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Considering an infectious etiology of sarcoidosis
Clinics in Dermatology (2007) 25, 259–266
Considering an infectious etiology of sarcoidosis Michael E. Ezzie, MD, Elliott D. Crouser, MD* Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University Medical Center, Columbus, OH 43210-1252, USA
Abstract Sarcoidosis is a systemic granulomatous disease of unknown cause. An infectious etiology of sarcoidosis has long been suspected, but only recently has scientific evidence provided a strong link between infectious agents and sarcoidosis. Moreover, recent advances in our understanding of the relationships between sarcoidosis phenotype and host genetic factors may further illuminate the mechanisms linking infection and sarcoidosis. © 2007 Elsevier Inc. All rights reserved.
Introduction Despite decades of research and thousands of publications on the topic, the cause of sarcoidosis remains unknown. Our current level of understanding is accurately reflected by Newman et al1 who recently described sarcoidosis as “… an immune-mediated multiorgan disorder of unknown origin, characterized by the presence of noncaseating granulomata.” Clinicians and scientists have entertained a number of possible causes, including infectious agents, genetic mutations, and various environmental exposures, with inconclusive results. The notion of a single causative agent is not in keeping with the worldwide distribution of disease. On the other hand, if there are multiple causes, then the near uniform reaction of patients with sarcoidosis to a common antigenic challenge (ie, the Kveim-Siltzbaum reagent) is difficult to reconcile. Based upon the available evidence, it seems likely that multiple factors, including host genetics and environmental exposures, independently contribute to the pathogenesis of sarcoidosis (Fig. 1). In this review, we present selected
* Corresponding author. Tel.: +1 614 293 4925; fax: +1 614 293 4799. E-mail address: [email protected] (E.D. Crouser). 0738-081X/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2007.03.003
highlights of decades of research in search of infectious etiologies of sarcoidosis.
Antigenic determinants of granulomatous inflammation As elucidated by Noor and Knox in this issue of the journal, sarcoidosis and other granulomatous diseases are characterized by a classic antigenic TH-1 immune response. Table 1 represents a partial list of agents known to cause granulomatous skin lesions, and these must be considered before the diagnosis of sarcoidosis is established. The notion that sarcoidosis is caused by a specific antigenic exposure has been postulated for some time, and proposed sarcoidosis-inducing agents represent a spectrum of organic and inorganic exposures including pine trees, clay soil, zirconium, aluminum, and talc.2-6 With respect to the latter, cosmetics often contain talc and other inert submicroscopic substances that are linked to granulomatous reactions of the skin3 and lungs.4 Recent investigations report the presence of birefringent particles within granulomas of the skin and other affected organs in more than 20% of patients with sarcoidosis.5 Furthermore,
260 an analysis of more than 700 cases of sarcoidosis enrolled in A Case Control Etiologic Study of Sarcoidosis (ACCESS) revealed that exposures to inhaled organic or inorganic antigens predispose to disease confined to the lung.6 It follows that dissemination of antigens within the host, as might occur in the context of certain infections, would favor systemic disease manifestations. The relevance of environmental exposures to the development of sarcoidosis is further supported by strong associations between certain occupations and the risk of developing sarcoidosis. Among the US Navy enlisted men (1965-1993), the incidence of sarcoidosis was highest among aircraft carrier personnel, presumably because of common environmental exposures. 7 A dose-response correlation between exposure to burning wood (eg, woodburning stoves) and sarcoidosis,8 and the clustering of sarcoidosis among firefighters in relation to common smoke exposures,9 suggests that inhalation of particles present in smoke may promote sarcoidosis. Numerous anecdotal associations between occupation and sarcoidosis risk such as these have been reported, but objective evidence of increased sarcoidosis risk attendant to certain occupational exposures, including industrial organic dusts (eg, farming), was only recently confirmed by the ACCESS group.10 Indisputable support for a role of protein antigens in the development of granulomas in the context of sarcoidosis is provided by several lines of evidence. In 1941, the results of an experiment wherein heat-inactivated protein extracts derived from lymph nodes or spleens of patients with systemic sarcoidosis (Kveim reagent) were injected subcutaneously in patients with sarcoidosis or disease-free controls were reported. A local granulomatous response that was pathologically identical to sarcoidosis was observed after several weeks exclusively in the patients with sarcoidosis.11 This reaction, later referred to as the KveimSiltzbach test, emerged as a standardized test for the diagnosis of sarcoidosis.12 Subsequent attempts to characterize the Kveim antigen identified a protein or proteins sequestered in immune cells, but the specific identity of the proteins was not ascertained.13 In search of a possible infectious etiology of sarcoidosis, analysis of Kveim reagent by polymerase chain reaction (PCR) using universal primers detecting highly conserved sequences of bacterial ribosomal 16S RNA failed to detect bacterial contamination14; however, the presence of other bacterial elements (eg, proteins) or nonbacterial infectious agents were not considered in these analyses.
Evidence supporting an infectious cause of sarcoidosis Parkes et al15 were among the first to provide objective evidence for an infectious cause of sarcoidosis. A casecontrol analysis was applied to 96 cases of sarcoidosis diagnosed in the Isle of Man from 1962 to 1983. Sarcoidosis
M.E. Ezzie, E.D. Crouser
Fig. 1 Proposed relationships between environmental exposures and sarcoidosis phenotype. The cumulative evidence supports the view that multiple environmental exposures, including antigens derived from infectious and noninfectious sources, are capable of inducing sarcoidosis in predisposed individuals. Host-related variables, including drugs (eg, nicotine, interferon alfa), genetics, and perhaps other unidentified factors, are proposed to strongly influence the disease phenotype.
was observed to affect the sexes equally and occurred in 38 cases (39.6%) who had been in contact with the disease before diagnosis, compared with 2 (1.2%) of the combined control groups, which were made up of age- and sexmatched disease-free individuals and members of the local tuberculosis registry. The sarcoidosis contacts included members of the same household, colleagues at work, and close friends. The authors noted that a bias may have been introduced because diseased patients would inevitably be more aware of the disease in others and would be more likely to mention previous contact than the controls. Further analysis of the data using the case-control test for spacetime clustering developed by Smith and Pike16 identified significantly more links between cases separated by time intervals of less than 10 years and distances of less than 100 m and localizing to clusters whose contact was by place of residence or work. More linked cases were diagnosed less than 3 years apart than would be expected by chance. This evidence has long been considered to support the view that sarcoidosis is a communicable disease.17 Apparent transmission of sarcoidosis from organ donors to recipients further supports a potential infectious cause. In one case, the recipient of an allogeneic bone marrow transplant developed sarcoidosis within 3 months of the procedure. Notably, pulmonary sarcoidosis had been diagnosed in the bone marrow donor 2 years before.18 Other cases of donor-to-recipient transmission of sarcoidosis,19 as well as transmission from recipient to donated organ,20 have been reported, but the transmittable agent was not identified in any of these case reports.
Considering an infectious etiology of sarcoidosis Table 1
Causes of granulomatous inflammation of the skin
Clinical variants
Characterization
Infectious
Mycobacteria Tuberculosis Atypical mycobacteria Syphilis (secondary or tertiary) Cat-scratch disease (Bartonella henselae) Pseudomycoses Actinomycoses Nocardiosis Botryomycosis Invasive fungal infections Histoplasmosis Spirotrichosis Aspergillosis Leishmaniasis (Leishmania species) Demodicidosis (Demodex species) Herpes simplex virus Chancre (Haemophilus ducreyi) Scabies (Sarcoptes scabei) Donovanosis (Calymmatobacterium granulomatis) Granulomatous rosacea Sarcoidosis Crohn's disease Granuloma annulare and actinic granuloma Granulomatous cheilitis Necrobiosis lipoidica Necrobiotic xanthogranuloma Granulomatous vasculitis Wegener's vasculitis Churg-Strauss disease Foreign body granuloma
Inflammatory, unknown cause
Inflammatory, identifiable etiology Neoplastic
Nongranulomatous diseases misnamed as granuloma
Granulomatous mycosis fungoides Lymphomas with histiocytic infiltration (Lennert's disease) Granuloma faciale Lymphomatoid granulomatosis Lethal midline granuloma
This table is a reproduction, with slight modification, of data available at the following internet Web site: http://www.thedoctorsdoctor.com/ diseases/skin_granuloma.htm#ddx.
The observed seasonality of sarcoidosis is often cited as evidence for an infectious cause. The incidence of sarcoidosis is noted to peak during springtime, a pattern that is conserved in geographically and ethnically isolated countries.21,22 It is interesting to note that many of the cases diagnosed during the springtime were characterized by acute onset, the presence of erythema nodosum, and a favorable outcome.23,24 It is interesting to speculate that a specific
261 infection or class of infectious agents is responsible for this specific sarcoidosis phenotype. The following section considers specific infectious agents that are suggested to be causally linked to sarcoidosis.
Mycobacteria Various mycobacterial infections can present with skin lesions that are clinically and pathologically indistinguishable from those caused by sarcoidosis.25-27 In this context, PCR analysis of tissues obtained from patients with sarcoidosis of Mediterranean descent revealed the presence of DNA specific to Mycobacterium species at a much higher rate than in tuberculosis-negative controls.28,29 Similarly, 60% of diseased lung and lymph node tissues from patients with sarcoidosis recruited from southeastern United States were noted to contain mycobacterial DNA, most of which were classified as Mycobacterium tuberculosis.30 In contrast, mycobacterium DNA was not found in either bronchoalveolar fluid or tissues of Germans with sarcoidosis, leading the investigators to conclude that “granulomatous lesions in sarcoidosis may not be due to mycobacterial infections.”31 Exciting new evidence explains why highly sensitive molecular techniques (eg, PCR) often fail to identify the genetic fingerprint of infectious agents in tissues of patients with sarcoidosis or in the Kveim reagent. Using selective proteomic analysis of poorly soluble protein aggregates derived from affected tissues, Moller et al identified M. tuberculosis catalase-peroxidase (mKatG) in most sarcoidosis cases and in none of the tissues from disease-free controls. Nearly one half of the sarcoidosis cases, moreover, had circulating IgG antibodies to recombinant mKatG, compared with none of the purified protein derivative negative controls.32 Considering that subcutaneous injection of the Kveim reagent, a proteinaceous derivative of sarcoidosis tissues, elicits a delayed local granulomatous response in patients with sarcoidosis, and systemic injection of complete Freund's adjuvant (containing mycobacterial antigens) produces pulmonary manifestations that closely resembles human sarcoidosis,33 it is apparent that nonviable components of M. tuberculosis are capable of inducing a sarcoidosis-like response. This evidence, however, fails to fulfill Koch's postulates, which are a series of conditions that must be met to establish a microorganism as the causative agent of disease. Namely, the organism must be detected in all cases of the disease; inoculations of organisms cultured from diseased humans must produce disease in susceptible animals; and from these animals, the organism must be isolated and grown in culture. Disease caused by nonviable components of microorganisms, thus, cannot be classified as an infectious disease. Nonetheless, the findings of mycobacterial proteins in the affected tissues, in conjunction with a specific antibody response to these proteins in affected individuals, provide strong evidence that at least some cases of sarcoidosis are caused by a sustained immunologic reaction to retained infectious antigens.
262
Propionibacteria Based on association studies, exposures other than Mycobacterium species are incriminated as potential sarcoidosis-causing infections. Dissimilarities between the distribution of tuberculosis and sarcoidosis in Japanese populations argue against a tuberculosis etiology in this population.34 In a small Japanese cohort, Propionibacterium DNA, and not M. tuberculosis, was detected in the vitreous fluid of the eyes of patients with sarcoidosis with uveitis and in none of the disease-free controls.35 Likewise, a multicenter study of lymph node samples from controls and patients with sarcoid found either Propionibacterium acnes or Propionibacterium granulosum DNA by PCR analysis in 106 of 108 lymph nodes from patients with sarcoidosis. A significant number of controls, however, also harbored propionibacteria DNA, but in lower copy numbers.36 The observation by Ebe et al37 that Propionibacterium promotes a brisk cellular immune response in patients with sarcoidosis supports a causal link between Propionibacterium and sarcoidosis in the Japanese population. From analyses of skin lesions, however, it is apparent that Propionibacterium plays a lesser role in the Greek population wherein Mycobacterium species prevails.28 Animal studies provide the most convincing evidence of a causal link between Propionibacterium and sarcoidosis. When injected into rats and rabbits, P. acnes causes a local granulomatous reaction.38 Remarkably, extrapulmonary sensitization of mice to heat-killed P. acnes (2-week intervals) induced pulmonary TH-1 granulomatous inflammation predominantly in the subpleural and peribronchovascular regions, as is often observed in sarcoidosis. The authors of this study proposed that granulomas formed in response to indigenous P. acnes colonizing the lungs, which is supported by alleviation of granulomatous lung disease after eradication of P. acnes using antibiotics (minocycline).39 In this context, it is interesting to note that resolution of cutaneous sarcoidosis has been reported after treatment with minocycline.40 Future studies are needed to determine if this ubiquitous organism, found on the skin of healthy individuals, could be an etiologic agent of human sarcoidosis.
Other bacteria Based upon similarities in the clinical presentation of Lyme disease and sarcoidosis, a number of clinical investigators have hypothesized that Borrelia burgdorferi is a sarcoidosis-causing agent. This notion is apparently supported by the finding of elevated levels of circulating antibodies against B. burgdorferi in a cohort of Chinese patients with sarcoidosis.41 Only 8% to 15% of the patients with high antibody titers, however, had detectable B. burgdorferi DNA in the affected tissues.42 An increased seroprevalence of B. burgdorferi was also found in one Japanese study (32.6% sarcoidosis vs 4% controls),43 whereas other studies found no
M.E. Ezzie, E.D. Crouser association between B. burgdorferi and sarcoidosis in other ethnic groups.44-46 Considered together, it would appear that exposure to this microorganism is restricted to certain subpopulations of patients with sarcoidosis, and evidence for causality is currently lacking. Rickettsia helvetica recently emerged as another possible cause of sarcoidosis based upon postmortem evaluation of 2 Swedish patients with sarcoidosis. Both patients demonstrated the presence of Rickettsia DNA, and a retrospective analysis of archived biopsy material from 30 Swedish patients with sarcoidosis confirmed immunohistochemical evidence of Rickettsia-like organisms in 26 cases. 47 Although a follow-up study in a Scandinavian cohort, performed by Planck et al,48 revealed no serologic signs of rickettsial infection in 20 well-characterized patients with sarcoidosis, it is notable that tissue samples were not analyzed. It is possible that the conflicting results of these investigations are explained by diminished antibody response after the pathogen is effectively confined within granuloma. This interpretation is in keeping with the observation that certain M. tuberculosis antigens become undetectable in the context of latent infection.49
Cell wall-deficient bacteria To the extent that sarcoidosis represents a chronic infection, it is reasonable to speculate that antibiotics would be beneficial. Anecdotal reports of the benefits of tetracyclines for cutaneous sarcoidosis are noteworthy.40 Tetracyclines and related drugs, however, possess immunesuppressing qualities and could thereby influence disease.50 Alternatively, antibiotic treatment may facilitate the clearance of living organisms that are normally undetected by standard pathology and microbiology approaches. Schaumann51 first reported peculiar corpuscles in the tissues of patients with sarcoidosis in 1941. Immunohistochemical analyses performed by Ang and Moscovic52 and Alavi and Moscovic53 showed that Schaumann bodies express specific M. tuberculosis antigens, suggesting that these inclusions represent cellular breakdown products or perhaps intact cell wall–deficient (CWDF) microorganisms of mycobacterial derivation. The latter is supported by investigations by Johnson et al,54 who performed ultrastructural analyses of transbronchial biopsies obtained from a small cohort of patients with sarcoidosis (n = 9) revealing the presence of CWDF mycobacteria adjacent to granulomas, whereas no inclusions were seen in 4 control lungs, and by Almenoff et al,55 who documented the growth of CWDF bacteria under specialized blood culture conditions in most of the patients (95%) with sarcoidosis. No organisms were grown from the blood of 20 disease-free controls. A recent study, however, involving a large number of patients (197 sarcoidosis and 150 controls) from 10 institutions in the United States indicated no difference in the incidence of positive CWDF mycobacteria cultures in blood samples derived from patients with sarcoidosis. 56 Rather than
Considering an infectious etiology of sarcoidosis analyzing blood cultures, it may be more appropriate to use highly sensitive techniques (eg, PCR) to detect organisms in the affected tissues. Using this approach, el-Zaatari et al57 demonstrated contamination with atypical mycobacterium strains in 5 of 6 cultured isolates of skin from patients with sarcoidosis. At this time, a causal relationship between CWDF mycobacterium and sarcoidosis is not established, but further investigation appears to be warranted.
Viruses Various viral agents, including Epstein-Barr virus, herpes simplex virus, and human T-cell leukemia-lymphoma virus 1,58-60 have been reported in association with sarcoidosis. In most cases, viral exposure was indicated by serologic data, and tissue confirmation (eg, viral cultures, PCR) was lacking. Notable exceptions include the study by Di Alberti et al58 who found human herpes virus-8 DNA to be much more prevalent in various tissues derived from patients with sarcoidosis compared with controls (38/39 vs 6/113, P < .0001). Subsequent studies of similar design, but performed in different patient populations, failed to detect the presence of human herpes virus-8 in granulomatous tissues in patients with sarcoidosis.28,61,62 Despite these conflicting results, strong evidence supports the likelihood that enhanced immune responses attendant to active viral infections favor the development of sarcoidosis. It is well documented that sarcoidosis occurs in response to immune stimulation by interferon alfa, a potent stimulator of T-cell activity, particularly in the setting of chronic hepatitis C infection. 63,64 The unexpectedly high incidence of sarcoidosis in untreated patients with hepatitis C suggests that the granulomatous inflammatory response is specifically directed against the hepatitis C virus.65,66 Likewise, newly diagnosed sarcoidosis in conjunction with HIV infection and in the setting of HIV infection after treatment with highly active antiretroviral therapy incriminates HIV as another potential sarcoidosis-causing infection.67 The cumulative experience, thus, suggests that sarcoidosis may arise from any number of infectious agents, and the risk of developing the disease may depend on the prevalence of the diseasecausing antigen and the susceptibility of the host.
Host immunity and sarcoidosis risk A number of studies, including ACCESS,68 corroborate the observation that cigarette smoking actually reduces the risk of developing sarcoidosis but does not reduce the severity of disease.69 The lower prevalence of disease in smokers may relate to alteration of the immune response, as reflected by impaired cytokine and chemokine production by bronchial epithelial cells in response to infectious stimuli70 and impaired clearance of infection by the immune system.71 In this regard, nicotine is shown to suppress signal transducer
263 and activator of transcription 3 in macrophages, thereby attenuating tumor necrosis factor α production.72 Furthermore, cigarette smoking favors the release of cytokines favoring a TH-2 immune response (eg, interleukin 13),73 as opposed to the TH-1 immune response typical of sarcoidosis. These findings support the view that the host's immune status is a critical determinant of sarcoidosis.
The interface between genetics and infection: lessons learned from other granulomatous diseases Given a common environmental exposure, what factors determine who will develop sarcoidosis? Do genetic factors account for abnormal regulation of the immune response to specific infections leading to sustained granulomatous inflammation? Recent evidence from patients with idiopathic granulomatous diseases other than sarcoidosis provides insight into these questions. Blau syndrome and Crohn's disease are chronic granulomatous disorders that were, until recently, believed to be of autoimmune causes. Blau syndrome is characterized by granulomatous inflammation of the eyes (uveitis), skin, and joints, whereas Crohn's disease is a relapsing granulomatous disease involving the intestines and, in some cases, the eyes (uveitis), skin, and joints. Genetic linkage analyses of cohorts with Blau syndrome and Crohn's disease identified a common susceptibility locus at 16p12-q12.74 This locus harbors a gene that encodes a 1040-amino acid protein composed of 2 amino acid terminal recruitment domains (CARDs) linked to a nucleotide-binding domain and multiple leucine-rich repeats. CARD15, predominantly expressed in monocytes, is of particular interest because it is linked to granuloma formation. More focused analyses of the CARD15 gene have recently confirmed mutations of CARD15 in patients with Blau syndrome and Crohn's disease. Specifically, mutations of the nucleotide-binding domain are linked to Blau syndrome, and mutations of the leucine-rich repeat region are found in Crohn's disease.75 It is reasoned that mutation of the leucine-rich repeat region, which recognizes specific bacterial antigens (eg, muramyl dipeptide), explains why Crohn's disease primarily affects the intestines,76 whereas mutation of the nucleotide-binding domain region is associated with extraintestinal disease. Similar mutations within the 16p12-q21 locus, however, were not identified in a small cohort of African Americans with sarcoidosis.77 The authors of the latter study could not exclude a dominant gene with a relative risk of less than 5 or a recessive gene with a relative risk of less than 3 over the entire 16p12-q21 interval (P < .05), and this study does not exclude the possibility that CARD15 mutations are linked to sarcoidosis in other patient populations. In this context, Japanese patients possessing a mutation of the gene encoding CARD15 present with a precocious form of a disease resembling adult-onset sarcoidosis.78 Considered together, these findings imply
264 that functional abnormalities of intracellular antigen-sensing complexes, of which the NOD2/CARD15 complex is a component,79 support granuloma formation. Several mechanisms may contribute to granuloma formation in patients with functional alterations of the NOD2/CARD15 complex. Using Crohn's disease as an example, a sentinel study by Ogura et al80 provides convincing evidence that a loss-of-function mutation of the NOD2/CARD15 complex is associated with chronic granulomatous inflammation in the gut. Loss-of-function mutations of NOD2/CARD15 are also associated with delayed bacterial clearance, impaired activation of proinflammatory signal transduction pathways (eg, NF-κβ) in response to bacterial antigen,76 defective posttranscriptional release of interleukin 1β from macrophages,81 and activation of the immune system by way of other arms of the innate immune system, especially toll-like receptors.76 Furthermore, reduced activity of CARD15-dependent signaling pathways is shown to inhibit the secretion of antimicrobial substances (defensins)76,82 and thereby influences the effector-regulatory balance of macrophages such that antigenic exposure produces chronic inflammation.83 It is interesting to note that alveolar macrophages of patients with sarcoidosis are permissive to infection, and infection is associated with supernormal activation of NF-κβ–dependent signaling pathways, which promote the release of inflammatory cytokines.84 The mechanisms regulating excessive NF-κβ activation during sarcoidosis are unclear, but it is reasonable to speculate that a primary defect in the innate immune response and attendant impaired antigen clearance could be the cause.
Candidate sarcoidosis-causing genes and their relation to infection As discussed in detail by Culver et al in this issue of the Journal, HLA-DRB1, located on chromosome 6, has been identified as a consistent risk factor for sarcoidosis, especially in the African-American cohort, in which the populationattributable risk is 16%.85 Likewise, a genome screen performed in 63 German families performed by Schürmann et al86 identified linkage of sarcoidosis to a genetic locus in the short arm of chromosome 6 (6p21), which is the location of the HLA-DRB1 allele. A subsequent study carried out sequential SNP mapping of 6p21 in a German cohort, leading to the discovery of a gene mutation of the butyrophilin-like 2 (BTNL2) gene, which results in truncation and loss-offunction of the protein. Interestingly, structural modeling of BTNL2 reveals homology with B7 proteins, which normally down-regulate T-cell function. This would explain why the BTNL2 mutation contributes to sustained T-cell activation, particularly in response to mycobacterium exposure.87 As such, the BTNL2 mutation is expected to support a Th1 immune response, thereby promoting the granulomatous inflammatory response that is typical of sarcoidosis. Of note,
M.E. Ezzie, E.D. Crouser in the German cohort, the HLA-DRB1 allele was found to be linked to sarcoidosis, but only in the presence of the truncating BTNL2 allele, indicating that the BTNL2 is likely to be the sarcoidosis-causing gene, accounting for approximately 23% of the population-associated risk, whereas HLADRB1 may be a disease-modifying gene.87 Support for the latter is provided by another German study wherein a chronic sarcoidosis phenotype was observed to correlate with the presence of M. tuberculosis DNA fragments and HLADRB1*11 or -DRB1*15 alleles, whereas self-limited sarcoidosis was associated with no detectable M. tuberculosis DNA and the HLA-DRB1*03 allele,88 suggesting that genetic factors dictating altered presentation and clearance of infectious antigens have important implications for the disease phenotype. In summary, the existing evidence supports the potential for multiple infectious causes of a sarcoidosis, wherein the phenotype is determined by the infectious agent and the immune characteristics of the host. Advancing our understanding of the events transpiring at the interface between the host's immune system (eg, of genetic cause) and environment is likely to provide the keys to understanding the pathogenesis of sarcoidosis leading to the development of more effective therapies. It is interesting to speculate that treatment may become personalized according to specific sarcoidosis subtypes. In this context, variables pertaining to the genetic characteristics of the host and/or environmental exposures are likely to explain diversity between ethnic groups in terms of organ manifestations and disease severity.89 In the future, advances in our understanding of disease mechanisms and treatment are likely to arise from investigations designed to identify the sarcoidosis-causing genes associated with specific sarcoidosis phenotypes, and the implications of each genotype in terms of the immune response to environmental antigens.
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265 31. Richter E, Greinert U, Kirsten D, et al. Assessment of mycobacterial DNA in cells and tissues of mycobacterial and sarcoid lesions. Am J Respir Crit Care Med 1996;153:375-80. 32. Song Z, Marzilli L, Greenlee BM, et al. Mycobacterial catalaseperoxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med 2005;201:755-67. 33. Bergeron A, Laissy JP, Loiseau P, Schouman-Claeys E, Hance AJ, Tazi A. Computed tomography of pulmonary sarcoid-like granulomas induced by complete Freund's adjuvant in rats. Eur Respir J 2001;18: 357-61. 34. Hosoda Y, Sasagawa S, Yamaguchi T. Sarcoidosis and tuberculosis: epidemiological similarities and dissimilarities. A review of a series of studies in a Japanese work population (1941-1996) and the general population (1959-1984). Sarcoidosis Vasc Diffuse Lung Dis 2004;21: 85-93. 35. Yasahara T, Tada R, Nakano Y, et al. The presence of Propionibacterium spp. In the vitreous fluid of uveitis patients with sarcoidosis. Acta Ophthalmol Scand 2005;83:364-9. 36. Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol 2002;40:198-204. 37. Ebe Y, Ikushima S, Yamaguchi T, et al. Proliferative response of peripheral blood cells and levels of antibody to recombinant protein from Propionibacterium acnes DNA expression library in Japanese patients with sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2000;17: 256-65. 38. Ichiyasu H, Suga M, Matsukawa A, et al. Functional roles of MCP-1 in Propionibacterium acnes–induced, T cell-mediated pulmonary granulomatosis in rabbits. J Leukoc Biol 1999;65:482-91. 39. Nishiwaka T, Yoneyama H, Eishi Y, et al. Indigenous pulmonary Propionibacterium acnes primes the host in the development of sarcoid-like pulmonary granulomatosis in mice. Am J Pathol 2004; 165:631-9. 40. Bachelez H, Senet P, Cadranel J, Kaouhkov A, Dubertret L. The use of tetracyclines for the treatment of sarcoidosis. Arch Dermatol 2001;137: 69-73. 41. Hua B, Li QD, Wang FM, Ai CX, Luo WC. Borrelia burgdorferi infection may be the cause of sarcoidosis. Chin Med J (Engl) 1992;105: 560-3. 42. Lian W, Luo W. Borrelia burgdorferi DNA in biological samples from patients with sarcoidosis using the polymerase chain reaction technique. Chin Med Sci J 1995;10:93-5. 43. Ishihara M, Ohno S, Ono H, et al. Seroprevalence of anti-Borrelia antibodies among patients with confirmed sarcoidosis in a region of Japan where Lyme borreliosis is endemic. Graefes Arch Clin Exp Ophthalmol 1998;236:280-4. 44. Morris JT, Longfield RN. Sarcoidosis and ELISA for Borrelia burgdorferi. South Med J 1994;87:590-1. 45. Arcangeli G, Calabro S, Cisno F, Zambotto FM, Drigo R, Ferraresso A. Determination of antibodies to Borrelia burgdorferi in sarcoidosis. Sarcoidosis 1994;11:32-3. 46. Martens H, Zollner B, Zissel G, Burdon D, Schlaak M, MullerQuernheim J. Anti-Borrelia burgdorferi immunoglobulin seroprevalence in pulmonary sarcoidosis: a negative report. Eur Respir J 1997;10:1356-8. 47. Nilsson K, Pahlson C, Lukinius A, Eriksson L, Nilsson L, Lindquist O. Presence of Rickettsia helvetica in granulomatous tissue from patients with sarcoidosis. J Infect Dis 2002;185:1128-38. 48. Planck A, Eklund A, Grunewald J, Vene S. No serologic evidence of Rickettsia helvetica infection in Scandinavian sarcoidosis patients. Eur Respir J 2004;24:811-3. 49. Silva VM, Kanaujia G, Gennaro ML, Menzies D. Factors associated with humoral response to ESAT-6, 38 kDa and 14 kDa in patients with a spectrum of tuberculosis. Int J Tuberc Lung Dis 2003;7: 478-84. 50. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol 2006;54:258-65.
266 51. Schaumann J. On the nature of certain peculiar corpuscles present in tissue of lymphogranulomatosis benigna. Acta Med Scand 1941;106: 648-52. 52. Ang SC, Moscovic EA. Cross-reactive and species specific Mycobacterium tuberculosis antigens in the immunoprofile of Schaumann bodies: a major clue to the etiology of sarcoidosis. Histol Histopathol 1996;11:125-34. 53. Alavi HA, Moscovic EA. Immunolocalization of cell-wall–deficient forms of Mycobacterium tuberculosis complex in sarcoidosis and in sinus histiocytosis of lymph nodes draining carcinoma. Histol Histopathol 1996;11:683-94. 54. Johnson LA, Edsell JR, Austin JH, Ellis K. Pulmonary sarcoidosis: could mycoplasma-like organisms be a cause? Sarcoidosis Vasc Diffuse Lung Dis 1996;13:38-42. 55. Almenoff PL, Johnson A, Lesser M, Mattman LH. Growth of acid fast L forms from the blood of patients with sarcoidosis. Thorax 1996;51: 530-3. 56. Brown ST, Brett I, Almenoff PL, Lesser M, Terrin M, Teirstein AS, ACCESS Research Group. Recovery of cell wall-deficient organisms from blood does not distinguish patients with sarcoidosis and control subjects. Chest 2003;123:413-7. 57. el-Zaatari FA, Naser SA, Markesich DC, Kalter DC, Engstand L, Graham DY. Identification of Mycobacterium avium complex in sarcoidosis. J Clin Microbiol 1996;34:2240-5. 58. Di Alberti L, Piattelli A, Artese L, et al. Human herpesvirus 8 variants in sarcoid tissues. Lancet 1997;350:1655-61. 59. Bassoe CF, Hausken T, Bostad L, Kristofferson EK. Co-occurrence of Epstein-Barr virus and ascites in sarcoidosis. Scand J Infect Dis 2004;36:232-4. 60. McKee DH, Young AC, Haeney M. Sarcoidosis and HTLV-1 infection. J Clin Pathol 2005;58:996-7. 61. Knoell KA, Hendrix Jr JD, Stoler MH, Patterson JW, Montes CM. Absence of human herpesvirus 8 in sarcoidosis and Crohn disease granulomas. Arch Dermatol 2005;141:909-10. 62. Maeda H, Niimi T, Sato S, et al. Human herpesvirus 8 is not associated with sarcoidosis in Japanese patients. Chest 2000;118:923-7. 63. Bolukbas C, Bolukbas FF, Kebdir T, et al. Development of sarcoidosis during interferon alpha 2b and ribavirin combination therapy for chronic hepatitis C—a case report and review of the literature. Acta Gastreonterol Belg 2005;68:432-4. 64. Celik G, Sen E, Ulger AF, et al. Sarcoidosis caused by interferon therapy. Respirology 2005;10:535-40. 65. Ramos-Casals M, Mana J, Nardi N, et al, HISPAMEC Study Group. Sarcoidosis in patients with chronic hepatitis C virus infection: analysis of 68 cases. Medicine (Baltimore) 2005;84:69-80. 66. Tsimpoukas F, Goritsas C, Papadopoulos N, Trigidou R, Ferti A. Sarcoidosis in untreated chronic hepatitis C virus infection. Scand J Gastroenterol 2004;39:401-3. 67. Foulon G, Wislez M, Naccache JM, et al. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin Infect Dis 2004;38:418-25. 68. Newman LS, Rose CS, Bresnitz EA, et al, ACCESS Research Group. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med 2004;170:1324-30. 69. Valeyre D, Soler P, Clerici C, et al. Smoking and pulmonary sarcoidosis: effect of cigarette smoking on prevalence, clinical manifestations, alveolitis, and the evolution of disease. Thorax 1988;43:516-24. 70. Laan M, Bozinovski S, Anderson GP. Production of inflammatory cytokines by suppressing the activation of activator protein-1 in bronchial epithelial cells. J Immunol 2004;173:4164-70.
M.E. Ezzie, E.D. Crouser 71. Drannik AG, Pouladi MA, Robbins CS, Goncharova SI, Kianpour S, Stampfli MR. Impact of cigarette smoking on clearance and inflammation after Pseudomonas aeruginosa infection. Am J Respir Crit Care Med 2004;170:1164-71. 72. de Jonge WJ, van der Zanden EP, The FO, et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2STAT3 signaling pathway. Nat Immunol 2005;6:844-51. 73. Cozen W, Diaz-Sanchez D, Gauderman WJ, et al. Th1 and Th2 cytokines and IgE levels in identical twins with varying levels of cigarette consumption. J Clin Immunol 2004;24:617-22. 74. Tromp G, Kuivaniemi H, Raphael S, et al. Genetic linkage of familial granulomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16. Am J Hum Genet 1996;59:1097-107. 75. Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Gen 2001;29:19-20. 76. Kobayashi KS, Chamaillard M, Ogura Y, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005;307:731-4. 77. Rybicki BA, Maliarik MJ, Bock CH, et al. The Blau syndrome gene is not a major risk factor for sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:203-8. 78. Kanazawa N, Okafuji I, Kambe N, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kB activation: common genetic etiology with Blau syndrome. Blood 2005;105: 1195-7. 79. Martinon F, Tschopp J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 2004;117: 561-74. 80. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001;411: 603-6. 81. Li J, Moran T, Swanson E, et al. Regulation of IL-8 and IL-1beta expression in Crohn's disease associated NOD2/CARD15 mutations. Hum Mol Genet 2004;13:1715-25. 82. Aldhous MC, Nimmo ER, Satsangi J. NOD2/CARD15 and the Paneth cell: another piece in the genetic jigsaw of inflammatory bowel disease. Gut 2003;52:1533-5. 83. Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 2003;3:521-33. 84. Conron M, Bondeson J, Pantelidis P, et al. Alveolar macrophages and T cells from sarcoid, but not normal lung, are permissive to adenoviral infection and allow analysis of NF-kappa b-dependent signaling pathways. Antioxid Redox Signal 2001;25:141-9. 85. Rossman MD, Thompson B, Fredrick M, et al, ACCESS Group. HLA_DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. Am J Hum Genet 2003;73:720-35. 86. Schürmann M, Reichel P, Müller-Myhsok B, Schlaak M, MüllerQuernheim J, Schwinger E. Results from a genome-wide search for predisposing genes in sarcoidosis. Am J Respir Crit Care Med 2001;164: 840-6. 87. Valentonyte R, Hampe J, Huse K, et al. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet 2005; 37:357-64. 88. Grosser M, Luther T, Fuessel M, Bickardt J, Magdolen V, Baretton G. Clinical course of sarcoidosis in dependence on HLA-DRB1 allele frequencies, inflammatory markers, and the presence of M. tuberculosis DNA fragments. Sarcoidosis Vasc Diffuse Lung Dis 2005;22:66-74. 89. Baughman RP, Lower EE, du Bois RM. Sarcoidosis. Lancet 2003;361: 1111-8.
Considering an infectious etiology of sarcoidosis Michael E. Ezzie, MD, Elliott D. Crouser, MD* Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University Medical Center, Columbus, OH 43210-1252, USA
Abstract Sarcoidosis is a systemic granulomatous disease of unknown cause. An infectious etiology of sarcoidosis has long been suspected, but only recently has scientific evidence provided a strong link between infectious agents and sarcoidosis. Moreover, recent advances in our understanding of the relationships between sarcoidosis phenotype and host genetic factors may further illuminate the mechanisms linking infection and sarcoidosis. © 2007 Elsevier Inc. All rights reserved.
Introduction Despite decades of research and thousands of publications on the topic, the cause of sarcoidosis remains unknown. Our current level of understanding is accurately reflected by Newman et al1 who recently described sarcoidosis as “… an immune-mediated multiorgan disorder of unknown origin, characterized by the presence of noncaseating granulomata.” Clinicians and scientists have entertained a number of possible causes, including infectious agents, genetic mutations, and various environmental exposures, with inconclusive results. The notion of a single causative agent is not in keeping with the worldwide distribution of disease. On the other hand, if there are multiple causes, then the near uniform reaction of patients with sarcoidosis to a common antigenic challenge (ie, the Kveim-Siltzbaum reagent) is difficult to reconcile. Based upon the available evidence, it seems likely that multiple factors, including host genetics and environmental exposures, independently contribute to the pathogenesis of sarcoidosis (Fig. 1). In this review, we present selected
* Corresponding author. Tel.: +1 614 293 4925; fax: +1 614 293 4799. E-mail address: [email protected] (E.D. Crouser). 0738-081X/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2007.03.003
highlights of decades of research in search of infectious etiologies of sarcoidosis.
Antigenic determinants of granulomatous inflammation As elucidated by Noor and Knox in this issue of the journal, sarcoidosis and other granulomatous diseases are characterized by a classic antigenic TH-1 immune response. Table 1 represents a partial list of agents known to cause granulomatous skin lesions, and these must be considered before the diagnosis of sarcoidosis is established. The notion that sarcoidosis is caused by a specific antigenic exposure has been postulated for some time, and proposed sarcoidosis-inducing agents represent a spectrum of organic and inorganic exposures including pine trees, clay soil, zirconium, aluminum, and talc.2-6 With respect to the latter, cosmetics often contain talc and other inert submicroscopic substances that are linked to granulomatous reactions of the skin3 and lungs.4 Recent investigations report the presence of birefringent particles within granulomas of the skin and other affected organs in more than 20% of patients with sarcoidosis.5 Furthermore,
260 an analysis of more than 700 cases of sarcoidosis enrolled in A Case Control Etiologic Study of Sarcoidosis (ACCESS) revealed that exposures to inhaled organic or inorganic antigens predispose to disease confined to the lung.6 It follows that dissemination of antigens within the host, as might occur in the context of certain infections, would favor systemic disease manifestations. The relevance of environmental exposures to the development of sarcoidosis is further supported by strong associations between certain occupations and the risk of developing sarcoidosis. Among the US Navy enlisted men (1965-1993), the incidence of sarcoidosis was highest among aircraft carrier personnel, presumably because of common environmental exposures. 7 A dose-response correlation between exposure to burning wood (eg, woodburning stoves) and sarcoidosis,8 and the clustering of sarcoidosis among firefighters in relation to common smoke exposures,9 suggests that inhalation of particles present in smoke may promote sarcoidosis. Numerous anecdotal associations between occupation and sarcoidosis risk such as these have been reported, but objective evidence of increased sarcoidosis risk attendant to certain occupational exposures, including industrial organic dusts (eg, farming), was only recently confirmed by the ACCESS group.10 Indisputable support for a role of protein antigens in the development of granulomas in the context of sarcoidosis is provided by several lines of evidence. In 1941, the results of an experiment wherein heat-inactivated protein extracts derived from lymph nodes or spleens of patients with systemic sarcoidosis (Kveim reagent) were injected subcutaneously in patients with sarcoidosis or disease-free controls were reported. A local granulomatous response that was pathologically identical to sarcoidosis was observed after several weeks exclusively in the patients with sarcoidosis.11 This reaction, later referred to as the KveimSiltzbach test, emerged as a standardized test for the diagnosis of sarcoidosis.12 Subsequent attempts to characterize the Kveim antigen identified a protein or proteins sequestered in immune cells, but the specific identity of the proteins was not ascertained.13 In search of a possible infectious etiology of sarcoidosis, analysis of Kveim reagent by polymerase chain reaction (PCR) using universal primers detecting highly conserved sequences of bacterial ribosomal 16S RNA failed to detect bacterial contamination14; however, the presence of other bacterial elements (eg, proteins) or nonbacterial infectious agents were not considered in these analyses.
Evidence supporting an infectious cause of sarcoidosis Parkes et al15 were among the first to provide objective evidence for an infectious cause of sarcoidosis. A casecontrol analysis was applied to 96 cases of sarcoidosis diagnosed in the Isle of Man from 1962 to 1983. Sarcoidosis
M.E. Ezzie, E.D. Crouser
Fig. 1 Proposed relationships between environmental exposures and sarcoidosis phenotype. The cumulative evidence supports the view that multiple environmental exposures, including antigens derived from infectious and noninfectious sources, are capable of inducing sarcoidosis in predisposed individuals. Host-related variables, including drugs (eg, nicotine, interferon alfa), genetics, and perhaps other unidentified factors, are proposed to strongly influence the disease phenotype.
was observed to affect the sexes equally and occurred in 38 cases (39.6%) who had been in contact with the disease before diagnosis, compared with 2 (1.2%) of the combined control groups, which were made up of age- and sexmatched disease-free individuals and members of the local tuberculosis registry. The sarcoidosis contacts included members of the same household, colleagues at work, and close friends. The authors noted that a bias may have been introduced because diseased patients would inevitably be more aware of the disease in others and would be more likely to mention previous contact than the controls. Further analysis of the data using the case-control test for spacetime clustering developed by Smith and Pike16 identified significantly more links between cases separated by time intervals of less than 10 years and distances of less than 100 m and localizing to clusters whose contact was by place of residence or work. More linked cases were diagnosed less than 3 years apart than would be expected by chance. This evidence has long been considered to support the view that sarcoidosis is a communicable disease.17 Apparent transmission of sarcoidosis from organ donors to recipients further supports a potential infectious cause. In one case, the recipient of an allogeneic bone marrow transplant developed sarcoidosis within 3 months of the procedure. Notably, pulmonary sarcoidosis had been diagnosed in the bone marrow donor 2 years before.18 Other cases of donor-to-recipient transmission of sarcoidosis,19 as well as transmission from recipient to donated organ,20 have been reported, but the transmittable agent was not identified in any of these case reports.
Considering an infectious etiology of sarcoidosis Table 1
Causes of granulomatous inflammation of the skin
Clinical variants
Characterization
Infectious
Mycobacteria Tuberculosis Atypical mycobacteria Syphilis (secondary or tertiary) Cat-scratch disease (Bartonella henselae) Pseudomycoses Actinomycoses Nocardiosis Botryomycosis Invasive fungal infections Histoplasmosis Spirotrichosis Aspergillosis Leishmaniasis (Leishmania species) Demodicidosis (Demodex species) Herpes simplex virus Chancre (Haemophilus ducreyi) Scabies (Sarcoptes scabei) Donovanosis (Calymmatobacterium granulomatis) Granulomatous rosacea Sarcoidosis Crohn's disease Granuloma annulare and actinic granuloma Granulomatous cheilitis Necrobiosis lipoidica Necrobiotic xanthogranuloma Granulomatous vasculitis Wegener's vasculitis Churg-Strauss disease Foreign body granuloma
Inflammatory, unknown cause
Inflammatory, identifiable etiology Neoplastic
Nongranulomatous diseases misnamed as granuloma
Granulomatous mycosis fungoides Lymphomas with histiocytic infiltration (Lennert's disease) Granuloma faciale Lymphomatoid granulomatosis Lethal midline granuloma
This table is a reproduction, with slight modification, of data available at the following internet Web site: http://www.thedoctorsdoctor.com/ diseases/skin_granuloma.htm#ddx.
The observed seasonality of sarcoidosis is often cited as evidence for an infectious cause. The incidence of sarcoidosis is noted to peak during springtime, a pattern that is conserved in geographically and ethnically isolated countries.21,22 It is interesting to note that many of the cases diagnosed during the springtime were characterized by acute onset, the presence of erythema nodosum, and a favorable outcome.23,24 It is interesting to speculate that a specific
261 infection or class of infectious agents is responsible for this specific sarcoidosis phenotype. The following section considers specific infectious agents that are suggested to be causally linked to sarcoidosis.
Mycobacteria Various mycobacterial infections can present with skin lesions that are clinically and pathologically indistinguishable from those caused by sarcoidosis.25-27 In this context, PCR analysis of tissues obtained from patients with sarcoidosis of Mediterranean descent revealed the presence of DNA specific to Mycobacterium species at a much higher rate than in tuberculosis-negative controls.28,29 Similarly, 60% of diseased lung and lymph node tissues from patients with sarcoidosis recruited from southeastern United States were noted to contain mycobacterial DNA, most of which were classified as Mycobacterium tuberculosis.30 In contrast, mycobacterium DNA was not found in either bronchoalveolar fluid or tissues of Germans with sarcoidosis, leading the investigators to conclude that “granulomatous lesions in sarcoidosis may not be due to mycobacterial infections.”31 Exciting new evidence explains why highly sensitive molecular techniques (eg, PCR) often fail to identify the genetic fingerprint of infectious agents in tissues of patients with sarcoidosis or in the Kveim reagent. Using selective proteomic analysis of poorly soluble protein aggregates derived from affected tissues, Moller et al identified M. tuberculosis catalase-peroxidase (mKatG) in most sarcoidosis cases and in none of the tissues from disease-free controls. Nearly one half of the sarcoidosis cases, moreover, had circulating IgG antibodies to recombinant mKatG, compared with none of the purified protein derivative negative controls.32 Considering that subcutaneous injection of the Kveim reagent, a proteinaceous derivative of sarcoidosis tissues, elicits a delayed local granulomatous response in patients with sarcoidosis, and systemic injection of complete Freund's adjuvant (containing mycobacterial antigens) produces pulmonary manifestations that closely resembles human sarcoidosis,33 it is apparent that nonviable components of M. tuberculosis are capable of inducing a sarcoidosis-like response. This evidence, however, fails to fulfill Koch's postulates, which are a series of conditions that must be met to establish a microorganism as the causative agent of disease. Namely, the organism must be detected in all cases of the disease; inoculations of organisms cultured from diseased humans must produce disease in susceptible animals; and from these animals, the organism must be isolated and grown in culture. Disease caused by nonviable components of microorganisms, thus, cannot be classified as an infectious disease. Nonetheless, the findings of mycobacterial proteins in the affected tissues, in conjunction with a specific antibody response to these proteins in affected individuals, provide strong evidence that at least some cases of sarcoidosis are caused by a sustained immunologic reaction to retained infectious antigens.
262
Propionibacteria Based on association studies, exposures other than Mycobacterium species are incriminated as potential sarcoidosis-causing infections. Dissimilarities between the distribution of tuberculosis and sarcoidosis in Japanese populations argue against a tuberculosis etiology in this population.34 In a small Japanese cohort, Propionibacterium DNA, and not M. tuberculosis, was detected in the vitreous fluid of the eyes of patients with sarcoidosis with uveitis and in none of the disease-free controls.35 Likewise, a multicenter study of lymph node samples from controls and patients with sarcoid found either Propionibacterium acnes or Propionibacterium granulosum DNA by PCR analysis in 106 of 108 lymph nodes from patients with sarcoidosis. A significant number of controls, however, also harbored propionibacteria DNA, but in lower copy numbers.36 The observation by Ebe et al37 that Propionibacterium promotes a brisk cellular immune response in patients with sarcoidosis supports a causal link between Propionibacterium and sarcoidosis in the Japanese population. From analyses of skin lesions, however, it is apparent that Propionibacterium plays a lesser role in the Greek population wherein Mycobacterium species prevails.28 Animal studies provide the most convincing evidence of a causal link between Propionibacterium and sarcoidosis. When injected into rats and rabbits, P. acnes causes a local granulomatous reaction.38 Remarkably, extrapulmonary sensitization of mice to heat-killed P. acnes (2-week intervals) induced pulmonary TH-1 granulomatous inflammation predominantly in the subpleural and peribronchovascular regions, as is often observed in sarcoidosis. The authors of this study proposed that granulomas formed in response to indigenous P. acnes colonizing the lungs, which is supported by alleviation of granulomatous lung disease after eradication of P. acnes using antibiotics (minocycline).39 In this context, it is interesting to note that resolution of cutaneous sarcoidosis has been reported after treatment with minocycline.40 Future studies are needed to determine if this ubiquitous organism, found on the skin of healthy individuals, could be an etiologic agent of human sarcoidosis.
Other bacteria Based upon similarities in the clinical presentation of Lyme disease and sarcoidosis, a number of clinical investigators have hypothesized that Borrelia burgdorferi is a sarcoidosis-causing agent. This notion is apparently supported by the finding of elevated levels of circulating antibodies against B. burgdorferi in a cohort of Chinese patients with sarcoidosis.41 Only 8% to 15% of the patients with high antibody titers, however, had detectable B. burgdorferi DNA in the affected tissues.42 An increased seroprevalence of B. burgdorferi was also found in one Japanese study (32.6% sarcoidosis vs 4% controls),43 whereas other studies found no
M.E. Ezzie, E.D. Crouser association between B. burgdorferi and sarcoidosis in other ethnic groups.44-46 Considered together, it would appear that exposure to this microorganism is restricted to certain subpopulations of patients with sarcoidosis, and evidence for causality is currently lacking. Rickettsia helvetica recently emerged as another possible cause of sarcoidosis based upon postmortem evaluation of 2 Swedish patients with sarcoidosis. Both patients demonstrated the presence of Rickettsia DNA, and a retrospective analysis of archived biopsy material from 30 Swedish patients with sarcoidosis confirmed immunohistochemical evidence of Rickettsia-like organisms in 26 cases. 47 Although a follow-up study in a Scandinavian cohort, performed by Planck et al,48 revealed no serologic signs of rickettsial infection in 20 well-characterized patients with sarcoidosis, it is notable that tissue samples were not analyzed. It is possible that the conflicting results of these investigations are explained by diminished antibody response after the pathogen is effectively confined within granuloma. This interpretation is in keeping with the observation that certain M. tuberculosis antigens become undetectable in the context of latent infection.49
Cell wall-deficient bacteria To the extent that sarcoidosis represents a chronic infection, it is reasonable to speculate that antibiotics would be beneficial. Anecdotal reports of the benefits of tetracyclines for cutaneous sarcoidosis are noteworthy.40 Tetracyclines and related drugs, however, possess immunesuppressing qualities and could thereby influence disease.50 Alternatively, antibiotic treatment may facilitate the clearance of living organisms that are normally undetected by standard pathology and microbiology approaches. Schaumann51 first reported peculiar corpuscles in the tissues of patients with sarcoidosis in 1941. Immunohistochemical analyses performed by Ang and Moscovic52 and Alavi and Moscovic53 showed that Schaumann bodies express specific M. tuberculosis antigens, suggesting that these inclusions represent cellular breakdown products or perhaps intact cell wall–deficient (CWDF) microorganisms of mycobacterial derivation. The latter is supported by investigations by Johnson et al,54 who performed ultrastructural analyses of transbronchial biopsies obtained from a small cohort of patients with sarcoidosis (n = 9) revealing the presence of CWDF mycobacteria adjacent to granulomas, whereas no inclusions were seen in 4 control lungs, and by Almenoff et al,55 who documented the growth of CWDF bacteria under specialized blood culture conditions in most of the patients (95%) with sarcoidosis. No organisms were grown from the blood of 20 disease-free controls. A recent study, however, involving a large number of patients (197 sarcoidosis and 150 controls) from 10 institutions in the United States indicated no difference in the incidence of positive CWDF mycobacteria cultures in blood samples derived from patients with sarcoidosis. 56 Rather than
Considering an infectious etiology of sarcoidosis analyzing blood cultures, it may be more appropriate to use highly sensitive techniques (eg, PCR) to detect organisms in the affected tissues. Using this approach, el-Zaatari et al57 demonstrated contamination with atypical mycobacterium strains in 5 of 6 cultured isolates of skin from patients with sarcoidosis. At this time, a causal relationship between CWDF mycobacterium and sarcoidosis is not established, but further investigation appears to be warranted.
Viruses Various viral agents, including Epstein-Barr virus, herpes simplex virus, and human T-cell leukemia-lymphoma virus 1,58-60 have been reported in association with sarcoidosis. In most cases, viral exposure was indicated by serologic data, and tissue confirmation (eg, viral cultures, PCR) was lacking. Notable exceptions include the study by Di Alberti et al58 who found human herpes virus-8 DNA to be much more prevalent in various tissues derived from patients with sarcoidosis compared with controls (38/39 vs 6/113, P < .0001). Subsequent studies of similar design, but performed in different patient populations, failed to detect the presence of human herpes virus-8 in granulomatous tissues in patients with sarcoidosis.28,61,62 Despite these conflicting results, strong evidence supports the likelihood that enhanced immune responses attendant to active viral infections favor the development of sarcoidosis. It is well documented that sarcoidosis occurs in response to immune stimulation by interferon alfa, a potent stimulator of T-cell activity, particularly in the setting of chronic hepatitis C infection. 63,64 The unexpectedly high incidence of sarcoidosis in untreated patients with hepatitis C suggests that the granulomatous inflammatory response is specifically directed against the hepatitis C virus.65,66 Likewise, newly diagnosed sarcoidosis in conjunction with HIV infection and in the setting of HIV infection after treatment with highly active antiretroviral therapy incriminates HIV as another potential sarcoidosis-causing infection.67 The cumulative experience, thus, suggests that sarcoidosis may arise from any number of infectious agents, and the risk of developing the disease may depend on the prevalence of the diseasecausing antigen and the susceptibility of the host.
Host immunity and sarcoidosis risk A number of studies, including ACCESS,68 corroborate the observation that cigarette smoking actually reduces the risk of developing sarcoidosis but does not reduce the severity of disease.69 The lower prevalence of disease in smokers may relate to alteration of the immune response, as reflected by impaired cytokine and chemokine production by bronchial epithelial cells in response to infectious stimuli70 and impaired clearance of infection by the immune system.71 In this regard, nicotine is shown to suppress signal transducer
263 and activator of transcription 3 in macrophages, thereby attenuating tumor necrosis factor α production.72 Furthermore, cigarette smoking favors the release of cytokines favoring a TH-2 immune response (eg, interleukin 13),73 as opposed to the TH-1 immune response typical of sarcoidosis. These findings support the view that the host's immune status is a critical determinant of sarcoidosis.
The interface between genetics and infection: lessons learned from other granulomatous diseases Given a common environmental exposure, what factors determine who will develop sarcoidosis? Do genetic factors account for abnormal regulation of the immune response to specific infections leading to sustained granulomatous inflammation? Recent evidence from patients with idiopathic granulomatous diseases other than sarcoidosis provides insight into these questions. Blau syndrome and Crohn's disease are chronic granulomatous disorders that were, until recently, believed to be of autoimmune causes. Blau syndrome is characterized by granulomatous inflammation of the eyes (uveitis), skin, and joints, whereas Crohn's disease is a relapsing granulomatous disease involving the intestines and, in some cases, the eyes (uveitis), skin, and joints. Genetic linkage analyses of cohorts with Blau syndrome and Crohn's disease identified a common susceptibility locus at 16p12-q12.74 This locus harbors a gene that encodes a 1040-amino acid protein composed of 2 amino acid terminal recruitment domains (CARDs) linked to a nucleotide-binding domain and multiple leucine-rich repeats. CARD15, predominantly expressed in monocytes, is of particular interest because it is linked to granuloma formation. More focused analyses of the CARD15 gene have recently confirmed mutations of CARD15 in patients with Blau syndrome and Crohn's disease. Specifically, mutations of the nucleotide-binding domain are linked to Blau syndrome, and mutations of the leucine-rich repeat region are found in Crohn's disease.75 It is reasoned that mutation of the leucine-rich repeat region, which recognizes specific bacterial antigens (eg, muramyl dipeptide), explains why Crohn's disease primarily affects the intestines,76 whereas mutation of the nucleotide-binding domain region is associated with extraintestinal disease. Similar mutations within the 16p12-q21 locus, however, were not identified in a small cohort of African Americans with sarcoidosis.77 The authors of the latter study could not exclude a dominant gene with a relative risk of less than 5 or a recessive gene with a relative risk of less than 3 over the entire 16p12-q21 interval (P < .05), and this study does not exclude the possibility that CARD15 mutations are linked to sarcoidosis in other patient populations. In this context, Japanese patients possessing a mutation of the gene encoding CARD15 present with a precocious form of a disease resembling adult-onset sarcoidosis.78 Considered together, these findings imply
264 that functional abnormalities of intracellular antigen-sensing complexes, of which the NOD2/CARD15 complex is a component,79 support granuloma formation. Several mechanisms may contribute to granuloma formation in patients with functional alterations of the NOD2/CARD15 complex. Using Crohn's disease as an example, a sentinel study by Ogura et al80 provides convincing evidence that a loss-of-function mutation of the NOD2/CARD15 complex is associated with chronic granulomatous inflammation in the gut. Loss-of-function mutations of NOD2/CARD15 are also associated with delayed bacterial clearance, impaired activation of proinflammatory signal transduction pathways (eg, NF-κβ) in response to bacterial antigen,76 defective posttranscriptional release of interleukin 1β from macrophages,81 and activation of the immune system by way of other arms of the innate immune system, especially toll-like receptors.76 Furthermore, reduced activity of CARD15-dependent signaling pathways is shown to inhibit the secretion of antimicrobial substances (defensins)76,82 and thereby influences the effector-regulatory balance of macrophages such that antigenic exposure produces chronic inflammation.83 It is interesting to note that alveolar macrophages of patients with sarcoidosis are permissive to infection, and infection is associated with supernormal activation of NF-κβ–dependent signaling pathways, which promote the release of inflammatory cytokines.84 The mechanisms regulating excessive NF-κβ activation during sarcoidosis are unclear, but it is reasonable to speculate that a primary defect in the innate immune response and attendant impaired antigen clearance could be the cause.
Candidate sarcoidosis-causing genes and their relation to infection As discussed in detail by Culver et al in this issue of the Journal, HLA-DRB1, located on chromosome 6, has been identified as a consistent risk factor for sarcoidosis, especially in the African-American cohort, in which the populationattributable risk is 16%.85 Likewise, a genome screen performed in 63 German families performed by Schürmann et al86 identified linkage of sarcoidosis to a genetic locus in the short arm of chromosome 6 (6p21), which is the location of the HLA-DRB1 allele. A subsequent study carried out sequential SNP mapping of 6p21 in a German cohort, leading to the discovery of a gene mutation of the butyrophilin-like 2 (BTNL2) gene, which results in truncation and loss-offunction of the protein. Interestingly, structural modeling of BTNL2 reveals homology with B7 proteins, which normally down-regulate T-cell function. This would explain why the BTNL2 mutation contributes to sustained T-cell activation, particularly in response to mycobacterium exposure.87 As such, the BTNL2 mutation is expected to support a Th1 immune response, thereby promoting the granulomatous inflammatory response that is typical of sarcoidosis. Of note,
M.E. Ezzie, E.D. Crouser in the German cohort, the HLA-DRB1 allele was found to be linked to sarcoidosis, but only in the presence of the truncating BTNL2 allele, indicating that the BTNL2 is likely to be the sarcoidosis-causing gene, accounting for approximately 23% of the population-associated risk, whereas HLADRB1 may be a disease-modifying gene.87 Support for the latter is provided by another German study wherein a chronic sarcoidosis phenotype was observed to correlate with the presence of M. tuberculosis DNA fragments and HLADRB1*11 or -DRB1*15 alleles, whereas self-limited sarcoidosis was associated with no detectable M. tuberculosis DNA and the HLA-DRB1*03 allele,88 suggesting that genetic factors dictating altered presentation and clearance of infectious antigens have important implications for the disease phenotype. In summary, the existing evidence supports the potential for multiple infectious causes of a sarcoidosis, wherein the phenotype is determined by the infectious agent and the immune characteristics of the host. Advancing our understanding of the events transpiring at the interface between the host's immune system (eg, of genetic cause) and environment is likely to provide the keys to understanding the pathogenesis of sarcoidosis leading to the development of more effective therapies. It is interesting to speculate that treatment may become personalized according to specific sarcoidosis subtypes. In this context, variables pertaining to the genetic characteristics of the host and/or environmental exposures are likely to explain diversity between ethnic groups in terms of organ manifestations and disease severity.89 In the future, advances in our understanding of disease mechanisms and treatment are likely to arise from investigations designed to identify the sarcoidosis-causing genes associated with specific sarcoidosis phenotypes, and the implications of each genotype in terms of the immune response to environmental antigens.
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