285

Etiologic Role of Infectious Agents David R. Moller, MD1

1 Division of Pulmonary and Critical Care Medicine, Department of

Medicine, The Johns Hopkins University, Baltimore, Maryland Semin Respir Crit Care Med 2014;35:285–295.

Abstract

Keywords

► ► ► ► ►

sarcoidosis Th1 immunity mycobacteria Propionibacteria serum amyloid A

Address for correspondence David R. Moller, MD, Division of Pulmonary and Critical Care Medicine, Department of Medicine, The Johns Hopkins University, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (e-mail: [email protected]).

A consensus statement found in most peer-reviewed literature on sarcoidosis is that the etiology of sarcoidosis is unknown. It is timely to review whether this statement should be revised. Many infectious agents meet the basic requirements of inducing granulomatous inflammation and immunologic responses consistent with sarcoidosis including oligoclonal expansion of CD4þ T cells, polarized Th1 and possibly Th17 responses, and dysregulated regulatory T-cell function. Studies over the past decade provide increasing and complementary data to implicate a role for infectious agents in sarcoidosis etiology. These studies used different methodologies such as polymerase chain reaction and mass spectrometry to document microbial nucleic acids and proteins in sarcoidosis tissues. Multiple studies report antigen-specific immune responses to specific microbial proteins in sarcoidosis. In aggregate, these studies provide compelling evidence that mycobacteria play a major etiologic role in sarcoidosis in the United States and Europe. Studies from Japan support a role for Propionibacteria as a major etiologic agent in the country. There is controversy over how these (or other) infectious agents cause sarcoidosis. The hypothesis that chronic sarcoidosis is caused by a viable, replicating mycobacterial or other infection has no direct pathologic, microbiologic, or clinical evidence. A novel hypothesis links microbial triggers to a sarcoidosis outcome from the accumulation of aggregated proinflammatory serum amyloid A within granulomas, providing a mechanism for chronic disease in the absence of any viable tissue infection. Further studies are needed to provide more definitive evidence for these competing hypotheses before the statement that the etiology of sarcoidosis is unknown becomes obsolete.

Sarcoidosis is a multisystem inflammatory disorder associated with noncaseating granulomatous inflammation at the sites of disease.1 Sarcoidosis can involve nearly any part of the body with the most frequently involved organs other than lymph nodes involving the lung, skin, and eyes that are exposed to the outside environment. There is great heterogeneity in the clinical manifestations and outcomes in sarcoidosis. Almost all sarcoidosis is defined by a mutually exclusive outcome of either remission of the inflammation, usually occurring within the first 2 to 3 years, or chronic, unremitting inflammation that is typically lifelong in its duration. One challenge for the medical community is to understand the pathways leading to these separate outcomes.

Issue Theme Sarcoidosis; Guest Editors, Joachim Müller-Quernheim, MD, David R. Moller, MD, and Antje Prasse, MD

A consensus statement found in the most peer-reviewed literature on sarcoidosis is that the etiology of sarcoidosis is unknown.1 This conclusion is aided by conflicting concepts regarding the actual definition and classification of sarcoidosis. For example, a definition of sarcoidosis that excludes isolated organ involvement, particularly of the lung or skin, because of the uncertainty of excluding local granulomatous reactions from inorganic dusts or particles, will narrow the scope of potential causes by excluding agents such as beryllium, zirconium, or, possibly, many cases linked to World Trade Center dust exposure.2,3 Since the initial descriptions of sarcoidosis, an infectious cause for this disease has been postulated based on the

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DOI http://dx.doi.org/ 10.1055/s-0034-1376859. ISSN 1069-3424.

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Edward S. Chen, MD1

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clinical and histological overlap between sarcoidosis and infectious granulomatous diseases such as tuberculosis and leprosy. An infectious etiology of sarcoidosis can readily explain multisystem involvement, but the challenge is to understand the mechanisms by which any hypothesized infectious agent causes chronic, progressive disease. In this article, we report on recent research studies that provide increasing, even compelling, evidence that implicates a microbial etiology for much of sarcoidosis. We discuss controversial and opposing concepts that the link between a microbial etiology and chronic disease pathogenesis involves a chronic, viable, and replicating microbial infection4,5 versus the recently proposed concept by the authors that the link between candidate microbial triggers and chronic disease results from the local accumulation of aggregates of the host protein, serum amyloid A (SAA), that follows successful immune control of an infectious agent.6,7 This latter hypothesis not only explains cardinal clinical features of sarcoidosis but is also consistent with the lack of evidence that an active replicating infection exists in chronic sarcoidosis patients, many of whom are treated for years with potent immunosuppressive therapies.

Basic Requirements Any etiological agent of sarcoidosis must be capable of inducing epithelioid granulomas and the associated immunological dysregulation found at the sites of disease.8 Granulomas are presumed to form around a nidus of poorly soluble material through the spatial assembly of mononuclear phagocytes, lymphocytes, epithelioid cells, fibroblasts and occasional B cells, NK cells, and other matrix-associated cells. The initial responding cells are expected to be innate phagocytic cells that express pattern recognition receptors such as the Toll-like receptors (TLR).9 These cells attempt to engulf or surround the inciting pathogen and release cytokines such as tumor necrosis factor (TNF) and other cytokines and chemokines that facilitate cell recruitment for granuloma formation. With phagocytosis of the pathogen or its components, pathogen-derived proteins prime the adaptive immune system when these foreign antigens are displayed on the surface of MHC class I or II molecules. The adaptive immune response associated with granulomatous inflammation is usually associated with an effector T-cell response dominated by a Thelper (Th)-1 (as seen in tuberculosis), Th2 (as seen in schistosomiasis), or Th17 profile (as seen in hypersensitivity pneumonitis).10–12 These T-cell–mediated responses result in different histopathologic patterns depending on the complex set of pro- and anti-inflammatory cytokines released by innate and adaptive immune cells. In sarcoidosis, studies from the past two decades provide evidence that sarcoidosis is associated with highly polarized Th1 immunity at the sites of disease, with increased expression of interferon-gamma (IFNγ) and the Th1-promoting immunoregulatory cytokines interleukin (IL)-12 and IL18.13–16 Experimental models demonstrate that TNF, IL6, and other proinflammatory cytokines play an important role in granuloma formation, but these mediators are not specific Seminars in Respiratory and Critical Care Medicine

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for Th1-dominant granulomatous processes and also assist granuloma formation dominated by Th2 or Th17 immune responses.14 There are conflicting reports regarding the role of Th17 responses in sarcoidosis and it remains uncertain whether Th17 responses are necessary to orchestrate granulomatous inflammation or play a supportive role in promoting remission or chronicity or other disease phenotype in sarcoidosis.17–21 Further studies are needed to clarify the role of Th17 responses and any link to specific etiologic agents. Another requirement for any proposed etiological trigger of sarcoidosis is that such an agent induces oligoclonal expansion of CD4þ (and occasionally CD8þ) T cells at the sites of inflammation.22 This requirement was first demonstrated by the finding that T cells at the sites of inflammation have a biased and restricted repertoire of T-cell receptor (TCR) gene expression consistent with an oligoclonal expansion of specific αβ-positive T cells in response to conventional antigens.23–25 The most striking example of this biased TCR gene expression is the increased frequency of the AV2S3þ (Vα2.3) lung T cells from Scandinavian patients with pulmonary sarcoidosis who express MHC class II HLA-DRB10301 alleles.25,26 There is increasing evidence for abnormal regulatory T-cell responses in sarcoidosis. For example, several studies suggest that persistent inflammation in sarcoidosis results from inadequate regulatory T cell (Treg) function that is incapable of suppressing TNF or IFNγ.27–29 These studies support the development of novel treatment strategies based on restoring or augmenting local Treg function as recently suggested by investigators using vasoactive intestinal peptide to regulate lung inflammation.30 Although the exact pathways that govern dysregulated Treg responses are still unclear, any etiologic agent of sarcoidosis should be capable of inducing or interacting with effector host immune responses to regulate the phenotypic variants of multisystem granulomatous inflammation in sarcoidosis. Many studies of sarcoidosis have focused on specific innate receptors that have been implicated in pathways involving host defense to infectious agents. Recent studies demonstrate enhanced responses to TLR2 stimulation, including enhanced induction of TNF, in cells from the blood and lung of sarcoidosis patients.6,31,32 For example, a recent study examined the role of different TLR2 receptors because TLR2 interacts with innate ligands as a heterodimer with other TLR subunits; this study found that sarcoidosis bronchoalveolar lavage (BAL) cells showed differential responsiveness, with increased production of TNF and IL6 in response to ligands for the TLR2/1 heterodimer and reduced responses to TLR2/6 ligands.32 A role for TLR2 in sarcoidosis is further supported by animal models where experimental granulomatous inflammation is attenuated in the absence of functional TLR2.6,32 Although these enhanced or reduced responses are not clearly linked to specific polymorphisms of the TLR2 gene,33,34 a recent candidate gene association study links risk for developing sarcoidosis with polymorphisms in the downstream MyD88 adaptor protein.35 Another report found enhanced expression of TNF and IL12/IL23p40 in response to stimulation of the nucleotide-binding oligomerization domain 1 (NOD1) receptor in a subset of sarcoidosis patients, suggesting that

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An infectious etiology of sarcoidosis is supported indirectly by epidemiologic studies. A seasonal peak incidence of sarcoidosis occurring in the spring months in both the Northern and Southern hemispheres supports an environmental cause of sarcoidosis, potentially of microbial origin.42 There are also reports of clustering of cases of sarcoidosis in geographic regions such as the Isle of Mann, Sweden, and Japan that suggest an environmental, possible infectious cause.43,44 Although many incidental cases of sarcoidosis were discovered through mass screening efforts for tuberculosis, epidemiological studies did not established links between prior exposure to tuberculosis and BCG vaccination with the risk of developing sarcoidosis.45 These studies do not address the possibility that nontuberculous mycobacteria may play an important role in sarcoidosis.

intradermal inoculation of a suspension of sarcoidosis spleen or lymph node homogenate in patients with sarcoidosis.47–49 Granulomatous inflammation develops at a Kveim reaction site 4 to 6 weeks after injection, a time course similar to the development of granulomas in the Mitsuda reaction to lepromins in patients with tuberculous leprosy.50 Louis Siltzbach and other investigators from around the world demonstrated that a single, validated reagent was positive in up to 80% of sarcoidosis patients and was highly specific with < 1% false positives, findings that have been confirmed by recent studies.51,52 The Kveim reaction site demonstrates granulomas indistinguishable from diseased tissues. The site is characterized by CD4þ T-cell infiltration.53 By analogy with infectious granulomatous disorders such as leprosy, the Kveim reagent is thought to contain antigens, possibly from an infectious agent, that induce an immune-mediated granulomatous response. Consistent with this hypothesis, our group reported the preferential expression of select TCR Vβ genes at Kveim– Siltzbach reaction sites, indicative of a conventional antigenspecific response.24 Biochemical characteristics of the Kveim reagent include the properties that the granuloma-inducing component with the extract is resistant to neutral detergents, with relative heat, acid, and protease resistance, but loses its potency when treated with potent denaturants.49,54 We exploited these properties to identify pathogenic antigens in sarcoidosis tissues using a novel limited proteomic approach with mass spectrometry.55 These studies led to the identification of a candidate pathogenic tissue antigen, mycobacterial catalaseperoxidase (mKatG), thus directly implicating a mycobacterial etiology for sarcoidosis in the United States.

ACCESS Study

Candidate Infectious Agents

The multicenter, U.S.-based ACCESS (A Case Control Etiologic Study of Sarcoidosis) study was designed to detect environmental, occupational, and other demographic factors associated with an increase or decrease in the risk of developing sarcoidosis.46 The study enrolled more than 700 biopsyproven sarcoidosis cases with age, sex, race, and geographically matched control subjects who were identified through random-digit dialing selection. The prestudy goal was to identify risk factors with greater than a twofold risk (odds ratio) when > 5% of subjects were exposed. The study failed to identify any such exposures that met these criteria. The ACCESS study identified occupational exposure to insecticides, pesticides, and mold/mildew to be associated with a modest 1.5-fold increase risk of sarcoidosis.46 The authors speculated that these associations that reflected exposure to microbialrich environments were not directly linked to sarcoidosis causation. However, the study was not designed to directly explore a role for infectious agents in sarcoidosis etiology.

Most studies of infectious agents involved in sarcoidosis etiology have been based on hypothesis-driven research focused on individual microbial species (►Table 1). The longest held hypothesis links mycobacterial infection with sarcoidosis given their clinical and histologic similarities. Scattered reports of acid-fast organisms in sarcoidosis tissues were later published, but the lack of wider confirmation of these reports in clinical practice and the lack of direct histologic or culture evidence of mycobacteria in sarcoidosis tissues led researchers to explore other infectious etiologies.

microbial products might also interact with immune responses through these innate pattern recognition receptors.36 Of interest, mutations in the NOD2 gene are strongly associated with a clinical triad of joint, eye, and skin involvement observed in a subset of pediatric sarcoidosis cases,37 although this linkage does not appear to be present in adult sarcoidosis.38–41 Many infectious agents are well established to meet all of these basic requirements: inducing granulomatous inflammation, polarized Th1 (and possibly Th17) responses, oligoclonal expansion of pathogenic antigen-specific responses, pathogenic regulatory T-cell responses, and interactions with innate immune receptors to initiate and regulate the subsequent inflammatory and host-protective responses.

Epidemiologic Support for an Infectious Etiology

Kveim Reaction One clue to the etiology of sarcoidosis is the Kveim–Siltzbach reaction, a delayed granulomatous cutaneous reaction to the

Historical Perspective Studies in the 1960s and 1970s suggested there was a transmissible agent responsible for sarcoidosis. Mitchell et al suggested a transmissible agent was found in sarcoidosis tissues following passage in experimental animals.56 Acidfast organisms were reported to be derived from sarcoidosis tissues after passing through fine filters that would collect most organisms.57 Other researchers reported findings in the 1990s that suggested a transmissible agent in sarcoidosis was derived from cell-wall deficient or L-form organisms, possibly of mycobacterial origin.58 However, none of these studies Seminars in Respiratory and Critical Care Medicine

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Table 1 Methods that provide evidence for infectious agents linked to sarcoidosis etiology Agent

Direct evidence in tissues

Indirect evidence

Mycobacteria

Tuberculostearic acid • Gas chromatography/mass spectrometry Mycobacterial proteins • Immunohistochemistry • Mass spectrometry • Protein immunoblot Mycobacterial nucleic acids • Polymerase chain reaction • In situ hybridization

Immunological responses • Serum antibody titers to specific mycobacterial antigens • T-cell responses to specific mycobacterial antigens

Propionibacteria

Isolation of organism from sarcoidosis and control tissues • Culture methods Propionibacterial lipoteichoic acid • Protein immunoblot Propionibacterial proteins • Protein immunoblot Propionibacterial nucleic acids • In situ hybridization • Polymerase chain reaction

Immunological responses • Serum antibody titers to specific propionibacterial antigens • Specific cellular immune responses to specific propionibacterial antigens

Other bacteria

Borrelia nucleic acids • Polymerase chain reaction

Convalescent titers reported • Chlamydia

Viruses

Convalescent titers reported • EBV • CMV • HSV • HHV-6/8 • HIV • HTLV1

have been reproduced with more modern technology along with polymerase chain reaction (PCR) methods that should allow identification of cell-wall–deficient organisms by their nucleic acid signatures. The only blinded, case-controlled study of cell-wall–deficient organisms in sarcoidosis was performed by Teirstein and coworkers who found no difference between sarcoidosis cases and controls when analyzing blood samples using culture techniques for cell-wall–deficient forms and confirmatory microscopic examination.59

Transplantation Insights Reports of granulomatous inflammation developing after receiving bone marrow or solid organ transplants from donors with sarcoidosis have suggested this is the result of a transmissible agent in sarcoidosis.60–63 One report suggests that these events may reflect the immunogenetics of the donor MHC haplotypes being associated with an increased risk of developing sarcoidosis.64 The development of granulomatous inflammation in donor allografts following lung, heart, liver, and kidney transplantation into recipients with sarcoidosis also suggests that the responsible agents for sarcoidosis may be transmittable.65–72 Using in situ hybridization, one study demonstrated that the recurrent granulomas in the transplanted lung were from the recipient’s immune system,73 and another study demonstrated the presence of mycobacterial DNA using PCR.74 Recently, one study found that peripheral blood mononuclear cells isolated Seminars in Respiratory and Critical Care Medicine

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from human immunodeficiency virus (HIV)-infected subjects receiving antiretroviral therapy produce Th1 cytokine responses when stimulated ex vivo with Kveim reagent suggesting that the presence of stimulatory antigens in sarcoidosis tissues may enhance immune reconstitution in HIV.75 Despite these associations, no studies have demonstrated the presence of live replicating organisms either by direct culture or histological staining in transplant allografts. One potential explanation is that the transmissible agents in transplant cases are actually donor or recipient immune cells themselves73 (e.g., mononuclear phagocytes) that contain pathogenic microbial antigens and/or pathogenic autoantigens or misfolded proteins that induce granuloma formation after trafficking to tissues.

Mycobacterial Etiology Evidence for a mycobacterial etiology of sarcoidosis has an uneven history with conflicting reports in support of and against this hypothesis. Using conventional staining methods, there have been isolated reports of detecting acid-fast bacilli by histological staining or by detecting remnants of mycobacterial compounds such as tuberculostearic acid by gas chromatography with mass spectrometry.76 Recently, researchers employing PCR have looked for evidence of any mycobacterial nucleic acid “fingerprint” in sarcoidosis tissues. A metaanalysis of studies published between 1980 and 2006 concluded that in aggregate, 26% of sarcoidosis tissues had

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evidence of mycobacterial nucleic acids (DNA, RNA) with the odds of finding mycobacteria nucleic acids in sarcoidosis tissues 10- to 20-fold greater than in control tissues.77 Our group used a limited proteomic approach based on the physicochemical properties of the Kveim reaction to attempt to discover pathogenic antigens in sarcoidosis tissues.55 Specifically, this approach was solely based on the hypothesis that the granuloma-inducing agent contained within Kveim reagent would be heat, protease, micronuclease, and neutral detergent resistant and sensitive to potent denaturants. These assumptions did not depend on any a priori hypothesis as to the nature of any potential microbial or autoimmune pathogenic antigen(s). Sarcoidosis tissue extracts were analyzed by mass spectrometry and protein immunoblot using antibodies from sarcoidosis and control sera. We discovered a specific mycobacterial protein, the catalase peroxidase protein (mKatG), was present in a majority of sarcoidosis tissues. These results were confirmed in archived sarcoidosis biopsies by in situ hybridization using probes for katG DNA and mycobacterial 16s rRNA. In our study, nearly one-half of patients with sarcoidosis demonstrated antigen-specific responses to recombinant mKatG characterized by immunoglobulin G–specific antibodies to mKatG specific in the blood compared with no responses in PPD (Purified Protein Derivative) test-negative controls.55 In a follow-up study, we found that a majority of patients with sarcoidosis from the United States and Sweden demonstrated Th1 cytokine and/or T-cell proliferative responses to mKatG, with preferential recruitment of mKatG-reactive T cells to the lung, supporting a role for mKatG as a pathogenic antigen in sarcoidosis.78 Newer evidence adds supports to the view that mycobacterial antigens are present in sarcoidosis tissues. Dubaniewicz and colleagues used immunohistochemistry to detect mycobacterial heat shock proteins in lymph nodes from patients with sarcoidosis.79 Using a directed candidate approach, Drake and coworkers screened sarcoidosis tissue samples by mass spectrometry and detected a mass-to-charge (m/z) signal compatible with the mycobacterial protein, ESAT6.80 There is increasing evidence that patients with sarcoidosis have adaptive immune responses to mycobacterial antigens. Some studies reported the presence of circulating antibodies against mycobacterial cell culture extracts in subsets of patients with sarcoidosis.81,82 Drake and colleagues demonstrated blood and lung T-cell responses to mycobacterial proteins ESAT-6, antigen-85A, and superoxide dismutase in sarcoidosis patients, and Dubaniewicz and coworkers found sarcoidosis patients have immune responses to mycobacterial heat shock proteins.83–85 Other researchers confirm that sarcoidosis patients have humoral or T-cell responses to Mycobacterium tuberculosis proteins or peptides derived from ESAT-6 and/or CFP-10.86–89 Importantly, there is evidence of a genetic link to mycobacterial responses in sarcoidosis. For example, DRB11101 is one of several class II HLA alleles associated with risk for developing sarcoidosis.90 A recent study of sarcoidosis patients reported that blocking antibodies to HLA-DR and HLADQ but not to HLA-DP inhibited peripheral blood T-cell activation by peptides from either ESAT6 or mKatG.91 They

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reported that ESAT-6 and katG peptides presented antigenpresenting cells expressing DRB11101-induced Th-1 responses from sarcoidosis T cells, suggesting that sarcoidosis risk associated with this allele may be due to immune responses to mycobacterial proteins. A study from Sweden found that mKatG induced a pronounced multifunctional cytokine profile (simultaneous IFNγ and TNF production) in T cells expressing the AV2S3 T-cell receptor suggesting such responses may contribute to the self-remitting Löfgren syndrome experienced by Scandinavian patients, many of whom express HLA-DRB10301 alleles.92 Indirect support for a mycobacterial etiology of sarcoidosis is provided by studies that compare peripheral blood gene expression patterns in sarcoidosis and tuberculosis. These studies are consistent in finding extensive overlap between the transcriptomic signatures in sarcoidosis and tuberculosis infection, supporting a mycobacterial etiology of sarcoidosis.93–96 Analysis of sarcoidosis tissues, immune responses to mycobacterial proteins, and transcriptome studies provide complementary data to support the premise that sarcoidosis is associated with prior tissue infection to mycobacteria in at least a large subset of sarcoidosis patients from the United States and Europe. In contrast to these studies, there is no direct evidence that viable mycobacterial organisms are present in sarcoidosis tissues. For example, in 2004, Milman and colleagues reported that they could not detect mycobacterial organisms after long-term culture of surgical biopsies in sarcoidosis.97 This finding is also consistent with experience in the clinical arena, where culture or histologic evidence of mycobacteria (or other infectious agent) is lacking in biopsy specimens from sarcoidosis patients. To test the hypothesis that antimycobacterial antibiotics may be beneficial in sarcoidosis, Drake and colleagues performed a randomized, placebo control clinical trial in patients with pulmonary and severe skin sarcoidosis using oral concomitant levofloxacin, ethambutol, azithromycin, and rifampin regimen.98 They reported beneficial effects on sarcoidosis skin lesions, some with ulcerated lesions that likely were superinfected with bacterial organisms. The authors suggested anti-inflammatory effects of the antibiotics may have contributed to clinical improvement, given the changes found in specific immune response gene expression profiles after treatment, but suggested a direct antimycobacterial effect remained possible. These investigators noted they detected no direct evidence of a viable mycobacterial infection in the skin of these subjects in their study.

Propionibacterial Etiology Japanese investigators described nearly 35 years ago the isolation of the commensal organism Propionibacterium acnes by culture in sarcoidosis lung and lymph node tissues.99 Many years later, Eishi and colleagues reported detecting propionibacterial DNA in 98% of sarcoidosis tissues from Japan and Europe and in 0 to 60% of control tissues.100 These investigators also described preferential cellular immune responses to the P. acnes trigger factor protein in sarcoidosis Seminars in Respiratory and Critical Care Medicine

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patients.101 An animal model of granulomatous lung inflammation induced by heat-killed P. acnes has been described, supporting the potential of this bacterium to cause granulomatous inflammation.102,103 Recently, P. acnes was reported to be frequently detected in the lung and lymph nodes of individuals without sarcoidosis,104 and in sarcoidosis tissues with a distribution irrespective of granulomatous involvement.80 Eishi and colleagues suggests P. acnes can cause latent infection in the lung and lymph nodes of sarcoidosis patients in a cell-wall–deficient form that is endogenously activated under certain conditions, proliferating at the site of latent infection and causing sarcoidosis in those patients with immune hypersensitivity to P. acnes.5 This hypothesis remains controversial, given the lack of wider confirmation that viable, replicating propionibacterial organisms are present in sarcoidosis and other control biopsy specimens.

typically are treated for many years with corticosteroid therapy, potent immunosuppressive drugs, and/or anti-TNF therapies without pathologic or microbiologic evidence of a chronic tissue infection. There is also no evidence that antimicrobial therapy is beneficial in sarcoidosis through their antimicrobial effects with the possible exception of ulcerated severe sarcoidosis skin lesions—for which bacterial superinfection seems probable in at least some cases.98 Reports of minocycline being beneficial in a small subset of patients with skin sarcoidosis remain contrary to wider clinical experience where this antimicrobial has not been found effective in multisystem sarcoidosis. Other antimicrobials with activity against propionibacterial species have not reported to be beneficial in sarcoidosis. These observations provide a challenge for researchers promoting this pathogenic model of sarcoidosis to explain.

Other Infectious Etiologies

Nonviable Infectious Etiology Hypothesis

Associations between nonbacterial and atypical bacterial pathogens and sarcoidosis have been reported in small case series. One study detected a “Borrelia-like” organism in 36 of 39 (92%) of cutaneous sarcoidosis tissue samples by focusfloating microscopy with 46% of samples confirmed by PCR.105 This is in contrast to earlier studies that failed to demonstrate higher rates of Borrelia exposure in sarcoidosis patients.106–110 Descriptions of sarcoidosis-like reactions with bilateral hilar lymphadenopathy111 or nodular lung lesions112 in patients later found to have Chlamydia or Cryptococcus infections emphasize the importance of excluding these active infections in specific cases, but there is no evidence that these pathogens play a direct etiologic role in sarcoidosis. High titers of antibodies against lymphotropic viruses (Epstein–Barr virus, cytomegalovirus, human herpesvirus [HHV] type 6, HHV-8, HIV, and human T-lymphotrophic virus type 1) have been described in patients with sarcoidosis but may reflect generalized B-cell activation in sarcoidosis because a viral infection (acute or chronic) has not been substantiated by viral cultures or tissue analysis.113–117

The lack of evidence for an active, replicating infection in sarcoidosis pathogenesis must be reconciled with the increasing evidence that sarcoidosis is associated with prior mycobacterial infection or possible pathogenic immune responses to commensal bacteria such as P. acnes. These observations lead to the hypothesis that exposure to specific microbes may trigger sarcoidosis, but that the resulting local highly polarized Th1 and in some patients, Th17 immune responses are sufficient for permanent immune control of the triggering infectious agent.6 In the case of sarcoidosis linked to prior mycobacterial infection, the authors suggest that sarcoidosis is a rare pathobiologic outcome of a mycobacterial infection where there is permanent immune control but with an associated pathobiologic outcome of chronic granulomatous inflammation. Consistent with this hypothesis, one study found that Löfgren and chronic sarcoidosis patients express HLA-DR alleles that recognize M. tuberculosis and M. avium epitopes with higher affinity than HLA-DR alleles found in tuberculosis-infected subjects, suggesting sarcoidosis represents a hyperreactive end of the spectrum of antimycobacterial responses.118 Studies in populations with a high prevalence of tuberculosis suggest that sarcoidosis and control subjects have similar T-cell responses to mycobacterial antigens86,88 and “ambient” levels of mycobacterial DNA in biopsy tissues,119 suggesting that greater HLA class II binding affinity for mycobacterial antigens may account for the hyperimmune local Th1 immune response against M. tuberculosis antigens in sarcoidosis despite the detection of a low number of M. tuberculosis genomes in sarcoidosis tissues.118,119 If sarcoidosis is not caused by a viable, replicating infectious agent, the challenge for researchers is to determine the mechanisms that result in a “sarcoidosis” outcome after successful immune control of a mycobacterial or other infectious trigger.

Viable Infection Hypothesis Since sarcoidosis was first described, an infectious etiology has been the dominant theory in the medical literature. Reasons for this fact include not only the clinical and histopathologic similarities to granulomatous infectious diseases but also form a lack of compelling hypotheses that could otherwise explain a chronic progressive granulomatous disease in the absence of some type of chronic infection. The hypothesis that chronic sarcoidosis is a result of a viable and replicating infectious agent suffers from a lack of direct evidence for this scenario. There have been no reproducible reports of viable organisms cultured from sarcoidosis tissues, with the possible exception of P. acnes organisms in which there is little difference between sarcoidosis and controls.104 The hypothesis that noncultivable bacterial or mycobacterial species exist undetected in chronic sarcoidosis is difficult to reconcile with the fact that patients with chronic sarcoidosis Seminars in Respiratory and Critical Care Medicine

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Serum Amyloid A Hypothesis The authors propose that the pathobiologic outcome of sarcoidosis involves a specific and abnormal host response

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Fig. 1 In this scenario, misfolded amyloid-like serum amyloid A (SAA) aggregates serve as a “seed” that provides a poorly soluble nidus and a template for further SAA aggregation within sarcoidosis granulomas. SAA and SAA peptides released from the granulomas stoke a feed-forward stimulation of macrophages and T cells that amplifies polarized Th1 responses to local pathogenic antigens with production of TNF, Th1promoting cytokines, and IL10 (which partially dampens the inflammatory response). These effects are mediated in part through TLR2. Persistent tissue antigens may derive from degradation-resistant pathogenic microbial antigens, new antigens trapped by the granuloma matrix and cells, or from induction of autoimmune responses. This pathobiologic course continues unabated unless there is clearance of aggregated SAA and local pathogenic antigens with downregulation of Th1 responses. Although the model depicts mycobacterial organisms as inciting agents, nonmycobacterial microbes or environmental agents could trigger a similar pathobiologic outcome. (Reproduced with permission from Chen and Moller.) 7

involving the aggregation and accumulation of the amyloid precursor protein, SAA within granulomas.6 This hypothesis initially derived from our recognition that the granulomainducing component in Kveim reagent, derived from the insoluble fraction of sarcoidosis tissues, had physiochemical properties that paralleled those of amyloid or prion proteins. On the basis of these observations, our research group investigated whether sarcoidosis tissues contained amyloid, prion, or amyloid precursor proteins using immunohistochemical methods.6 Among those proteins tested, SAA was the only amyloid, prion, or amyloid precursor protein to be intensely expressed within sarcoidosis granulomas. Importantly, quantitative morphometry demonstrated that the extent of SAA expression in sarcoidosis granulomas was 1 to 4 log folds greater than granulomas from all other infectious and noninfectious granulomatous diseases that were studied suggesting that SAA may play a disease-specific role in sarcoidosis. We found that sarcoidosis granulomas showed little positive staining with amyloid-binding dyes Congo Red and thioflavin-T, suggesting that SAA deposits in sarcoidosis granulomas are present predominantly in a nonfibrillar form. SAA deposition correlated with the number of CD3þ T cells and not CD68þ macrophages within granulomas suggesting that SAA expression is regulated by local CD3þ T cells. We

found that SAA stimulated greater expression of TNF, the Th1inducing monokine IL18, and the immunoregulatory cytokine IL10 in BAL cells from sarcoidosis patients than control subjects, effects which were blunted through blockade of TLR2.6 We also showed that SAA promoted the persistence of experimental Th1-mediated granulomatous lung inflammation, effects that were mediated in part through INFγ, TNF, and TLR2.6 SAA is not only a precursor protein for AA amyloid, but is a highly conserved, highly induced acute phase reactant that is present in both invertebrates and vertebrates, suggesting it has been evolutionarily conserved for highly essential roles.120 In humans, SAA is a multifunctional ligand that has been identified to interact with multiple innate receptors, including TLR2, RAGE, CD36, and FPRL1, which have roles in innate immune responses to pathogens, atherogenesis, and wound healing.121–123 The predominant AA amyloid protein type found in amyloidotic tissues corresponds to the Nterminal two-thirds of A-SAA.120 A recent study found that full-length SAA spontaneously forms marginally stable fibrils at 37°C that can dissociate upon changes in temperature or alkalinity,124 suggesting SAA may contribute to the formation of nonamyloid deposits.125 Given that SAA interacts with lipids and structural proteins, we suspect that SAA may Seminars in Respiratory and Critical Care Medicine

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contribute to the “stickiness” of granulomas. Experimental models demonstrate that established granulomas may “trap” circulating immune cells and pathogens including mycobacteria and prions.126 Prior to our study, SAA was reported to be upregulated in the blood of sarcoidosis patients.127–130 These studies were investigating SAA as an acute phase reactant and proposed SAA as a biomarker of active inflammation, not as a pathway critical to disease pathogenesis. Consistent with the potential for SAA as a biomarker in sarcoidosis, our study showed that elevated levels of SAA in BAL fluid correlated with chest X-ray stage.6 Miyoshi and colleagues failed to find SAA was a marker of progressive pulmonary inflammation assessed radiographically,131 though the latex agglutination assay they used for SAA measurement was less than a thousand-fold as sensitive as the ELISA assay reported by the authors in their study. Recently, in a more comprehensive study of SAA, Rottoli and coworkers reported that SAA levels in blood correlated with stage of disease and disease activity.132 Together, these studies suggest a potential for SAA to serve as a biomarker in sarcoidosis, though further studies will be needed to define its clinical utility. On the basis of the known physicochemical and biologic effects of SAA and the data in our study of SAA in sarcoidosis, we propose that sarcoidosis is triggered by a microbial infection (most often mycobacterial) that induces a hyperimmune Th1 response which kills the infecting agent, but induces the accumulation of aggregated SAA at the sites of granuloma formation (►Fig. 1).6,7 This initial deposition of SAA serves as a nidus for granuloma formation and leads to the subsequent, slowly progressive, self-aggregation of SAA within granulomas similar to the progressive accumulation in AA amyloidosis. SAA contributes to the sequestration of pathogenic antigens within granulomas through its stickiness and binding to lipophilic compounds. SAA and its fragments released from the sites of granuloma formation result in a feed-forward amplification that sustains the local polarized Th1 immune responses to pathogenic tissue antigens. This mechanism offers an explanation of how chronic granulomatous inflammation progresses in sarcoidosis in the absence of a viable, replicating infectious agent. This mechanism is consistent with cardinal clinical features of sarcoidosis, including the typical slow progression of the granulomatous inflammation without effective treatment. If this hypothesis is correct, resolution of sarcoidosis will depend on the clearance of both aggregated SAA and pathogenic antigens at the sites of granulomatous inflammation. The development of a preclinical model that mimics these pathways involving SAA would allow testing this hypothesis and whether disruption of this pathway could be therapeutic or curative.

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References 1 Statement on sarcoidosis. Joint Statement of the American Tho-

racic 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 Seminars in Respiratory and Critical Care Medicine

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the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 1999;160(2):736–755 Saltini C, Amicosante M. Beryllium disease. Am J Med Sci 2001; 321(1):89–98 Izbicki G, Chavko R, Banauch GI, et al. World Trade Center “sarcoid-like” granulomatous pulmonary disease in New York City Fire Department rescue workers. Chest 2007;131(5): 1414–1423 Drake WP. When a commensal becomes a pathogen. Sarcoidosis Vasc Diffuse Lung Dis 2008;25(1):10–11 Eishi Y. Etiologic link between sarcoidosis and Propionibacterium acnes. Respir Investig 2013;51(2):56–68 Chen ES, Song Z, Willett MH, et al. Serum amyloid A regulates granulomatous inflammation in sarcoidosis through Toll-like receptor-2. Am J Respir Crit Care Med 2010;181(4):360–373 Chen ES, Moller DR. Sarcoidosis—scientific progress and clinical challenges. Nat Rev Rheumatol 2011;7(8):457–467 Müller-Quernheim J, Prasse A, Zissel G. Pathogenesis of sarcoidosis. Presse Med 2012;41(6, Pt 2):e275–e287 Clay H, Davis JM, Beery D, Huttenlocher A, Lyons SE, Ramakrishnan L. Dichotomous role of the macrophage in early Mycobacterium marinum infection of the zebrafish. Cell Host Microbe 2007;2(1):29–39 Romagnani S. Regulation of the T cell response. Clin Exp Allergy 2006;36(11):1357–1366 Simonian PL, Roark CL, Wehrmann F, et al. Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis. J Immunol 2009;182(1):657–665 Joshi AD, Fong DJ, Oak SR, et al. Interleukin-17-mediated immunopathogenesis in experimental hypersensitivity pneumonitis. Am J Respir Crit Care Med 2009;179(8):705–716 Moller DR, Forman JD, Liu MC, et al. Enhanced expression of IL-12 associated with Th1 cytokine profiles in active pulmonary sarcoidosis. J Immunol 1996;156(12):4952–4960 Zissel G, Prasse A, Müller-Quernheim J. Sarcoidosis—immunopathogenetic concepts. Semin Respir Crit Care Med 2007;28(1): 3–14 Greene CM, Meachery G, Taggart CC, et al. Role of IL-18 in CD4þ T lymphocyte activation in sarcoidosis. J Immunol 2000;165(8): 4718–4724 Shigehara K, Shijubo N, Ohmichi M, et al. IL-12 and IL-18 are increased and stimulate IFN-gamma production in sarcoid lungs. J Immunol 2001;166(1):642–649 Dagur PK, Biancotto A, Wei L, et al. MCAM-expressing CD4(þ) T cells in peripheral blood secrete IL-17A and are significantly elevated in inflammatory autoimmune diseases. J Autoimmun 2011;37(4):319–327 Facco M, Cabrelle A, Teramo A, et al. Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax 2011;66(2):144–150 Ten Berge B, Paats MS, Bergen IM, et al. Increased IL-17A expression in granulomas and in circulating memory T cells in sarcoidosis. Rheumatology (Oxford) 2012;51(1):37–46 Wikén M, Idali F, Al Hayja MA, Grunewald J, Eklund A, Wahlström J. No evidence of altered alveolar macrophage polarization, but reduced expression of TLR2, in bronchoalveolar lavage cells in sarcoidosis. Respir Res 2010;11:121 Judson MA, Marchell RM, Mascelli M, et al. Molecular profiling and gene expression analysis in cutaneous sarcoidosis: the role of interleukin-12, interleukin-23, and the T-helper 17 pathway. J Am Acad Dermatol 2012;66(6):901–910, e1–e2 Moller DR. Involvement of T cells and alterations in T cell receptors in sarcoidosis. Semin Respir Infect 1998;13(3):174–183 Moller DR. T-cell receptor genes in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1998;15(2):158–164 Klein JT, Horn TD, Forman JD, Silver RF, Teirstein AS, Moller DR. Selection of oligoclonal V beta-specific T cells in the intradermal response to Kveim-Siltzbach reagent in individuals with sarcoidosis. J Immunol 1995;154(3):1450–1460

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

292

Chen et al.

25 Grunewald J, Janson CH, Eklund A, et al. Restricted V alpha 2.3

45 Sutherland I, Mitchell DN, Hart PD. Incidence of intrathoracic

gene usage by CD4þ T lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients correlates with HLA-DR3. Eur J Immunol 1992;22(1):129–135 Grunewald J, Hultman T, Bucht A, Eklund A, Wigzell H. Restricted usage of T cell receptor V alpha/J alpha gene segments with different nucleotide but identical amino acid sequences in HLA-DR3þ sarcoidosis patients. Mol Med 1995;1(3): 287–296 Miyara M, Amoura Z, Parizot C, et al. The immune paradox of sarcoidosis and regulatory T cells. J Exp Med 2006;203(2): 359–370 Taflin C, Miyara M, Nochy D, et al. FoxP3þ regulatory T cells suppress early stages of granuloma formation but have little impact on sarcoidosis lesions. Am J Pathol 2009;174(2): 497–508 Rappl G, Pabst S, Riemann D, et al. Regulatory T cells with reduced repressor capacities are extensively amplified in pulmonary sarcoid lesions and sustain granuloma formation. Clin Immunol 2011;140(1):71–83 Prasse A, Zissel G, Lützen N, et al. Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. Am J Respir Crit Care Med 2010;182(4):540–548 Wikén M, Grunewald J, Eklund A, Wahlström J. Higher monocyte expression of TLR2 and TLR4, and enhanced pro-inflammatory synergy of TLR2 with NOD2 stimulation in sarcoidosis. J Clin Immunol 2009;29(1):78–89 Gabrilovich MI, Walrath J, van Lunteren J, et al. Disordered Tolllike receptor 2 responses in the pathogenesis of pulmonary sarcoidosis. Clin Exp Immunol 2013;173(3):512–522 Veltkamp M, Wijnen PA, van Moorsel CH, et al. Linkage between Toll-like receptor (TLR) 2 promotor and intron polymorphisms: functional effects and relevance to sarcoidosis. Clin Exp Immunol 2007;149(3):453–462 Sato M, Kawagoe T, Meguro A, et al. Toll-like receptor 2 (TLR2) gene polymorphisms are not associated with sarcoidosis in the Japanese population. Mol Vis 2011;17:731–736 Daniil Z, Mollaki V, Malli F, et al. Polymorphisms and haplotypes in MyD88 are associated with the development of sarcoidosis: a candidate-gene association study. Mol Biol Rep 2013;40(7): 4281–4286 Rastogi R, Du W, Ju D, et al. Dysregulation of p38 and MKP-1 in response to NOD1/TLR4 stimulation in sarcoid bronchoalveolar cells. Am J Respir Crit Care Med 2011;183(4):500–510 Kanazawa N, Okafuji I, Kambe N, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. Blood 2005;105(3):1195–1197 Martin TM, Doyle TM, Smith JR, Dinulescu D, Rust K, Rosenbaum JT. Uveitis in patients with sarcoidosis is not associated with mutations in NOD2 (CARD15). Am J Ophthalmol 2003;136(5): 933–935 Schürmann M, Valentonyte R, Hampe J, Müller-Quernheim J, Schwinger E, Schreiber S. CARD15 gene mutations in sarcoidosis. Eur Respir J 2003;22(5):748–754 Milman N, Nielsen OH, Hviid TV, Fenger K. CARD15 single nucleotide polymorphisms 8, 12 and 13 are not increased in ethnic Danes with sarcoidosis. Respiration 2007;74(1):76–79 Akahoshi M, Ishihara M, Namba K, et al. Mutation screening of the CARD15 gene in sarcoidosis. Tissue Antigens 2008;71(6): 564–567 Wilsher ML. Seasonal clustering of sarcoidosis presenting with erythema nodosum. Eur Respir J 1998;12(5):1197–1199 Parkes SA, Baker SB, Bourdillon RE, et al. Incidence of sarcoidosis in the Isle of Man. Thorax 1985;40(4):284–287 Hosoda Y, Hiraga Y, Odaka M, et al. A cooperative study of sarcoidosis in Asia and Africa: analytic epidemiology. Ann N Y Acad Sci 1976;278:355–367

sarcoidosis among young adults participating in a trial of tuberculosis vaccines. BMJ 1965;2(5460):497–503 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(12):1324–1330 Williams RH, Nickerson DA. Skin reactions in sarcoid. Proc Soc Exp Biol Med 1935;33:403–405 Kveim A. En ny og spesifikk kutan-reacksjon ved Boecks Sarcoid (On a new and specific cutaneous reaction in Boeck’s sarcoid). Nord Med 1941;9:169–172 Chase MW. The preparation and standardization of Kveim testing antigen. Am Rev Respir Dis 1961;84(5):86–88 Kooij R, Gerritsen T. On the nature of the Mitsuda and the Kveim reaction. Dermatologica 1958;116(1):1–27 Siltzbach LE. The Kveim test in sarcoidosis. A study of 750 patients. JAMA 1961;178:476–482 Teirstein AS. Kveim antigen: what does it tell us about causation of sarcoidosis? Semin Respir Infect 1998;13(3):206–211 Tüzüner N, Ulkü B, Uraz S, Güngen G, Demiric S, Celikoglu S. The distribution of T cell subsets of Kveim and sarcoid granulomata. An immunohistological investigation of blood, Kveim test sites and sarcoid tissue lesions from 16 patients. Sarcoidosis 1991; 8(1):14–18 Munro CS, Mitchell DN. The Kveim response: still useful, still a puzzle. Thorax 1987;42(5):321–331 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(5): 755–767 Mitchell DN, Rees RJ, Goswami KK. Transmissible agents from human sarcoid and Crohn’s disease tissues. Lancet 1976;2(7989): 761–765 Mitchell DN, Rees RJ. A transmissible agent from sarcoid tissue. Lancet 1969;2(7611):81–84 Almenoff PL, Johnson A, Lesser M, Mattman LH. Growth of acid fast L forms from the blood of patients with sarcoidosis. Thorax 1996;51(5):530–533 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 between patients with sarcoidosis and control subjects. Chest 2003;123(2):413–417 Heyll A, Meckenstock G, Aul C, et al. Possible transmission of sarcoidosis via allogeneic bone marrow transplantation. Bone Marrow Transplant 1994;14(1):161–164 Sundar KM, Carveth HJ, Gosselin MV, Beatty PG, Colby TV, Hoidal JR. Granulomatous pneumonitis following bone marrow transplantation. Bone Marrow Transplant 2001;28(6):627–630 Gooneratne L, Lim ZY, Vivier Ad, et al. Sarcoidosis as an unusual cause of hepatic dysfunction following reduced intensity conditioned allogeneic stem cell transplantation. Bone Marrow Transplant 2007;39(8):511–512 Morita R, Hashino S, Kubota K, et al. Donor cell-derived sarcoidosis after allogeneic BMT. Bone Marrow Transplant 2009;43(6): 507–508 Pukiat S, McCarthy PL Jr, Hahn T, et al. Sarcoidosis-associated MHC Ags and the development of cutaneous and nodal granulomas following allogeneic hematopoietic cell transplant. Bone Marrow Transplant 2011;46(7):1032–1034 Johnson BA, Duncan SR, Ohori NP, et al. Recurrence of sarcoidosis in pulmonary allograft recipients. Am Rev Respir Dis 1993; 148(5):1373–1377 Ramakers K, De Wever W, Coolen J, Verschakelen J. Recurrent sarcoidosis after lung transplantation. JBR-BTR 2012;95(6):368 Fidler HM, Hadziyannis SJ, Dhillon AP, Sherlock S, Burroughs AK. Recurrent hepatic sarcoidosis following liver transplantation. Transplant Proc 1997;29(5):2509–2510

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Chen et al.

68 Vanatta JM, Modanlou KA, Dean AG, et al. Outcomes of orthotopic

87 Ahmadzai H, Cameron B, Chui JJ, Lloyd A, Wakefield D, Thomas PS.

liver transplantation for hepatic sarcoidosis: an analysis of the United Network for Organ Sharing/Organ Procurement and Transplantation Network data files for a comparative study with cholestatic liver diseases. Liver Transpl 2011;17(9): 1027–1034 Oni AA, Hershberger RE, Norman DJ, et al. Recurrence of sarcoidosis in a cardiac allograft: control with augmented corticosteroids. J Heart Lung Transplant 1992;11(2, Pt 1): 367–369 Akashi H, Kato TS, Takayama H, et al. Outcome of patients with cardiac sarcoidosis undergoing cardiac transplantation—singlecenter retrospective analysis. J Cardiol 2012;60(5):407–410 Shen SY, Hall-Craggs M, Posner JN, Shabazz B. Recurrent sarcoid granulomatous nephritis and reactive tuberculin skin test in a renal transplant recipient. Am J Med 1986;80(4):699–702 Aouizerate J, Matignon M, Kamar N, et al. Renal transplantation in patients with sarcoidosis: a French multicenter study. Clin J Am Soc Nephrol 2010;5(11):2101–2108 Milman N, Andersen CB, Burton CM, Iversen M. Recurrent sarcoid granulomas in a transplanted lung derive from recipient immune cells. Eur Respir J 2005;26(3):549–552 Klemen H, Husain AN, Cagle PT, Garrity ER, Popper HH. Mycobacterial DNA in recurrent sarcoidosis in the transplanted lung—a PCR-based study on four cases. Virchows Arch 2000;436(4): 365–369 Segal JL, Thompson JF, Charter RA. A novel immunogen to modulate cytokine production and promote immune system reconstitution in HIV-AIDS. Am J Ther 2012;19(5):317–323 Hanngren A, Odham G, Eklund A, Hoffner S, Stjernberg N, Westerdahl G. Tuberculostearic acid in lymph nodes from patients with sarcoidosis. Sarcoidosis 1987;4(2):101–104 Gupta D, Agarwal R, Aggarwal AN, Jindal SK. Molecular evidence for the role of mycobacteria in sarcoidosis: a meta-analysis. Eur Respir J 2007;30(3):508–516 Chen ES, Wahlström J, Song Z, et al. T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis. J Immunol 2008;181(12):8784–8796 Dubaniewicz A, Dubaniewicz-Wybieralska M, Sternau A, et al. Mycobacterium tuberculosis complex and mycobacterial heat shock proteins in lymph node tissue from patients with pulmonary sarcoidosis. J Clin Microbiol 2006;44(9):3448–3451 Oswald-Richter KA, Beachboard DC, Seeley EH, et al. Dual analysis for mycobacteria and propionibacteria in sarcoidosis BAL. J Clin Immunol 2012;32(5):1129–1140 Chapman JS. Mycobacterial and mycotic antibodies in sera of patients with sarcoidosis. Results of studies using agar doublediffusion technique. Ann Intern Med 1961;55:918–924 Reid JD, Chiodini RJ. Serologic reactivity against Mycobacterium paratuberculosis antigens in patients with sarcoidosis. Sarcoidosis 1993;10(1):32–35 Drake WP, Dhason MS, Nadaf M, et al. Cellular recognition of Mycobacterium tuberculosis ESAT-6 and KatG peptides in systemic sarcoidosis. Infect Immun 2007;75(1):527–530 Dubaniewicz A, Trzonkowski P, Dubaniewicz-Wybieralska M, Dubaniewicz A, Singh M, Myśliwski A. Mycobacterial heat shock protein-induced blood T lymphocytes subsets and cytokine pattern: comparison of sarcoidosis with tuberculosis and healthy controls. Respirology 2007;12(3):346–354 Oswald-Richter KA, Beachboard DC, Zhan X, et al. Multiple mycobacterial antigens are targets of the adaptive immune response in pulmonary sarcoidosis. Respir Res 2010;11:161 Agarwal R, Gupta D, Srinivas R, Verma I, Aggarwal AN, Laal S. Analysis of humoral responses to proteins encoded by region of difference 1 of Mycobacterium tuberculosis in sarcoidosis in a high tuberculosis prevalence country. Indian J Med Res 2012; 135(6):920–923

Peripheral blood responses to specific antigens and CD28 in sarcoidosis. Respir Med 2012;106(5):701–709 Inui N, Suda T, Chida K. Use of the QuantiFERON-TB Gold test in Japanese patients with sarcoidosis. Respir Med 2008;102(2): 313–315 Hörster R, Kirsten D, Gaede KI, et al. Antimycobacterial immune responses in patients with pulmonary sarcoidosis. Clin Respir J 2009;3(4):229–238 Rossman MD, Thompson B, Frederick M, et al; ACCESS Group. HLA-DRB11101: a significant risk factor for sarcoidosis in blacks and whites. Am J Hum Genet 2003;73(4):720–735 Oswald-Richter K, Sato H, Hajizadeh R, et al. Mycobacterial ESAT6 and katG are recognized by sarcoidosis CD4þ T cells when presented by the American sarcoidosis susceptibility allele, DRB11101. J Clin Immunol 2010;30(1):157–166 Wikén M, Ostadkarampour M, Eklund A, et al. Antigen-specific multifunctional T-cells in sarcoidosis patients with Lofgren’s syndrome. Eur Respir J 2012;40(1):110–121 Koth LL, Solberg OD, Peng JC, Bhakta NR, Nguyen CP, Woodruff PG. Sarcoidosis blood transcriptome reflects lung inflammation and overlaps with tuberculosis. Am J Respir Crit Care Med 2011; 184(10):1153–1163 Thillai M, Eberhardt C, Lewin AM, et al. Sarcoidosis and tuberculosis cytokine profiles: indistinguishable in bronchoalveolar lavage but different in blood. PLoS ONE 2012;7(7):e38083 Maertzdorf J, Weiner J III, Mollenkopf HJ, et al; TBornotTB Network. Common patterns and disease-related signatures in tuberculosis and sarcoidosis. Proc Natl Acad Sci U S A 2012; 109(20):7853–7858 Zhou T, Zhang W, Sweiss NJ, et al. Peripheral blood gene expression as a novel genomic biomarker in complicated sarcoidosis. PLoS ONE 2012;7(9):e44818 Milman N, Lisby G, Friis S, Kemp L. Prolonged culture for mycobacteria in mediastinal lymph nodes from patients with pulmonary sarcoidosis. A negative study. Sarcoidosis Vasc Diffuse Lung Dis 2004;21(1):25–28 Drake WP, Oswald-Richter K, Richmond BW, et al. Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study. JAMA Dermatol 2013;149(9):1040–1049 Homma JY, Abe C, Chosa H, et al. Bacteriological investigation on biopsy specimens from patients with sarcoidosis. Jpn J Exp Med 1978;48(3):251–255 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(1):198–204 Ebe Y, Ikushima S, Yamaguchi T, et al. Proliferative response of peripheral blood mononuclear 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(3):256–265 Nishiwaki 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(2):631–639 McCaskill JG, Chason KD, Hua X, et al. Pulmonary immune responses to Propionibacterium acnes in C57BL/6 and BALB/c mice. Am J Respir Cell Mol Biol 2006;35(3):347–356 Ishige I, Eishi Y, Takemura T, et al. Propionibacterium acnes is the most common bacterium commensal in peripheral lung tissue and mediastinal lymph nodes from subjects without sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2005;22(1):33–42 Derler AM, Eisendle K, Baltaci M, Obermoser G, Zelger B. High prevalence of ’Borrelia-like’ organisms in skin biopsies of sarcoidosis patients from Western Austria. J Cutan Pathol 2009; 36(12):1262–1268

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A. Determination of antibodies to Borrelia burgdorferi in sarcoidosis. Sarcoidosis 1994;11(1):32–33 Morris JT, Longfield RN. Sarcoidosis and ELISA for Borrelia burgdorferi. South Med J 1994;87(6):590–591 Ishihara M, Ishida T, Isogai E, et al. Detection of antibodies to Borrelia species among patients with confirmed sarcoidosis in a region where Lyme disease is nonendemic. Graefes Arch Clin Exp Ophthalmol 1996;234(12):770–773 Xu Z, Ma D, Luo W, Zhu Y. Detection of Borrelia burgdorferi DNA in granulomatous tissues from patients with sarcoidosis using polymerase chain reaction in situ technique. Chin Med Sci J 1996;11(4):220–223 Martens H, Zöllner B, Zissel G, Burdon D, Schlaak M, MüllerQuernheim J. Anti-Borrelia burgdorferi immunoglobulin seroprevalence in pulmonary sarcoidosis: a negative report. Eur Respir J 1997;10(6):1356–1358 Fretzayas A, Moustaki M, Priftis KN, Yiallouros P, Paschalidou M, Nicolaidou P. Bilateral hilar lymphadenopathy due to Chlamydia pneumoniae infection. Pediatr Pulmonol 2011;46(10):1038–1040 Yano S, Kobayashi K, Ikeda T, et al. Sarcoid-like reaction in Cryptococcus neoformans infection. BMJ Case Rep 2012;2012; Lebbé C, Agbalika F, Flageul B, et al. No evidence for a role of human herpesvirus type 8 in sarcoidosis: molecular and serological analysis. Br J Dermatol 1999;141(3):492–496 Biberfeld P, Petrén AL, Eklund A, et al. Human herpesvirus-6 (HHV-6, HBLV) in sarcoidosis and lymphoproliferative disorders. J Virol Methods 1988;21(1–4):49–59 Di Alberti L, Piattelli A, Artese L, et al. Human herpesvirus 8 variants in sarcoid tissues. Lancet 1997;350(9092):1655–1661 McKee DH, Young AC, Haeney M. Sarcoidosis and HTLV-1 infection. J Clin Pathol 2005;58(9):996–997 Rottoli P, Bianchi Bandinelli ML, Rottoli L, Zazzi M, Panzardi G, Valensin PE. Sarcoidosis and infections by human lymphotropic viruses. Sarcoidosis 1990;7(1):31–33 Saltini C, Pallante M, Puxeddu E, et al. M. avium binding to HLADR expressed alleles in silico: a model of phenotypic susceptibility to sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2008;25(2): 100–116 Zhou Y, Li HP, Li QH, et al. Differentiation of sarcoidosis from tuberculosis using real-time PCR assay for the detection and

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Chen et al.

quantification of Mycobacterium tuberculosis. Sarcoidosis Vasc Diffuse Lung Dis 2008;25(2):93–99 Uhlar CM, Whitehead AS. Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem 1999;265(2):501–523 Cheng N, He R, Tian J, Ye PP, Ye RD. Cutting edge: TLR2 is a functional receptor for acute-phase serum amyloid A. J Immunol 2008;181(1):22–26 Okamoto H, Katagiri Y, Kiire A, Momohara S, Kamatani N. Serum amyloid A activates nuclear factor-kappaB in rheumatoid synovial fibroblasts through binding to receptor of advanced glycation end-products. J Rheumatol 2008;35(5):752–756 Eklund KK, Niemi K, Kovanen PT. Immune functions of serum amyloid A. Crit Rev Immunol 2012;32(4):335–348 Ye Z, Bayron Poueymiroy D, Aguilera JJ, et al. Inflammation protein SAA2.2 spontaneously forms marginally stable amyloid fibrils at physiological temperature. Biochemistry 2011;50(43): 9184–9191 Kim SR, Kondo F, Otono Y, et al. Serum amyloid A and C-reactive protein positive nodule in alcoholic liver cirrhosis, hard to make definite diagnosis. Hepatol Res 2013 Cosma CL, Humbert O, Ramakrishnan L. Superinfecting mycobacteria home to established tuberculous granulomas. Nat Immunol 2004;5(8):828–835 Ehrenfeld M, Levartowsky D. Serum amyloid-A protein and sarcoidosis. Isr J Med Sci 1989;25(8):418–420 Salazar A, Maña J, Fiol C, et al. Influence of serum amyloid A on the decrease of high density lipoprotein-cholesterol in active sarcoidosis. Atherosclerosis 2000;152(2):497–502 Rubinstein I, Knecht A, de Beer FC, Baum GL, Pras M. Serum amyloid-A protein concentrations in sarcoidosis. Isr J Med Sci 1989;25(8):461–462 De Vries J, Rothkrantz-Kos S, van Dieijen-Visser MP, Drent M. The relationship between fatigue and clinical parameters in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2004;21(2): 127–136 Miyoshi S, Hamada H, Kadowaki T, et al. Comparative evaluation of serum markers in pulmonary sarcoidosis. Chest 2010;137(6): 1391–1397 Bargagli E, Magi B, Olivieri C, Bianchi N, Landi C, Rottoli P. Analysis of serum amyloid A in sarcoidosis patients. Respir Med 2011; 105(5):775–780

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