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1.  Dual Analysis for Mycobacteria and Propionibacteria in Sarcoidosis BAL 
Journal of clinical immunology  2012;32(5):1129-1140.
Purpose
Sarcoidosis is a non-caseating granulomatous disease for which a role for infectious antigens continues to strengthen. Recent studies have reported molecular evidence of mycobacteria or propionibacteria. We assessed for immune responses against mycobacterial and propionibacterial antigens in sarcoidosis bronchoalveolar lavage (BAL) using flow cytometry, and localized signals consistent with microbial antigens with sarcoidosis specimens, using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS).
Methods
BAL cells from 27 sarcoidosis, 14 PPD- controls, and 9 subjects with nontuberculosis mycobacterial (NTM) infections were analyzed for production of IFN-γ after stimulation with mycobacterial ESAT-6 and Propionibacterium acnes proteins. To complement the immunological data, MALDI-IMS was performed to localize ESAT-6 and Propionibacterium acnes signals within sarcoidosis and control specimens.
Results
CD4+ immunologic analysis for mycobacteria was positive in 17/27 sarcoidosis subjects, compared to 2/14 PPD-subjects, and 5/9 NTM subjects (p=00.008 and p=00.71 respectively, Fisher's exact test). There was no significant difference for recognition of P. acnes, which occurred only in sarcoidosis subjects that also recognized ESAT-6. Similar results were also observed for the CD8+ immunologic analysis. MALDI-IMS localized signals consistent with ESAT-6 only within sites of granulomatous inflammation, whereas P. acnes signals were distributed throughout the specimen.
Conclusions
MALDI-IMS localizes signals consistent with ESAT-6 to sarcoidosis granulomas, whereas no specific localization of P. acnes signals is detected. Immune responses against both mycobacterial and P. acnes are present within sarcoidosis BAL, but only mycobacterial signals are distinct from disease controls. These immunologic and molecular investigations support further investigation of the microbial community within sarcoidosis granulomas.
doi:10.1007/s10875-012-9700-5
PMCID: PMC3526106  PMID: 22552860
Sarcoidosis; mycobacteria; propionibacteria; bronchoalveolar lavage; mass spectrometry; MALDI-IMS
2.  Etiology of Sarcoidosis: Does Infection Play a Role? 
Sarcoidosis is a granulomatous inflammatory disorder of unclear etiology, which is known to affect multiple organ systems including the lungs, heart, skin, central nervous system, and eyes, among others. For this reason, sarcoidosis represents a systemic medical disorder that is clinically relevant to multiple medical sub-specialties. Despite extensive research, the etiology of sarcoidosis has yet to be elucidated, although most evidence supports that the pathogenetic mechanism of sarcoidosis is an aberrant immune response, driven by an unidentified antigen (or antigens) in genetically susceptible individuals. Multiple candidate etiologic agents, including microbial organisms and environmental agents, have been investigated, but study results are inconclusive. In this review, we describe the known histologic and immunologic features of sarcoidosis and discuss the evidence supporting a role for infectious processes in the pathogenesis of sarcoidosis.
PMCID: PMC3313528  PMID: 22461752
sarcoidosis; etiology; immunology; Mycobacterium; infection
3.  Uterine Sarcoidosis: A Rare Extrapulmonary Site of Sarcoidosis 
Case Reports in Rheumatology  2013;2013:706738.
Sarcoidosis is a multisystem disease which is most commonly manifested in the pulmonary system. However, extrapulmonary manifestations have also been frequently reported. Isolated occurrence of sarcoidosis in the genital system is rare and poses a diagnostic and therapeutic dilemma. Uterine sarcoidosis can present with cervical erosions, endometrial polypoid lesions, and recurrent serometra. In majority of cases, it is diagnosed by endometrial curettage, but it has also been detected by examination of hysterectomy, polypectomy, and autopsy specimens. Nonnecrotizing granulomas are the characteristic pathologic finding of sarcoidosis. However, many infectious and noninfectious etiologies including certain neoplasms can produce similar granulomatous reactions in the female genital tract. These conditions affect the female genital tract more commonly than sarcoidosis, and therefore it is important to rule out these conditions first before making a diagnosis of sarcoidosis. Treatment of sarcoidosis is different from treating these other conditions and the most commonly used systemic or local corticosteroids can be hazardous if the underlying cause is infection. In this case report, the clinical presentation, histopathology, clinical course, and treatment of a patient with isolated uterine sarcoidosis are described, and a brief literature review of sarcoidosis of the female genital tract is provided.
doi:10.1155/2013/706738
PMCID: PMC3671678  PMID: 23762732
4.  Superoxide dismutase A antigens derived from molecular analysis of sarcoidosis granulomas elicit systemic Th-1 immune responses 
Respiratory Research  2008;9(1):36.
Background
Sarcoidosis is an idiopathic granulomatous disease with pathologic and immunologic features similar to tuberculosis. Routine histologic staining and culture fail to identify infectious agents. An alternative means for investigating a role of infectious agents in human pathogenesis involves molecular analysis of pathologic tissues for microbial nucleic acids, as well as recognition of microbial antigens by the host immune system. Molecular analysis for superoxide dismutase A (sodA) allows speciation of mycobacteria. SodA is an abundantly secreted virulence factor that generates cellular immune responses in infected hosts. The purpose of this study is to investigate if target antigens of the sarcoidosis immune response can be identified by molecular analysis of sarcoidosis granulomas.
Methods
We detected sodA amplicons in 12 of 17 sarcoidosis specimens, compared to 2 of 16 controls (p = 0.001, two-tailed Fisher's exact test), and 3 of 3 tuberculosis specimens (p = 0.54). Analysis of the amplicons revealed sequences identical to M. tuberculosis (MTB) complex, as well as sequences which were genetically divergent. Using peripheral blood mononuclear cells (PBMC) from 12 of the 17 sarcoidosis subjects, we performed enzyme-linked immunospot assay (ELISPOT) to assess for immune recognition of MTB sodA peptides, along with PBMC from 26 PPD- healthy volunteers, and 11 latent tuberculosis subjects.
Results
Six of 12 sarcoidosis subjects recognized the sodA peptides, compared to one of 26 PPD- controls (p = 0.002), and 6/11 PPD+ subjects (p = .68). Overall, 10 of the 12 sarcoidosis subjects from whom we obtained PBMC and archival tissue possessed molecular or immunologic evidence for sodA.
Conclusion
Dual molecular and immunologic analysis increases the ability to find infectious antigens. The detection of Th-1 immune responses to sodA peptides derived from molecular analysis of sarcoidosis granulomas reveals that these are among the target antigens contributing to sarcoidosis granulomatous inflammation.
doi:10.1186/1465-9921-9-36
PMCID: PMC2383887  PMID: 18439270
5.  Sarcoidosis Th17 Cells are ESAT-6 Antigen Specific but Demonstrate Reduced IFN-γ Expression 
Journal of clinical immunology  2012;33(2):10.1007/s10875-012-9817-6.
Rationale
Sarcoidosis is a granulomatous disease of unknown etiology. Many patients with sarcoidosis demonstrate antigen-specific immunity to mycobacterial virulence factors. Th-17 cells are crucial to the immune response in granulomatous inflammation, and have recently been shown to be present in greater numbers in the peripheral blood and bronchoalveolar lavage (BAL) fluid (BALF) of sarcoidosis patients than healthy controls. It is unclear whether Th-17 cells in sarcoidosis are specific for mycobacterial antigens, or whether they have similar functionality to control Th-17 cells.
Methods
Flow cytometry was used to determine the numbers of Th-17 cells present in the peripheral blood and BALF of patients with sarcoidosis, the percentage of Th-17 cells that were specific to the mycobacterial virulence factor ESAT-6, and as well as to assess IFN-γ expression in Th-17 cells following polyclonal stimulation.
Results
Patients with sarcoidosis had greater numbers of Th-17 cells in the peripheral blood and BALF than controls and produced significantly more extracellular IL-17A (p=0.03 and p=0.02, respectively). ESAT-6 specific Th-17 cells were present in both peripheral blood and BALF of sarcoidosis patients (p<0.001 and p=0.03, respectively). After polyclonal stimulation, Th-17 cells from sarcoidosis patients produced less IFN-γ than healthy controls.
Conclusions
Patients with sarcoidosis have mycobacterial antigen-specific Th-17 cells peripherally and in sites of active sarcoidosis involvement. Despite the Th1 immunophenotype of sarcoidosis immunology, the Th-17 cells have reduced IFN-γ expression, compared to healthy controls. This reduction in immunity may contribute to sarcoidosis pathogenesis.
doi:10.1007/s10875-012-9817-6
PMCID: PMC3850764  PMID: 23073617
Sarcoidosis; Th-17; mycobacterial ESAT-6
6.  Identification of Mycobacterium avium complex in sarcoidosis. 
Journal of Clinical Microbiology  1996;34(9):2240-2245.
Cell wall-defective bacteria which later reverted to acid-fast bacilli have been isolated from sarcoid tissue. These have not been conclusively shown to be mycobacteria. Specific PCR assays were applied to identify mycobacterial nucleic acids in these cultured isolates and in fresh specimens obtained from patients with sarcoidosis. Positive amplification and hybridization were observed with Mycobacterium avium complex- and/or Mycobacterium paratuberculosis-specific probes in five of the six cultured isolates and two fresh skin biopsy samples and one cerebrospinal fluid specimen. There was no amplification or hybridization with Mycobacterium tuberculosis or M. avium subsp. silvaticum probes, respectively. Patients' sera were also tested for antibody reactivities by immunoblotting with M. paratuberculosis recombinant clones expressing the 36,000-molecular-weight antigen (36K antigen) (p36) and the 65K heat shock protein (PTB65K). All seven sarcoidosis, four of six tuberculosis, and all six leprosy patient serum specimens showed strong reactivity with p36 antigen. In contrast, 13 of 38 controls showed only weak reactivity with p36 (P = 0.002 for controls versus sarcoidosis samples). Similarly, PTB65K reacted with high intensity with sera from 5 of 5 sarcoidosis, 5 of 6 tuberculosis, and 5 of 6 leprosy patients, compared with its low-intensity reaction with 5 of 22 controls (P = 0.001 for controls versus sarcoidosis samples). This study demonstrates the isolation and/or identification of M. paratuberculosis or a closely related M. avium complex strain from sarcoid skin lesions and cerebrospinal fluid. Furthermore, the reactivity of antibodies in sarcoid patient sera against p36 and PTB65K antigens was comparable to the reactivity of sera obtained from patients with known mycobacterial disease. Collectively, these data provide further support for the theory of the mycobacterial etiology of sarcoidosis.
PMCID: PMC229225  PMID: 8862592
7.  Mycobacterium tuberculosis Antigen 85A Induces Th-1 Immune Responses in Systemic Sarcoidosis 
Journal of clinical immunology  2007;27(4):445-454.
Sarcoidosis is a granulomatous disease of unknown etiology, characterized by a Th-1 immunophenotype. Although humoral immune responses by sarcoidosis subjects to mycobacterial proteins have been detected, mycobacterial antigens capable of inducing cellular immune responses in sarcoidosis subjects have not been reported. We used the enzyme-linked immunospot assay to assess for recognition of the Mycobacterium tuberculosis mycolyl transferase, Antigen 85A, by peripheral blood mononuclear cells from 25 sarcoidosis subjects, 22 PPD− (purified protein derivative) healthy volunteers, and 16 PPD+ healthy subjects. Reactivity to Ag85A whole protein was observed in 15 of 25 sarcoidosis subjects compared to 2 of 22 PPD− subjects (p = 0.0006, Fisher’s exact test) and to 14 of 16 PPD+ subjects (p = 0.084, Fisher’s exact test). Monoclonal antibody against HLA-DR inhibited recognition. In addition to immune recognition of Ag85A whole protein, peptide-mapping studies identified four immunogenic Ag85A peptides, which induced Th-1 immune responses in individual sarcoidosis subjects, suggesting that multiple epitopes from a mycobacterial protein may have a role in sarcoidosis immunopathogenesis.
doi:10.1007/s10875-007-9080-4
PMCID: PMC3962023  PMID: 17357846
Sarcoidosis; mycobacteria; antigen; Th-1 immunophenotype
8.  Effects of broad-spectrum antimycobacterial therapy on chronic pulmonary sarcoidosis 
Background
Sarcoidosis is an idiopathic, granulomatous disease for which molecular and immunologic studies have shown an association between it and mycobacterial antigens. Microbial antigens can reduce expression of the tyrosine kinase Lck, which has been associated with sarcoidosis severity. Here we investigate the efficacy of Concomitant Levofloxacin, Ethambutol, Azithromycin, and Rifampin (the CLEAR regimen) for treatment of chronic, pulmonary sarcoidosis.
Methods
Fifteen chronic, pulmonary sarcoidosis patients with forced vital capacities (FVC) between 45–80% of predicted were enrolled in this open-label trial. The primary efficacy endpoint was change in absolute FVC from baseline to completion of therapy. Secondary endpoints were change in functional capacity measured by Six Minute Walk Distance (6MWD) and quality of life assessment measured by St. George’s Respiratory Questionnaire (SGRQ).
Results
Of 15 patients enrolled, 11 completed 4 weeks of therapy, and 8 completed 8 weeks of therapy. The CLEAR regimen was associated with an increase in FVC of 0.23 liters at 4 weeks and 0.42 liters at 8 weeks (P=0.0098 and 0.016, respectively). The 6MWD increased by 87 meters from baseline to 8 weeks (p=0.0078). The mean score of the validated SGRQ was improved at 8 weeks over baseline (p=0.023). Normalized expression of Lck and NF-κB was observed in those with clinical improvement.
Conclusions
The CLEAR regimen is associated with improved absolute FVC, as well as increased functional capacity and quality-of-life in selected chronic pulmonary sarcoidosis patients. Larger, randomized, controlled trials are needed to confirm these findings and to identify patients most likely to benefit from therapy.
PMCID: PMC3929334  PMID: 24284293
Sarcoidosis; Clinical trial; antibiotics
9.  Development of a Sarcoidosis Murine Lung Granuloma Model Using Mycobacterium Superoxide Dismutase A Peptide 
Sarcoidosis is characterized by noncaseating granulomas containing CD4+ T cells with a Th1 immunophenotype. Although the causative antigens remain unknown, independent studies noted molecular and immunologic evidence of mycobacterial virulence factors in sarcoidosis specimens. A major limiting factor in discovering new insights into the pathogenesis of sarcoidosis is the lack of an animal model. Using a distinct superoxide dismutase A peptide (sodA) associated with sarcoidosis granulomas, we developed a pulmonary model of sarcoidosis granulomatous inflammation. Mice were sensitized by a subcutaneous injection of sodA, incorporated in incomplete Freund's adjuvant (IFA). Control subjects consisted of mice with no sensitization (ConNS), sensitized with IFA only (ConIFA), or with Schistosoma mansoni eggs. Fourteen days later, sensitized mice were challenged by tail-vein injection of naked beads, covalently coupled to sodA peptides or to schistosome egg antigens (SEA). Histologic analysis revealed hilar lymphadenopathy and noncaseating granulomas in the lungs of sodA-treated or SEA-treated mice. Flow cytometry of bronchoalveolar lavage (BAL) demonstrated CD4+ T-cell responses against sodA peptide in the sodA-sensitized mice only. Cytometric bead analysis revealed significant differences in IL-2 and IFN-γ secretion in the BAL fluid of sodA-treated mice, compared with mice that received SEA or naked beads (P = 0.008, Wilcoxon rank sum test). ConNS and ConIFA mice demonstrated no significant formation of granuloma, and no Th1 immunophenotype. The use of microbial peptides distinct for sarcoidosis reveals a histologic and immunologic profile in the murine model that correlates well with those profiles noted in human sarcoidosis, providing the framework to investigate the molecular basis for the progression or resolution of sarcoidosis.
doi:10.1165/rcmb.2009-0350OC
PMCID: PMC3049230  PMID: 20348207
lung; sarcoidosis; granuloma; Mycobacterium soda; mouse
10.  Localization of Propionibacterium acnes in granulomas supports a possible etiologic link between sarcoidosis and the bacterium 
Modern Pathology  2012;25(9):1284-1297.
Sarcoidosis likely results from the exposure of a genetically susceptible subject to an environmental agent, possibly an infectious one. Mycobacterial and propionibacterial organisms are the most commonly implicated potential etiologic agents. Propionibacterium acnes is the only microorganism, however, found in sarcoid lesions by bacterial culture. To evaluate the pathogenic role of this indigenous bacterium, we screened for the bacterium in sarcoid and non-sarcoid tissues using immunohistochemical methods with novel P. acnes-specific monoclonal antibodies that react with cell-membrane-bound lipoteichoic acid (PAB antibody) and ribosome-bound trigger-factor protein (TIG antibody). We examined formalin-fixed and paraffin-embedded samples of lungs and lymph nodes from 196 patients with sarcoidosis, and corresponding control samples from 275 patients with non-sarcoidosis diseases. The samples were mostly from Japanese patients, with 64 lymph node samples from German patients. Immunohistochemistry with PAB antibody revealed small round bodies within sarcoid granulomas in 20/27 (74%) video-assisted thoracic surgery lung samples, 24/50 (48%) transbronchial lung biopsy samples, 71/81 (88%) Japanese lymph node samples, and 34/38 (89%) German lymph node samples. PAB antibody did not react with non-sarcoid granulomas in any of the 45 tuberculosis samples or the 34 samples with sarcoid reaction. In nongranulomatous areas, small round bodies detected by PAB antibody were found in alveolar macrophages of lungs and paracortical macrophages of lymph nodes from many sarcoid and some non-sarcoid patients. Large-spheroidal acid-fast bodies, Hamazaki–Wesenberg bodies, which were found in 50% of sarcoid and 15% of non-sarcoid lymph node samples, reacted with both PAB and TIG antibodies. Electron microscopy revealed that these Hamazaki–Wesenberg bodies had a single bacterial structure and lacked a cell wall with occasional protrusions from the body. The high frequency and specificity of P. acnes, detected by PAB antibody within sarcoid granulomas, indicates that this indigenous bacterium might be the cause of granuloma formation in many sarcoid patients.
doi:10.1038/modpathol.2012.80
PMCID: PMC3434354  PMID: 22596102
epithelioid cell granuloma; Hamazaki–Wesenberg body; lipoteichoic acid; trigger-factor protein
11.  Circulating cytokines in sarcoidosis: Phenotype-specific alterations for fibrotic and non-fibrotic pulmonary disease 
Cytokine  2013;61(3):906-911.
Aims
Sarcoidosis is a granulomatous disease of unknown etiology marked by tremendous clinical heterogeneity. Many patients enter remission with good long-term outcomes. Yet, chronic disease is not uncommon, and this important phenotype remains understudied. Identified alterations in local and circulating cytokines—specifically targeted for study, and often in the acute phase of disease—have informed our growing understanding of the immunopathogenesis of sarcoidosis. Our aim was to evaluate a broad panel of circulating cytokines in patients with chronic sarcoidosis. Among those with chronic disease, pulmonary fibrosis occurs in only a subset. To gain more insight into the determinants of the fibrotic response, we also determined if the phenotypes of fibrotic and non-fibrotic pulmonary sarcoidosis have distinct cytokine profiles.
Results
In patients with sarcoidosis compared to controls, IL-5 was decreased, and IL-7 was increased. Both of these comparisons withstood rigorous statistical correction for multiple comparisons. GM-CSF met a nominal level of significance. We also detected an effect of phenotype, where IL-5 was significantly decreased in non-fibrotic compared to fibrotic pulmonary sarcoidosis, and compared to controls. Compared to controls, there was a trend towards a significant increase in IL-7 in fibrotic, but not in non-fibrotic pulmonary sarcoidosis. In contrast, compared to controls, there was a trend towards a significant increase in GM-CSF in non-fibrotic, but not in fibrotic pulmonary sarcoidosis.
Conclusions
In a comprehensive evaluation of circulating cytokines in sarcoidosis, we found IL-5, IL-7, and GM-CSF to be altered. These findings provide a window into the immunopathogenesis of sarcoidosis. IL-7 is a novel sarcoidosis cytokine and, as a master regulator of lymphocytes, is an attractive target for further studies. By observing an effect of phenotype upon cytokine patterns, we also identify specific immune alterations which may contribute to clinical heterogeneity.
doi:10.1016/j.cyto.2012.12.016
PMCID: PMC3615886  PMID: 23384655
Sarcoidosis; Cytokines; Interleukin-5; Interleukin-7; Pulmonary fibrosis
12.  Childhood sarcoidosis: A rare but fascinating disorder 
Childhood sarcoidosis is a rare multisystemic granulomatous disorder of unknown etiology. In the pediatric series reported from the southeastern United States, sarcoidosis had a higher incidence among African Americans. Most reported childhood cases have occurred in patients aged 13–15 years. Macrophages bearing an increased expression of major histocompatibility class (MHC) II molecules most likely initiate the inflammatory response of sarcoidosis by presenting an unidentified antigen to CD4+ Th (helper-inducer) lymphocytes. A persistent, poorly degradable antigen driven cell-mediated immune response leads to a cytokine cascade, to granuloma formation, and eventually to fibrosis. Frequently observed immunologic features include depression of cutaneous delayed-type hypersensitivity and a heightened helper T cell type 1 (Th1) immune response at sites of disease. Circulating immune complexes, along with signs of B cell hyperactivity, may also be found. The clinical presentation can vary greatly depending upon the organs involved and age of the patient. Two distinct forms of sarcoidosis exist in children. Older children usually present with a multisystem disease similar to the adult manifestations, with frequent hilar lymphadenopathy and pulmonary infiltrations. Early-onset sarcoidosis is a unique form of the disease characterized by the triad of rash, uveitis, and arthritis in children presenting before four years of age. The diagnosis of sarcoidosis is confirmed by demonstrating a typical noncaseating granuloma on a biopsy specimen. Other granulmatous diseases should be reasonably excluded. The current therapy of choice for sarcoidosis in children with multisystem involvement is oral corticosteroids. Methotrexate given orally in low doses has been effective, safe and steroid sparing in some patients. Alternative immunosuppressive agents, such as azathioprine, cyclophosphamide, chlorambucil, and cyclosporine, have been tried in adult cases of sarcoidosis with questionable efficacy. The high toxicity profile of these agents, including an increased risk of lymphoproliferative disorders and carcinomas, has limited their use to patients with severe disease refractory to other agents. Successful steroid sparing treatment with mycophenolate mofetil was described in an adolescent with renal-limited sarcoidosis complicated by renal failure. Novel treatment strategies for sarcoidosis have been developed including the use of TNF-alpha inhibitors, such as infliximab. The long-term course and prognosis is not well established in childhood sarcoidosis, but it appears to be poorer in early-onset disease.
doi:10.1186/1546-0096-6-16
PMCID: PMC2559831  PMID: 18811966
13.  Isolated facial cutaneous sarcoidosis 
Isolated cutaneous sarcoidosis is a rare multisystemic granulomatous disorder of unknown etiology. Cutaneous lesions have been classified into specific and nonspecific depending on the presence of noncaseating granulomas on histopathologic studies. Macrophages most likely initiate the response of sarcoidosis by presenting unidentified antigens to CD4+ lymphocytes. A persistent poorly degradable antigen-driven CMI response leads to cytokine cascade, granulomaformation, and fibrosis. In the present study, we report a case of isolated cutaneous sarcoidosis, localized to the face, in an adolescent girl without systemic manifestations which is a rare entity.
doi:10.4103/0976-9668.95980
PMCID: PMC3361786  PMID: 22690059
Cutaneous; facial; sarcoidosis
14.  Dendritic Cells in the Pathogenesis of Sarcoidosis 
Sarcoidosis is a noncaseating granulomatous disease, likely of autoimmune etiology, that causes inflammation and tissue damage in multiple organs, most commonly the lung, but also skin, and lymph nodes. Reduced dendritic cell (DC) function in sarcoidosis peripheral blood compared with peripheral blood from control subjects suggests that blunted end organ cellular immunity may contribute to sarcoidosis pathogenesis. Successful treatment of sarcoidosis with tumor necrosis factor (TNF) inhibitors, which modulate DC maturation and migration, has also been reported. Together, these observations suggest that DCs may be important mediators of sarcoidosis immunology. This review focuses on the phenotype and function of DCs in the lung, skin, blood, and lymph node of patients with sarcoidosis. We conclude that DCs in end organs are phenotypically and functionally immature (anergic), while DCs in the lymph node are mature and polarize pathogenic Th1 T cells. The success of TNF inhibitors is thus likely secondary to inhibition of DC-mediated Th1 polarization in the lymph node.
doi:10.1165/rcmb.2009-0033TR
PMCID: PMC2809219  PMID: 19372243
sarcoidosis; granuloma; dendritic cell; macrophage; inflammation
15.  Sarcoidosis 2001 
Postgraduate Medical Journal  2001;77(905):177-180.
In every decade, sarcoidosis makes a chameleon-like change so its profile needs to be updated. It was first recognised as a dermatological curiosity which evolved into a multisystem disorder with bone cysts, uveitis, and intrathoracic involvement. New dimensions were uncovered by biochemistry and immunology, bringing it still nearer the elusive enigma, namely the cause of sarcoidosis. Aetiology includes an understanding of a genetic predisposition and environmental trigger factors. What was left undone in the 20th century will become evident in the 21st century with more sophisticated technology. Likewise, conventional treatments of the past will be superseded by cytokines and other magic bullets of the millennium.


Keywords: anergy; apoptosis; homoeostasis; cytokines
doi:10.1136/pmj.77.905.177
PMCID: PMC1741943  PMID: 11222825
16.  Toll-like receptor 2 (TLR2) gene polymorphisms are not associated with sarcoidosis in the Japanese population 
Molecular Vision  2011;17:731-736.
Purpose
Sarcoidosis is a systemic inflammatory disease characterized by the formation of non-caseating granulomas, with varied clinical manifestations. The common etiology of sarcoidosis is uncertain, but it is thought to be triggered by an exogenous antigenic stimulus, such as some bacterial proteins. Toll-like receptors (TLRs) recognize microbial components and elicit innate as well as adaptive immune responses. It has been reported that polymorphisms in TLR2 might be important in a small group of Caucasian sarcoidosis patients. The present study aimed to establish whether these findings are relevant to the Japanese population.
Methods
We genotyped 5 single-nucleotide polymorphisms (SNPs) in TLR2 and assessed the allelic diversity between 257 Japanese sarcoidosis patients and 193 Japanese healthy controls.
Results
No significant differences in the frequency of TLR2 alleles and haplotypes in the sarcoidosis cases were found in comparison with the controls. However, marginal associations were observed for TLR2 at rs3804099 and rs3804100 in sarcoidosis patients with cutaneous manifestations.
Conclusions
Our results suggest that TLR2 polymorphisms are not significantly related to the pathogenesis of sarcoidosis in the Japanese population.
PMCID: PMC3062517  PMID: 21437199
17.  Multiple mycobacterial antigens are targets of the adaptive immune response in pulmonary sarcoidosis 
Respiratory Research  2010;11(1):161.
Introduction
Sarcoidosis is a multisystem granulomatous disease for which the association with mycobacteria continues to strengthen. It is hypothesized that a single, poorly degradable antigen is responsible for sarcoidosis pathogenesis. Several reports from independent groups support mycobacterial antigens having a role in sarcoidosis pathogenesis. To identify other microbial targets of the adaptive immune response, we tested the ability of CD4+ and CD8+ T cells to recognize multiple mycobacterial antigens.
Methods
Fifty-four subjects were enrolled in this study: 31 sarcoidosis patients, nine non-tuberculosis mycobacterial (NTM) infection controls, and 14 PPD- controls. Using flow cytometry, we assessed for Th1 immune responses to ESAT-6, katG, Ag85A, sodA, and HSP.
Results
Alveolar T-cells from twenty-two of the 31 sarcoidosis patients produced a CD4+ response to at least one of ESAT-6, katG, Ag85A, sodA, or HSP, compared to two of 14 PPD- controls (p = 0.0008) and five of nine NTM controls (p = 0.44), while eighteen of the 31 sarcoidosis subjects tested produced a CD8+ response to at least one of the mycobacterial antigens compared to two of 14 PPD- controls (p = 0.009) and three of nine NTM controls (0.26). Not only did the BAL-derived T cells respond to multiple virulence factors, but also to multiple, distinct epitopes within a given protein. The detection of proliferation upon stimulation with the mycobacterial virulence factors demonstrates that these responses are initiated by antigen specific recognition.
Conclusions
Together these results reveal that antigen-specific CD4+ and CD8+ T cells responses to multiple mycobacterial epitopes are present within sites of active sarcoidosis involvement, and that these antigen-specific responses are present at the time of diagnosis.
doi:10.1186/1465-9921-11-161
PMCID: PMC2999599  PMID: 21092305
18.  Sarcoidosis, microvascular angina and aortitis: New dimensions of the ‘Takayasu syndrome’ – A case report 
A case of Takayasu aortitis associated with sarcoidosis presenting with recurrent angina is reported. This association has been called ‘Takayasu syndrome’, which reflects what is likely a shared etiology. Myocardial perfusion abnormalities have recently been documented in sarcoidosis, but this case clarifies for the first time that the angina in Takayasu syndrome is likely due to small vessel coronary arteritis. Corticosteroids and cytotoxic therapy have been shown to be beneficial in all forms of sarcoidosis related to vasculitis. Initiation of steroid therapy may provide relief of angina in patients with evidence of reversible ischemia in normal coronary arteries.
PMCID: PMC2733017  PMID: 22477304
Microvascular angina; Reversible ischemia; Sarcoidosis; Takayasu aortitis
19.  A Concise Review of Pulmonary Sarcoidosis 
This is an update on sarcoidosis, focusing on etiology, diagnosis, and treatment. In the area of etiopathogenesis, we now have a better understanding of the immune response that leads to the disease as well as genetic factors that modify both the risk for the disease and its clinical outcome. Several groups have also identified possible agents as a cause for sarcoidosis. Although none of these potential causes has been definitely confirmed, there is increasing evidence to support that one or more infectious agents may cause sarcoidosis, although this organism may no longer be viable in the patient. The diagnosis of sarcoidosis has been significantly aided by new technology. This includes the endobronchial ultrasound, which has been shown to increase the yield of needle aspiration of mediastinal and hilar lymph nodes. The positive emission tomography scan has proven useful for selecting possible biopsy sites by identifying organ involvement not appreciated by routine methodology. It has also helped in assessing cardiac involvement. The biologic agents, such as the anti–tumor necrosis factor antibodies, have changed the approach to refractory sarcoidosis. There is increasing evidence that the clinician can identify which patient is most likely to benefit from such therapy. As new and more potent antiinflammatory agents have been developed, it is clear that there are other factors that burden the patient with sarcoidosis, including fatigue and sarcoidosis-associated pulmonary hypertension. There have been several recent studies demonstrating treatment options for these problems.
doi:10.1164/rccm.201006-0865CI
PMCID: PMC3081278  PMID: 21037016
mycobacterium; HLA; Löfgren syndrome; infliximab; pulmonary hypertension
20.  Immune aspects of sarcoidosis. 
Postgraduate Medical Journal  1988;64(753):536-543.
Although the initiating factor(s) is unknown, it is now accepted that pulmonary sarcoidosis develops as a result of an over-stimulated local cellular immune response. Starting as a lymphocytic alveolitis, there is a progression to granuloma formation within the interstitium as stimulated T lymphocytes release mediators capable of attracting and activating monocytes to differentiate into macrophages and epithelioid cells. We are also aware that macrophage-like cells must act as antigen presenters to initiate T cell stimulation within the immune response. To date, interest in the alveolar macrophages of patients with sarcoidosis has focused more on their passive role as responders of the soluble T cell products released as the disease progresses. This paper explores the active role of mononuclear non-lymphoid cells as inducers of immune responses, by taking advantage of monoclonal antibodies capable of discriminating between phenotypically distinct subsets of macrophages. Recent results are presented that suggest a central role for these cells in controlling the course of this disease, focusing specifically on the mechanisms underlying the failure in some patients to resolve the interstitial inflammation and subsequently progressing to fibrosis. A new hypothesis proposes that aberrations in the functional capacity of macrophages may prohibit the emergence of a granuloma-resolving mechanism in some sarcoid patients.
PMCID: PMC2428907  PMID: 3074287
21.  Cellular Responses to Mycobacterial Antigens Are Present in Bronchoalveolar Lavage Fluid Used in the Diagnosis of Sarcoidosis▿ †  
Infection and Immunity  2009;77(9):3740-3748.
Considerable evidence supports the concept that CD4+ T cells are important in sarcoidosis pathogenesis, but the antigens responsible for the observed Th1 immunophenotype remain elusive. The epidemiologic association with bioaerosols and the presence of granulomatous inflammation support consideration of mycobacterial antigens. To explore the role of mycobacterial antigens in sarcoidosis immunopathogenesis, we assessed the immune recognition of mycobacterial antigens, the 6-kDa early secreted antigenic protein (ESAT-6) and catalase-peroxidase (KatG), by T cells derived from bronchoalveolar lavage (BAL) fluid obtained during diagnostic bronchoscopy. We report the presence of antigen-specific recognition of ESAT-6 and KatG in T cells from BAL fluid of 32/44 sarcoidosis subjects, compared to 1/27 controls (P < 0.0001). CD4+ T cells were primarily responsible for immune recognition (32/44 sarcoidosis subjects), although CD8+ T-cell responses were observed (25/41 sarcoidosis subjects). Recognition was significantly absent from BAL fluid cells of patients with other lung diseases, including infectious granulomatous diseases. Blocking of Toll-like receptor 2 reduced the strength of the observed immune response. The presence of immune responses to mycobacterial antigens in cells from BAL fluid used for sarcoidosis diagnosis suggests a strong association between mycobacteria and sarcoidosis pathogenesis. Inhibition of immune recognition with monoclonal antibody against Toll-like receptor 2 suggests that induction of innate immunity by mycobacteria contributes to the polarized Th1 immune response.
doi:10.1128/IAI.00142-09
PMCID: PMC2738026  PMID: 19596780
22.  Isolated Cervical Lymph Node Sarcoidosis Presenting in an Asymptomatic Neck Mass: A Case Report 
Sarcoidosis, a systemic granulomatous disease of unknown etiology. The presentation of sarcoidal granuloma in neck nodes without typical manifestations of systemic sarcoidosis is difficult to diagnose. We describe the case of a 37-year-old woman with an increasing mass on the right side of neck. The excisional biopsy from the neck mass showed noncaseating epithelioid cell granuloma of the lymph nodes. No evidence of mycobacterial or fungal infection was noted. Thoracic evaluations did not show enlargement of mediastinal lymph nodes or parenchymal abnormalities. Immunohistochemistry showed abundant expression of tumor necrosis factor-α in the granuloma. However, transforming growth factor-β was not expressed, although interleukin-1β was focally expressed. These immunohistochemical findings supported characterization of the granuloma and the diagnosis of sarcoidosis. Sarcoidosis can present with cervical lymph node enlargement without mediastinal or lung abnormality. Immunohistochemistry may support the diagnosis of sarcoidosis and characterization of granuloma.
doi:10.4046/trd.2013.75.3.116
PMCID: PMC3790023  PMID: 24101936
Sarcoidosis; Lymphatic Diseases; Neck; Immunohistochemistry
23.  Molecular analysis of sarcoidosis lymph nodes for microorganisms: a case–control study with clinical correlates 
BMJ Open  2013;3(12):e004065.
Introduction
Sarcoidosis is an incurable, chronic granulomatous disease primarily involving the lungs and lymph nodes of unknown aetiology, treated with non-specific anti-inflammatory/immunosuppressive drugs. Persistently symptomatic patients worsen with a disabling, potentially fatal clinical course. To determine a possible infectious cause, we correlated in a case-control study the clinical information with the presence of bacterial DNA in sarcoidosis mediastinal lymph nodes compared with control lymph nodes resected during cancer surgery.
Methods
We retrospectively studied formalin-fixed, paraffin-embedded, mediastinal lymph nodes from 30 patients with sarcoidosis and 30 control patients with lung cancer. Nucleic acids were extracted from nodes, evaluated by ribosomal RNA PCR for bacterial 16S ribosomal DNA and the results were sequenced and compared with a bacterial sequence library. Clinical information was correlated.
Results
11/30 (36.7%) of lymph nodes from patients with sarcoidosis had detectable bacterial DNA, significantly more than control patient lymph nodes (2/30, 6.7%), p=0.00516. At presentation, 19/30 (63.3%) patients with sarcoidosis were symptomatic including all patients with detectable bacterial DNA. Radiographically, there were 18 stage I and 12 stage II patients. All stage II patients were symptomatic and 75% had PCR-detectable bacteria. After a mean follow-up of 52.8±32.8 months, all patients with PCR-detectable bacteria in this series were persistently symptomatic requiring treatment.
Discussion
36.6% of patients with sarcoidosis had detectable bacterial DNA on presentation, all of these patients were quite symptomatic and most were radiographically advanced stage II. These findings suggest that bacterial DNA-positive, symptomatic patients have more aggressive sarcoidosis that persists long term and might benefit from antimicrobial treatment directed against this presumed chronic granulomatous infection.
doi:10.1136/bmjopen-2013-004065
PMCID: PMC3884606  PMID: 24366580
BACTERIOLOGY; MICROBIOLOGY
24.  Active Chronic Sarcoidosis is Characterized by Increased Transitional Blood B Cells, Increased IL-10-Producing Regulatory B Cells and High BAFF Levels 
PLoS ONE  2012;7(8):e43588.
Background
Sarcoidosis is a multisystemic disease of unknown etiology characterized by a disproportionate Th1 granulomatous immune response in the organs involved. Plasmatic hypergammaglobulinemia and B cell accumulation in granulomatous lesions suggest the possible role of humoral immune responses in the pathogenesis of sarcoidosis. The purpose of this study is to describe B cell peripheral compartment in sarcoidosis.
Methodology/Principal Findings
We analyzed blood B cell subsets and BAFF levels in 33 patients with chronic sarcoidosis (active sarcoidosis n = 18; inactive sarcoidosis n = 15) and 18 healthy donors. Active chronic sarcoidosis patients had significantly less circulating memory B cells (p<0.01), more transitional (p<0.01) and increased numbers of IL-10-producing regulatory B cells (p<0.05) compared with healthy donors and patients with inactive sarcoidosis. BAFF serum levels were significantly higher in patients with active sarcoidosis (p<0.01 versus healthy donors and inactive sarcoidosis patients) and strongly correlated with serum hypergammaglobulinemia (r = 0.53, p<0.01) and angiotensin converting enzyme levels (r = 0.61, p = <0.01).
Conclusions/Significance
These data show that there is an altered B cell homeostasis in active sarcoidosis and suggest BAFF antagonist drugs as potential new treatments of this disease.
doi:10.1371/journal.pone.0043588
PMCID: PMC3425471  PMID: 22927996
25.  Sarcoidosis: still a mystery? 
Sarcoidosis is a systemic granulomatous disease of unknown etiology. It has diverse clinical manifestations, most frequently including pulmonary disorders. It is associated with immunological abnormalities, the intricacies of which have yet to be clearly delineated. In the immunologically susceptible individual, genetic, environmental, nutritional, and socioeconomic factors may play a governing role in its development. Sarcoidosis is a diagnosis of exclusion established by clinical manifestations, radiologic findings, and histologic evidence of noncaseating epithelioid-cell granulomas in >1 organ. We will discuss parameters that are helpful in making this diagnosis.
PMCID: PMC1291305  PMID: 16369580

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