovascular disease in women (17). Conflict of Interest Statement : M.P.-G. has no declared conflict of interest.
Marc Peters-Golden, M.D. University of Michigan Health System Ann Arbor, Michigan References 1. Davies D, Wicks J, Powell RM, Puddicombe SM, Holgate ST. Airway remodeling in asthma: new insights. J Allergy Clin Immunol 2003;111: 215–225. 2. Selman M, King TE Jr, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001;134:136–151. 3. Marchand-Adam S, Marchal J, Cohen M, Soler P, Gerard B, Castier Y, Lese`che G, Valeyre D, Mal H, Aubier M, et al. Defect of hepatocyte growth factor secretion by fibroblasts in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003;168:1156–1161. 4. Savla U, Appel HJ, Sporn PH, Waters CM. Prostaglandin E2 regulates wound closure in airway epithelium. Am J Physiol Lung Cell Mol Physiol 2001;280:L421–L431. 5. Kohyama T, Ertl RF, Valenti V, Spurzem J, Kawamoto M, Nakamura Y, Veys T, Alegra L, Romberger D, Rennard SI. Prostaglandin E2 inhibits fibroblast chemotaxis. Am J Physiol Lung Cell Mol Physiol 2001;281:L1257–L1263. 6. Elias JA, Rossman MD, Zurier RB, Daniele RP. Human alveolar macrophage inhibition of lung fibroblast growth: a prostaglandin-dependent process. Am Rev Respir Dis 1985;131:94–99.
7. Goldstein RH, Polgar P. The effect and interaction of bradykinin and prostaglandins on protein and collagen production by lung fibroblasts. J Biol Chem 1982;257:8630–8633. 8. Kolodsick JE, Peters-Golden M, Larios J, Toews GB, Thannickal VJ, Moore BB. Prostaglandin E2 inhibits fibroblast to myofibroblast transition via E prostanoid receptor 2 (EP2) signaling and cyclic adenosine monophosphate elevation. Am J Respir Cell Mol Biol 2003;29:1–8. 9. Wilborn J, Crofford LJ, Burdick MD, Kunkel SL, Strieter RM, PetersGolden M. Fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenase-2. J Clin Invest 1995;95:1861–1868. 10. McAnulty RJ, Hernandez-Rodriguez NA, Mutsaers SE, Coker RK, Laurent GJ. Indomethacin suppresses the anti-proliferative effects of transforming growth factor-beta isoforms on fibroblast cell cultures. Biochem J 1997;321:639–643. 11. Klien JH, Adamson IYR. Fibroblast inhibition and prostaglandin secretion by alveolar epithelial cells exposed to silica. Lab Invest 1989;60: 808–813. 12. Lama V, Moore BB, Christensen P, Toews GB, Peters-Golden M. Prostaglandin E2 synthesis and suppression of fibroblast proliferation by alveolar epithelial cells is cyclooxygenase-2-dependent. Am J Respir Cell Mol Biol 2002;27:752–758. 13. Ware LB, Matthay MA. Keratinocyte and hepatocyte growth factors in the lung: role in lung development, inflammation, and repair. Am J Physiol Lung Cell Mol Physiol 2002;282:L924–L940. 14. Matsumoto K, Okazaki H, Nakamura T. Novel function of prostaglandins as inducers of gene expression of HGF and putative mediators of tissue regeneration. J Biochem (Tokyo) 1995;117:458–464. 15. Gohda E, Kuromitsu K, Matsunaga T, Miyazaki M, Yamamoto I. Synergism between interferon-gamma and cAMP in induction of hepatocyte growth factor in human skin fibroblasts. Cytokine 2000;12:780–785. 16. Takahashi M, Ota S, Hata Y, Mikami Y, Azuma N, Nakamura T, Terano A, Omata M. Hepatocyte growth factor as a key to modulate anti-ulcer actions of prostaglandins in stomach. J Clin Invest 1996;98:2604–2611. 17. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003; 349:523–534.
DOI: 10.1164/rccm.2309006
The Gene for Acute Sarcoidosis? A rheumatologist might order a test for human leukocyte antigen (HLA)-B27 in a patient with sacroiliitis to assess whether there is genetic predisposition to ankylosing spondylitis. In this issue of the Journal (pp. 1162–1166), Spagnolo and colleagues (1) report the association of a genetic trait with an acute form of sarcoidosis (Lofgren’s syndrome). Should pulmonologists now consider genetic testing in the evaluation of sarcoidosis? Certain granulomatous responses have been shown to reflect genetic traits. Chronic beryllium disease occurs in only 5% of exposed workers, but 95% of those patients who develop lung disease in response to beryllium carry a specific HLA DPB1 allele (2). Crohn’s disease and Blau’s syndrome (an autosomal dominant sarcoid-like illness in children) are both characterized by granuloma formation and an association with polymorphisms of the CARD15 gene on chromosome 16 (3). This gene appears to be involved in host recognition of bacterial peptidoglycans and thus may be critical to a balanced host response to intracellular bacterial invasion. Similar attempts to identify susceptibility genes in sarcoidosis have been relatively unrewarding, presumably reflecting the complex genetics of the disease. Sarcoidosis is characterized by broad variability in disease presentation and outcome, ranging from acute uncomplicated disease to chronic multi-system organ dysfunction (4). This creates difficulties in determining prognosis for individual patients. Genetic susceptibility to both the inciting antigen(s) and to the subsequent nature and intensity of the granulomatous response could account for
much of the variation in sarcoid disease phenotype. A recent emphasis has been placed on finding genetic traits that modify disease severity and course rather than disease susceptibility. Acute sarcoidosis frequently presents as Lofgren’s syndrome (4, 5). A biopsy is usually not required in this syndrome, since the constellation of erythema nodosum, anterior uveitis, arthralgia, and bilateral hilar lymphadenopathy is due to sarcoidosis in over 95% of cases in the Northeastern United States. If Lofgren’s syndrome is diagnosed, the likelihood of spontaneous remission in 12–24 months exceeds 95%. These data would suggest little need for genetic markers of diagnosis or disease outcome. Nevertheless, acute sarcoidosis can present without Lofgren’s syndrome, and some patients with Lofgren’s syndrome develop chronic disease. For these reasons, genetic markers suggestive of acute sarcoidosis may be clinically useful. Three major genetic associations with Lofgren’s syndrome have been reported. Several studies have shown that an activating polymorphism of the tumor necrosis factor-␣ gene (TNF␣; TNF-2 allele) is associated with Lofgren’s syndrome and erythema nodosum. This allele is associated with increased levels of TNF␣ during inflammatory responses and could explain some of the severe acute symptoms that are typical of Lofgren’s syndrome (6). Another study showed that the presence of the HLA allele DQB1*0201 is associated with Lofgren’s syndrome and may predict reduced risk of disease progression (7). As an HLA class II molecule, this disease association has been attributed to anomalous antigen
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processing or presentation. Finally, the study by Spagnolo and coworkers (1) shows that a cluster of polymorphisms of the C-C chemokine receptor (CCR)-2 gene, inherited together as a haplotype, is also associated with Lofgren’s syndrome (1). Is CCR-2 an appropriate gene to study in sarcoidosis? Candidate genes may be identified by genome-wide screens using linkage analysis or by a functional approach, where a specific gene is chosen based on its likely contribution to disease pathogenesis. Both approaches support the choice of CCR-2 as a candidate gene in sarcoidosis. A recent study, reporting a genome-wide search for genes predisposing to sarcoidosis, involved 63 families with two or more siblings diagnosed with sarcoidosis (8). This study confirmed a prominent association of sarcoidosis with the major histocompatibility locus on chromosome 6 (the site of HLA class II and TNF␣ genes). It also revealed an association with the short arm of chromosome 3 where the CCR-2 gene is located. CCR-2 is a chemokine receptor for the macrophage chemotactic proteins CCL-2, 8, 12, and 13. CCR-2 is expressed predominantly on macrophages, monocytes, dendritic cells, and T cells, and regulates inflammatory cell recruitment and function at sites of inflammatory responses (9). CCR-2 and its ligands have been shown to regulate cellular accumulation during granuloma formation in mice (10). Is there evidence that the CCR-2 haplotype reported by Spagnolo and coworkers is likely to be relevant to the Lofgren’s syndrome phenotype? At present, this is impossible to answer. Like many polymorphism association studies, the functional consequences, if any, of the reported CCR-2 polymorphisms are unknown. It is possible that through linkage disequilibrium these polymorphisms are inherited in conjunction with another genetically linked polymorphism of greater impact. The strength of these genetic associations must also be placed in perspective. Approximately 80% of patients with Lofgren’s syndrome express the reported alleles compared with 40% of the control population. In contrast, HLA B27 is present in 5–8% of the general population but in over 90% of patients with ankylosing spondylitis (11). The high prevalence of these alleles in the normal population emphasizes the fact that individual polymorphisms are unlikely to provide significant information alone. Indeed, it is probable that several genetic “hits” in combination are required to confer disease susceptibility and phenotype. It is increasingly evident that specific disease states and clinical manifestations are caused by inherited variations in gene expression and function. The expanding number of genetic association studies in sarcoidosis, such as that reported by Spagnolo and coworkers (1), are providing exciting insights into disease pathogenesis. We must now place an emphasis on showing that these genetic associations are reproducible in sarcoid cohorts (other than the 137 Dutch white patients studied in this article),
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and in understanding their functional consequences. Should a pulmonologist consider genetic testing in sarcoidosis? The answer remains no, but perhaps the time is approaching where the use of genetic analysis in complex diseases like sarcoidosis will be practical and clinically relevant. Conflict of Interest Statement : A.W.O. and J.S.B. have no declared conflict of interest.
Anthony W. O’Regan, M.B. Jeffrey S. Berman, M.D. Boston University School of Medicine Boston, Massachusetts References 1. Spagnolo P, Renzoni EA, Wells AU, Sato H, Grutters JC, Sestini P, Abdallah A, Gramiccioni E, Ruven HJT, du Bois RM, et al. C–C Chemokine receptor 2 and sarcoidosis: association with Lo¨fgren’s syndrome. Am J Respir Crit Care Med 2003;168:1162–1166. 2. Richeldi L, Sorrentino R, Saltini C. HLA-DPB1 glutamate 69: a genetic marker of beryllium disease. Science 1993;262:242–244. 3. Chamaillard M, Philpott D, Girardin SE, Zouali H, Lesage S, Chareyre F, Bui TH, Giovannini M, Zaehringer U, Penard-Lacronique V, et al. Gene–environment interaction modulated by allelic heterogeneity in inflammatory diseases. Proc Natl Acad Sci USA 2003;100:3455–3460. 4. 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). Am J Respir Crit Care Med 1999;160:736–755 5. Mana J, Gomez-Vaquero C, Montero A, Salazar A, Marcoval J, Valverde J, Manresa F, Pujol R. Lofgren’s syndrome revisited: a study of 186 patients. Am J Med 1999;107:240–245. 6. Seitzer U, Swider C, Stuber F, Suchnicki K, Lange A, Richter E, Zabel P, Mu¨ller-Quernheim J, Flad HD, Gerdes J. Tumour necrosis factor alpha promoter gene polymorphism in sarcoidosis. Cytokine 1997;9: 787–790. 7. Sato H, Grutters JC, Pantelidis P, Mizzon AN, Ahmad T, Van Houte AJ, Lammers JW, Van Den Bosch JM, Welsh KI, Du Bois RM. HLADQB1*0201: a marker for good prognosis in British and Dutch patients with sarcoidosis. Am J Respir Cell Mol Biol 2002;27:406–412. 8. Schurmann M, Reichel P, Muller-Myhsok B, Schlaak M, MullerQuernheim J, Schwinger E. Results from a genome-wide search for predisposing genes in sarcoidosis. Am J Respir Crit Care Med 2001;164: 840–846. 9. Charo IF, Peters W. Chemokine receptor 2 (CCR2) in atherosclerosis, infectious diseases, and regulation of T-cell polarization. Microcirculation 2003;10:259–264. 10. Warmington KS, Boring L, Ruth JH, Sonstein J, Hogaboam CM, Curtis JL, Kunkel SL, Charo IR, Chensue SW. 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 1999;154:1407–1416. 11. Khan MA. HLA-B27 and its subtypes in world populations. Curr Opin Rheumatol 1995;7:263–269.
DOI: 10.1164/rccm.2309005
Medicine on Lung Cancer Screening A Different Paradigm In this issue of the Journal (pp. 1167–1173), McWilliams and coworkers (1) address the laudable goal of stratifying individuals by risk for lung cancer to optimize computer tomography (CT) screening. For lung cancer, such a test would need to be more sensitive and specific than CT, be easily and rapidly performed, be acceptable to potential screenees, and cost less than CT screening (typically about $300). McWilliams and coworkers report on their baseline screening results. They still need to demonstrate that sputum cytology will perform well for considerably
smaller malignancies seen on annual repeat CT screening (2–3) because this determines the major value of screening. Baseline occurs only once for any screenee. Even if automated sputum cytometry were not useful on repeat screening, it may still be useful during baseline screening. Further analysis might even show it to be more useful when performed only in patients who have non-calcified nodules on CT. McWilliams and coworkers appear to have data to evaluate this option. McWilliams and coworkers enrolled 561 high-risk individuals
