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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.  Immunological Evidence for the Role of Mycobacteria in Sarcoidosis: A Meta-Analysis 
PLoS ONE  2016;11(8):e0154716.
Background
Sarcoidosis is a granulomatous disease, the etiology of which is currently unknown. The role of mycobacteria in the etiology of sarcoidosis has been extensively investigated. In this meta-analysis, we assessed the immunological evidence of the possible role of mycobacteria in the pathogenesis and development of sarcoidosis.
Methods
We performed a systematic search of relevant articles from PubMed, Embase and Cochrane Library databases published between January 1990 and October 2015. Data extracted from the articles were analyzed with Review Manager 5.3 (Cochrane Collaboration, Oxford, UK).
Results
In this meta-analysis, 13 case-control studies (733 participants) were considered eligible according to our criteria. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). The positivity incidence of the immune response (either the cell-mediated response or humoral response) in sarcoidosis patients was significantly higher than that in controls, as determined using fixed-effects model. The odds ratio (OR) of the positivity incidence of T-cell response in the patients with sarcoidosis versus the controls with PPD- or unknown PPD status was 5.54 (95% CI 3.56–8.61); the ORs were 16.70 (95% CI 8.19–34.08) and 1.48 (95% CI 0.74–2.96) for the two subgroups with PPD- controls and unknown PPD status respectively. However, the OR of the positivity incidence in patients with sarcoidosis versus PPD+ controls (latent tuberculosis infection; LTBI) was 0.26 (95% 0.10–0.66). Regarding the humoral response, pooled analysis of the positivity incidence revealed an OR (95%CI) of 20.43 (5.53–75.53) for the patients with sarcoidosis versus controls; the ORs were 11.93 (95% CI 2.15–66.27) and 41.97 (95% CI 5.24–336.15) in two subgroups of controls with PPD- and unknown PPD statuses respectively. Data on heterogeneity and evidence of publication bias were examined.
Conclusions
This meta-analysis confirmed the existence of an association between mycobacteria (especially M.tuberculosis) and sarcoidosis. The current available evidence indicates that some insoluble mycobacterial antigens that preferentially within the body are involved in the pathogenesis of sarcoidosis rather than the whole mycobacteria and that they elicit a type IV immune response.
doi:10.1371/journal.pone.0154716
PMCID: PMC4968811  PMID: 27479700
3.  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
4.  The etiologic role of infectious antigens in sarcoidosis pathogenesis 
Clinics in chest medicine  2015;36(4):561-568.
Sarcoidosis is a granulomatous disease of unknown etiology, characterized by a Th1 immunophenotype, most commonly involving the lung, skin, lymph node and eyes. Molecular and immunologic studies continue to strengthen the association of sarcoidosis with infectious antigens, particularly those derived from Propionibacterium and Mycobacterium species. Independent studies report the presence of microbial nucleic acids and proteins within sarcoidosis specimens. Complementary immunologic studies also support the role of infectious agents in sarcoidosis pathogenesis. Th-1 immune responses directed against mycobacterial virulence factors have been detected within sarcoidosis diagnostic bronchoalveolar lavage (BAL). Th1 and Th17 immune responses against propionibacteria have also been reported. More recently, case reports and clinical trials from Japanese, European and American investigators have emerged regarding the efficacy of antimicrobials against Propionibacterium and Mycobacterium species on pulmonary and cutaneous sarcoidosis. While these clinical investigations are not conclusive, they support increasing efforts to identify novel therapeutics, such as antimicrobials, that will impact the observed increase in sarcoidosis morbidity and mortality.
doi:10.1016/j.ccm.2015.08.001
PMCID: PMC4660257  PMID: 26593133
5.  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
6.  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
7.  Potential Etiologic Agents in Sarcoidosis 
The etiology of sarcoidosis remains uncertain. The hallmark of sarcoidosis is the epithelioid granuloma, which serves as a necessary starting point for considering disease etiology. Any etiologic agent of sarcoidosis must also explain the typical clinical behaviors and characteristic immunopathologic features of the disease. One clinical observation that serves as a bridge to the etiology of sarcoidosis is the Kveim reaction. In this reaction, local epithelioid granulomas develop several weeks after the intradermal injection of homogenates of sarcoidosis tissue. Our group capitalized on the known properties of the Kveim reagent to search for candidate pathogenic tissue antigens in sarcoidosis without other a priori hypotheses regarding possible microbial or autoimmune etiologies. Using a limited proteomics approach based on the physicochemical properties of Kveim reagent, we detected a limited number of poorly soluble antigenic proteins in sarcoidosis tissues by protein immunoblotting, using sarcoidosis sera. Matrix-associated laser desorption/ionization-time of flight mass spectrometry identified one of these antigens to be the Mycobacterium tuberculosis catalase–peroxidase protein (mKatG). We found IgG responses to recombinant mKatG in more than 50% of patients with sarcoidosis but rarely in purified protein derivative (PPD)-negative control subjects. These findings support the conclusion that mKatG is a tissue antigen and target of the adaptive immune response in sarcoidosis, providing further evidence of a mycobacterial etiology in a subset of sarcoidosis. More generally, the approach used in these studies might be employed to discover and validate other candidate pathogenic antigens in sarcoidosis or other granulomatous disorders.
doi:10.1513/pats.200608-155MS
PMCID: PMC2647598  PMID: 17684291
sarcoidosis; etiology; granuloma; proteomics; mycobacteria
8.  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
9.  Occupational Causes of Sarcoidosis 
Purpose of review
Sarcoidosis, the multiorgan, granulomatous disease of unknown etiology, remains mysterious. Several important investigations in the past two years add to accumulating evidence for both occupational and environmental causes of granulomatous inflammation.
Recent findings
This review considers the most recent studies that contribute to the hypothesis that sarcoidosis occurs when individuals are exposed to foreign antigens and to inorganic particulates that promote inflammation. Major recent findings, such as those emerging from the study of World Trade Center responders, the study of nanoparticles, and cases of work-associated sarcoidosis support the probability that occupational, as well as environmental, exposures to inflammatory stimuli trigger sarcoidosis-like illness. Major recent studies of microbially-rich indoor environments, including moldy indoor workplaces and mycobacterially-contaminated settings, contribute to the evidence that a variety of microbial antigens serve as targets for the hypersensitivity immune response in an inflammatory milieu.
Summary
There is increasing evidence that sarcoidosis can occur in workplace settings in which there is exposure to both foreign antigens and inorganic triggers of inflammation that promote an exuberant granulomatous immune response. It is likely that sarcoidosis has more than one cause.
doi:10.1097/ACI.0b013e3283515173
PMCID: PMC4196683  PMID: 22314258
Sarcoidosis; Occupation; Granuloma; Nanoparticle; World Trade Center
10.  Association of serum TNF-α, IL-8 and free light chain with HLA-DR B alleles expression in pulmonary and extra-pulmonary sarcoidosis 
Background
Sarcoidosis is a systemic disease of unknown etiology characterized histologically by the observation of non-caseating granulomas and several immunological abnormalities. Sarcoidosis is a multi-organ disorder which involves formation of granulomas in many tissues including the lungs (pulmonary) and others such as skin, bone, heart (extra pulmonary). Associations between human leukocyte antigens (HLA), the encoded cell surface receptor (HLA-DR) and sarcoidosis have been reported in several studies. Several HLA-DR alleles have been described as potential risk factors for sarcoidosis in distinct ethnic groups however evidence for a relationship between HLA-DR alleles and pulmonary and extra-pulmonary sarcoidosis (EPS) is still scarce. Although the etiology of the disease remains unclear, infectious and environmental factors have been postulated. Inflammatory cytokines and chemokines may play important roles in the pathogenesis of sarcoidosis and serum free light chain (FLC) numbers have been implicated in several immunologic disorders.
Purpose of the study
The aim of the present study was to investigate HLA associations with serum cytokines and FLC in Iranian patients with pulmonary (n = 86) and EPS (n = 46).
Results
We found that among the 16 HLA DRB alleles only *7 and *12 were different in sarcoidosis patients. The levels of TNF-α and IL-8 in pulmonary sarcoidosis patients were higher than in EPS (P < 0.05) whereas the levels of FLC subunits in EPS were higher than in pulmonary sarcoidosis.
Conclusion
This data may suggests a link between HLA-DRB *12 and sarcoidosis in Iranian population.
doi:10.1186/s12950-015-0066-3
PMCID: PMC4393873  PMID: 25866481
Sarcoidosis; HLA-DR; TNF-α; IL-8
11.  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
12.  Sarcoidosis following Mycobacterium tuberculosis infection: Coincidence or consequence 
We describe the case of a 47-year-old Caucasian male patient who developed sarcoidosis 18 months after he was diagnosed with pulmonary tuberculosis for which he was treated according to guidelines. The presentation of sarcoidosis was very similar to his first presentation when he was diagnosed with tuberculosis.
Mycobacterium tuberculosis as a possible aetiological agent in sarcoidosis has been point of debate since many years and has been studied thoroughly. Recent advances in immunologic and molecular techniques have strengthened the association between mycobacteria and sarcoidosis.1
Sarcoidosis is a systemic inflammatory disorder of unknown aetiology, characterised by the presence of non-caseating epitheloid cell granulomas. It is generally agreed that this is a tissue reaction to environmental agents in a genetically susceptible individual.2 Tuberculosis is an infectious disease caused by M. tuberculosis and characterised by caseating granulomas. In both clinical and histopathological features sarcoidosis is remarkably similar to tuberculosis and therefore can be difficult to distinguish.
First, this case report demonstrates the need of diagnostic testing when reactivation of tuberculosis is suspected. And second the role of M. tuberculosis in the aetiology of sarcoidosis will be discussed.
doi:10.1016/j.rmcr.2013.03.006
PMCID: PMC3949549  PMID: 26029621
Tuberculosis; Sarcoidosis; Aetiology
13.  Sarcoidosis 
Sarcoidosis is a multisystemic disorder of unknown cause characterized by the formation of immune granulomas in involved organs. It is an ubiquitous disease with incidence (varying according to age, sex, race and geographic origin) estimated at around 16.5/100,000 in men and 19/100,000 in women. The lung and the lymphatic system are predominantly affected but virtually every organ may be involved. Other severe manifestations result from cardiac, neurological, ocular, kidney or laryngeal localizations. In most cases, sarcoidosis is revealed by persistent dry cough, eye or skin manifestations, peripheral lymph nodes, fatigue, weight loss, fever or night sweats, and erythema nodosum. Abnormal metabolism of vitamin D3 within granulomatous lesions and hypercalcemia are possible. Chest radiography is abnormal in about 90% of cases and shows lymphadenopathy and/or pulmonary infiltrates (without or with fibrosis), defining sarcoidosis stages from I to IV. The etiology remains unknown but the prevailing hypothesis is that various unidentified, likely poorly degradable antigens of either infectious or environmental origin could trigger an exaggerated immune reaction in genetically susceptible hosts. Diagnosis relies on compatible clinical and radiographic manifestations, evidence of non-caseating granulomas obtained by biopsy through tracheobronchial endoscopy or at other sites, and exclusion of all other granulomatous diseases. The evolution and severity of sarcoidosis are highly variable. Mortality is estimated at between 0.5–5%. In most benign cases (spontaneous resolution within 24–36 months), no treatment is required but a regular follow-up until recovery is necessary. In more serious cases, a medical treatment has to be prescribed either initially or at some point during follow-up according to clinical manifestations and their evolution. Systemic corticosteroids are the mainstay of treatment of sarcoidosis. The minimal duration of treatment is 12 months. Some patients experience repeated relapses and may require long-term low-dose corticosteroid therapy during years. Other treatments (immunosuppressive drugs and aminoquinolins) may be useful in case of unsatisfactory response to corticosteroids, poor tolerance and as sparing agents when high doses of corticosteroids are needed for a long time. In some strictly selected cases refractory to standard therapy, specific antiTNF-α agents may offer precious improvement. Some patients benefit from topical corticosteroids.
doi:10.1186/1750-1172-2-46
PMCID: PMC2169207  PMID: 18021432
14.  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
15.  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
16.  Mycobacterium tuberculosis as a sarcoid factor? A case report of family sarcoidosis 
Patient: Male, 26
Final Diagnosis: Sarcoidosis
Symptoms: Disseminated lung parenchymal changes
Medication: —
Clinical Procedure: —
Specialty: Pulmonology
Objective:
Rare disease
Background:
Sarcoidosis is a granulomatous inflammatory disease that is induced by unknown antigen(s) in a genetically susceptible host. Although the direct link between Mycobacterium tuberculosis (MTB) infection and sarcoidosis can be excluded on the basis of a current knowledge, the non-infectious mechanisms may explain the causative role of mycobacterial antigens. The co-incidence of tuberculosis (TB) and sarcoidosis, and higher incidence of mycobacterial DNA in biological samples of sarcoid patients, have been reported by many authors.
Case Report:
We present a case in which MTB infection in 1 family member triggered a sarcoid reaction in the infected subject and 2 other non-infected family members. We discuss different aspects of diagnosis and differentiation, as well as up-to-date hypotheses on the possible mechanisms leading to sarcoid inflammation in patients exposed to MTB.
Conclusions:
This case series documents the possibility of familial spreading of sarcoidosis, and points to MTB as a potential etiological factor.
doi:10.12659/AJCR.890014
PMCID: PMC4026149  PMID: 24847413
Tuberculosis; Mycobacterium Tuberculosis; Sarcoidosis
17.  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
18.  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
19.  Sarcoidosis: Immunopathogenesis and Immunological Markers 
Sarcoidosis is a multisystem granulomatous disorder invariably affecting the lungs. It is a disease with noteworthy variations in clinical manifestation and disease outcome and has been described as an “immune paradox” with peripheral anergy despite exaggerated inflammation at disease sites. Despite extensive research, sarcoidosis remains a disease with undetermined aetiology. Current evidence supports the notion that the immune response in sarcoidosis is driven by a putative antigen in a genetically susceptible individual. Unfortunately, there currently exists no reliable biomarker to delineate the disease severity and prognosis. As such, the diagnosis of sarcoidosis remains a vexing clinical challenge. In this review, we outline the immunological features of sarcoidosis, discuss the evidence for and against various candidate etiological agents (infective and noninfective), describe the exhaled breath condensate, a novel method of identifying immunological biomarkers, and suggest other possible immunological biomarkers to better characterise the immunopathogenesis of sarcoidosis.
doi:10.1155/2013/928601
PMCID: PMC4590933  PMID: 26464848
20.  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
21.  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
22.  Sarcoidosis with Multi-organ Involvement Presenting as Ventricular Tachycardia 
Introduction:
Sarcoidosis is a granulomatous disease which can affect any organ, but most commonly presents with pulmonary manifestations. We present an unusual case of sarcoidosis with multiorgan involvement which initially manifested as ventricular tachycardia; the patient was subsequently found to have extensive cardiac, respiratory, skin, and hepatic involvement.
Case Report:
An otherwise healthy 35-year-old African American soldier presented to emergency care with hypotension and tachycardia greater than 200 beats per minute. He was found to be in sustained ventricular tachycardia with a pulse. Defibrillation was performed, the patient was loaded with amiodarone, and hospitalized. Cardiac catheterization showed no evidence of atherosclerotic coronary artery disease. A cardiac MRI revealed high density lesions in the lateral wall and apex, and diffusely decreased left ventricular wall motion. An implantable cardiac defibrillator (ICD) was placed. Further questioning revealed a six month history of twenty pounds weight loss, persistent nasal congestion, and subcutaneous nodules. Biopsy of two subcutaneous nodules from the left upper extremity and nasal mucosa biopsy demonstrated noncaseating granulomas. His evaluation was notable for a mixed pattern hepatic injury, normocytic anemia, elevated lactate dehydrogenase, and a CT chest showing hilar and mediastinal adenopathy with multiple pulmonary nodules. Sarcoidosis was suspected and additional testing for HIV, EBV, vasculitis, lymphoma, fungal infection, and mycobacterial infection was negative. Pulmonary function tests showed normal basic spirometry and DLCO. Transthoracic echocardiogram demonstrated normal ejection fraction, and an 8mm cystic structure partially incorporated in the left ventricular wall. This was suspected to be a granulomatous accumulation. Sestamibi imaging showed a dense defect involving the apex and a medium sized, moderate severity, inferior wall defect consistent with an infiltrative process. Interrogation of his ICD six months after placement demonstrated no recurrence of arrhythmia. Initially, he was treated with 40mg prednisone daily. After a three-month course he had continued active disease and was treated with infliximab. His treatment is ongoing; lab parameters are improving.
Discussion:
Cardiac sarcoidosis is rare. Conduction abnormalities are the most common finding, and arrhythmias are second. Heart failure, valvular dysfunction, and chronic effusion are also frequently observed, and one case report describes a large left atrial mass which behaved like a myxoma. This patient's case is unusual because of his large degree of sinus and cardiac involvement, as well as his unusual left ventricular cystic structure. Sarcoidosis should be considered in all patients who have unexplained structural heart disease, particularly young individuals. Treatment of cardiac sarcoidosis is aimed at controlling inflammation and preventing compromise of cardiac structure or function. Sources agree that steroids are an effective initial treatment, but the initial dose and optimal duration are unclear. This patient's course suggests that infliximab is an efficacious treatment option in severe cases.
PMCID: PMC4175938
23.  Development of a T7 Phage Display Library to Detect Sarcoidosis and Tuberculosis by a Panel of Novel Antigens 
EBioMedicine  2015;2(4):341-350.
Sarcoidosis is a granulomatous inflammatory disease, diagnosed through tissue biopsy of involved organs in the absence of other causes such as tuberculosis (TB). No specific serologic test is available to diagnose and differentiate sarcoidosis from TB. Using a high throughput method, we developed a T7 phage display cDNA library derived from mRNA isolated from bronchoalveolar lavage (BAL) cells and leukocytes of sarcoidosis patients. This complex cDNA library was biopanned to obtain 1152 potential sarcoidosis antigens and a microarray was constructed to immunoscreen two different sets of sera from healthy controls and sarcoidosis. Meta-analysis identified 259 discriminating sarcoidosis antigens, and multivariate analysis identified 32 antigens with a sensitivity of 89% and a specificity of 83% to classify sarcoidosis from healthy controls. Additionally, interrogating the same microarray platform with sera from subjects with TB, we identified 50 clones that distinguish between TB, sarcoidosis and healthy controls. The top 10 sarcoidosis and TB specific clones were sequenced and homologies were searched in the public database revealing unique epitopes and mimotopes in each group. Here, we show for the first time that immunoscreenings of a library derived from sarcoidosis tissue differentiates between sarcoidosis and tuberculosis antigens. These novel biomarkers can improve diagnosis of sarcoidosis and TB, and may aid to develop or evaluate a TB vaccine.
Highlights
•Immunity plays a major role in a vast array of human diseases.•Sarcoidosis shares similarities with non-infectious and infectious granulomatous diseases, including tuberculosis.•A highly sensitive and specific T7 phage library discriminates the immune signature between sarcoidosis patients and TB.
doi:10.1016/j.ebiom.2015.03.007
PMCID: PMC4465182  PMID: 26086036
T7 Phage library; Sarcoidosis; Tuberculosis; IgG; Microarray; Immunoscreening
24.  Mycobacterial catalase–peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis 
Sarcoidosis is a disease of unknown etiology characterized by noncaseating epithelioid granulomas, oligoclonal CD4+ T cell infiltrates, and immune complex formation. To identify pathogenic antigens relevant to immune-mediated granulomatous inflammation in sarcoidosis, we used a limited proteomics approach to detect tissue antigens that were poorly soluble in neutral detergent and resistant to protease digestion, consistent with the known biochemical properties of granuloma-inducing sarcoidosis tissue extracts. Tissue antigens with these characteristics were detected with immunoglobulin (Ig)G or F(ab′)2 fragments from the sera of sarcoidosis patients in 9 of 12 (75%) sarcoidosis tissues (150–160, 80, or 60–64 kD) but only 3 of 22 (14%) control tissues (all 62–64 kD; P = 0.0006). Matrix-assisted laser desorption/ionization time of flight mass spectrometry identified Mycobacterium tuberculosis catalase–peroxidase (mKatG) as one of these tissue antigens. Protein immunoblotting using anti-mKatG monoclonal antibodies independently confirmed the presence of mKatG in 5 of 9 (55%) sarcoidosis tissues but in none of 14 control tissues (P = 0.0037). IgG antibodies to recombinant mKatG were detected in the sera of 12 of 25 (48%) sarcoidosis patients compared with 0 of 11 (0%) purified protein derivative (PPD)− (P = 0.0059) and 4 of 10 (40%) PPD+ (P = 0.7233) control subjects, suggesting that remnant mycobacterial catalase–peroxidase is one target of the adaptive immune response driving granulomatous inflammation in sarcoidosis.
doi:10.1084/jem.20040429
PMCID: PMC2212832  PMID: 15753209
25.  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

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