Inflammation In Sarcoidosis Research Articles

Efficacy and Safety of Conventional Transbronchial Needle Aspiration in Sarcoidosis: A Systematic Review and Meta-analysis

Flexible bronchoscopic procedures are currently the most often employed technique for demonstrating granulomatous inflammation in sarcoidosis. Conventional transbronchial needle aspiration (TBNA) has been used for over 3 decades; however, it remains an underutilized technique, primarily due to the wide variations in the reported success rates and unconfirmed safety concerns. Herein we perform a systematic review and meta-analysis of studies to estimate the diagnostic yield and safety of TBNA in sarcoidosis. We searched the PubMed and EmBase databases for studies (1980 to January 2012) reporting the efficacy of TBNA in sarcoidosis. The quality of studies was assessed using the QualSyst tool. The efficacy of TBNA in individual studies was calculated as proportions and 95% CIs, and the results were pooled using a random effects model. Heterogeneity and publication bias were assessed for the individual outcomes. Our search yielded 21 studies (915 patients). The diagnostic yield of TBNA ranged from 6-90%, with the pooled efficacy being 62% (95% CI 52-71%) by the random effects model. TBNA was not associated with any major complication. The diagnostic yield increased to 83% if transbronchial lung biopsy (TBLB) was additionally performed, albeit with increased complications. There was evidence of heterogeneity and publication bias, which significantly decreased on sensitivity analysis after exclusion of retrospective studies. TBNA is an efficacious and safe procedure in the diagnosis of sarcoidosis. The performance of TBLB adds to the efficacy of TBNA. Hence, a combination of TBNA and TBLB should be routinely employed in diagnosis of sarcoidosis in those with enlarged mediastinal lymph nodes.

Th1/Th2/Th17‑related cytokines in the bronchoalveolar lavage fluid of patients with sarcoidosis: association with smoking

Sarcoidosis is a multiorgan granulomatous disease of unknown etiology. The predominance of Th1‑related cytokines is observed in the bronchoalveolar fluid (BALF) in pulmonary sarcoidosis. Recently, Th17 cells have been postulated to be involved in the pathogenesis of sarcoidosis. Sarcoidosis is more prevalent in nonsmokers than in smokers. The exact effect of smoking on granulomatous inflammation in this disease remains unclear. The aim of the study was to evaluate the Th1/Th2/Th17‑related cytokine concentration in the BALF of patients with pulmonary sarcoidosis in relation to smoking status. The study included 74 patients with confirmed pulmonary sarcoidosis. Data on smoking status were available for 61 patients (26 ever‑smokers, 35 never‑smokers; mean 11 ±9.1 pack-years in smokers). The concentrations of interleukin (IL) 17A (IL‑17A), IL‑10, IL‑6, IL‑4, and IL‑2 as well as interferon γ (IFN‑γ) and tumor necrosis factor α (TNF‑α) were measured in BALF supernatants using a flow cytometry method--the Cytometric Bead Array. The median concentration of IL‑6, IFN‑γ, and IL‑17A (2.19 pg/ml, 1.28 pg/ml, and 6.08 pg/ml, respectively) did not differ significantly between smokers and nonsmokers. TNF‑α, IL‑10, IL‑4 and IL‑2 levels were below the detection limit in most patients. We observed a significant correlation between IFN‑γ concentration and the number of macrophages in BALF (r = 0.66, P <0.05) and between IL‑17A and IL‑6 levels (r = 0.94, P <0.05). We confirmed a significant role of IL‑6, IFN‑γ, and IL-17A in the local inflammatory response in sarcoidosis. However, the interpretation of the limited number of cytokine measurements should be made with caution. Further studies are needed to explain the effect of smoking on the pathomechanism of inflammation in sarcoidosis.

7T Brain MR Imaging of Neurosarcoidosis: Preliminary Observations (S08.006)

Objective: To describe imaging characteristics of neurosarcoidosis on unenhanced 7T MRI. Background Non-caseating granulomatous inflammation in sarcoidosis is characterized by organized collections of mononuclear phagocytes, cells that are known to sequester microscopic quantities of calcium, iron and ferritin. We hypothesized that 7 tesla MR phase imaging, due to its high spatial resolution, sensitivity to these compounds, and ability to visualize tiny venous structures, would reveal novel features of neurosarcoidosis not currently visualized using 3T MRI. Design/Methods: Pilot study of 7T MRI in patients with neurosarcoidosis. Diagnosis was established by confirmatory biopsy of CNS tissue or extra-CNS tissue in patients with an otherwise typical neurological syndrome. Participants underwent imaging on a 7T GE scanner using a 2D T2*-weighted gradient echo sequence at 190 x 260 micron in-plane resolution (TR/TE=250/12 msec, 20 degree flip angle, 2 mm slice thickness, 3 signal averages). Magnitude and unwrapped phase images were generated from the raw image data using in-house software. Results: 7T MRI was performed in six patients with CNS sarcoidosis, 3 with definite disease and 3 with probable disease (the latter established by mediastinal/lung biopsy). All participants were on immunosuppressive therapy at time of imaging, and four had active disease at the time 7T MRI was performed. Three distinctive imaging features emerged: 1) several enhancing lesions at 3T were seen as T2* hypointense nodules on 7T images; 2) lesions seen on 3T T2-weighted sequences tended to spread across multiple veins in the white matter on 7T, rather than a single vein; 3) perimedullary veins on 7T sometimes appeared distorted in regions that corresponded to areas of meningeal and perivascular enhancement on 3T. These features differ in several respects from initial reports of 7T MRI of demyelinating plaques in MS. Conclusions: Active neurosarcoidosis lesions exhibit distinctive features on 7T MRI that may assist in noninvasive diagnosis. Supported by: American Academy of Neurology Clinical Research Training Fellowship (JMG). Disclosure: Dr. Gelfand has received personal compensation in an editorial capacity for Journal Watch Neurology. Dr. Green has received personal compensation for activities with Novartis and Biogen Idec as a consultant and/or participant on an advisory board and adjudication committee. Dr. Hess has nothing to disclose.

Sarcoidosis Blood Transcriptome Reflects Lung Inflammation and Overlaps with Tuberculosis

Sarcoidosis is a granulomatous disease of unknown etiology, although M. tuberculosis may play a role in the pathogenesis. The traditional view holds that inflammation in sarcoidosis is compartmentalized to involved organs. To determine whether whole blood gene expression signatures reflect inflammatory pathways in the lung in sarcoidosis and whether these signatures overlap with tuberculosis. We analyzed transcriptomic data from blood and lung biopsies in sarcoidosis and compared these profiles with blood transcriptomic data from tuberculosis and other diseases. Applying machine learning algorithms to blood gene expression data, we built a classifier that distinguished sarcoidosis from health in derivation and validation cohorts (92% sensitivity, 92% specificity). The most discriminative genes were confirmed by quantitative PCR and correlated with disease severity. Transcript profiles significantly induced in blood overlapped with those in lung biopsies and identified shared dominant inflammatory pathways (e.g., Type-I/II interferons). Sarcoidosis and tuberculosis shared more overlap in blood gene expression compared with other diseases using the 86-gene signature reported to be specific for tuberculosis and the sarcoidosis signature presented herein, although reapplication of machine learning algorithms could identify genes specific for sarcoidosis. These data indicate that blood transcriptome analysis provides a noninvasive method for identifying inflammatory pathways in sarcoidosis, that these pathways may be leveraged to complement more invasive procedures for diagnosis or assessment of disease severity, and that sarcoidosis and tuberculosis share overlap in gene regulation of specific inflammatory pathways.

Lung and blood Th1 and Th17 responses against mycobacterial antigens in patients with pulmonary sarcoidosis. (114.9)

Abstract Sarcoidosis is an inflammatory disorder characterized by granulomas most commonly affecting the lungs. The presence of mycobacterial antigens, and recently a specific protein, M. tuberculosis catalase-peroxidase (mKatG), in sarcoidosis tissue has been reported. Th1 cell responses against mKatG have been observed in sarcoidosis lung and peripheral blood cells. IL-17 and IFNγ were evaluated by ELISPOT after stimulation of bronchoalveolar lavage (BAL) fluid and peripheral blood cells with mKatG and M. tuberculosis PPD proteins. Two groups of sarcoidosis patients were compared: HLA-DR3 positive (good prognosis) versus HLA-DR3 negative (bad prognosis). We also did dual-color Fluorospot assay and immunohistochemistry for further characterization. Both mKatG and PPD stimulation of BAL cells resulted in higher frequencies of cells producing IFNγ compared to IL-17. We did not detect any significant difference between BAL and blood regarding IL-17 secretion after stimulation with mKatG, while significantly more BAL cells produced IFNγ in comparison to blood after stimulation with mKatG (p&amp;lt;0.05). Preliminary data do not indicate any difference between patient subgroups regarding IL-17 production. The existence of IL-17+ cells in the granulomas also supports the role of IL-17 in sarcoidosis. The observed Th17 responses against mycobacterial antigens could contribute to the inflammation in sarcoidosis, although they generally occur at lower frequencies than corresponding Th1 responses.

Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis

Oxidative stress and low antioxidant levels are implicated in the aetiology of sarcoidosis, an inflammatory disease. Quercetin is a potent dietary antioxidant that also displays anti-inflammatory activities. Consequently, the aim is to examine the effect of quercetin supplementation on markers of oxidative stress and inflammation in sarcoidosis.A double-blind intervention study has been conducted with two groups of non-smoking, un-treated sarcoidosis patients, matched for age and gender. One group was given 4x500 mg quercetin (n = 12) orally within 24 h, the other one placebo (n = 6). Plasma malondialdehyde levels were used as marker of oxidative damage, plasma ratios of TNFα/IL-10 and IL-8/IL-10 as pro-inflammatory markers.Quercetin supplementation improved the antioxidant defence, indicated by the increased total plasma antioxidant capacity. Moreover, quercetin supplementation also reduced markers of oxidative stress and inflammation in the blood of sarcoidosis patients. The effects of quercetin supplementation appeared to be more pronounced when the levels of the oxidative stress and inflammation markers were higher at baseline.Sarcoidosis patients might benefit from the use of antioxidants, such as quercetin, to reduce the occurring oxidative stress as well as inflammation. The effects of long-term use of antioxidant supplementation in sarcoidosis, using e.g. quercetin, on improvement of lung function remain to be investigated. (www.clinicaltrials.gov; NCT-00402623).

The selected genetic polymorphisms of metalloproteinases MMP2, 7, 9 and MMP inhibitor TIMP2 in sarcoidosis

SummaryBackgroundIncreased activity of metalloproteinases may play a role in the initiation and propagation of inflammation in sarcoidosis, and may also be one of the factors responsible for the development of lung fibrosis. The aim of this study was to verify whether polymorphisms of MMP2 C-735T, MMP7 A-181G, MMP9 T-1702A and tissue inhibitor of metalloproteinase (TIMP)2 G-418C predispose to sarcoidosis.Material/MethodsThe study included 139 patients with sarcoidosis and 100 healthy subjects. MMPs and TIMP2 mRNA were measured in peripheral blood lysate using real-time RT-PCR. DNA for genetic polymorphism was extracted from peripheral blood by GTC method. Protein concentrations in peripheral blood lysates were measured by ELISA, and MMP2 and 9 activities in BAL fluid were estimated by gel zymography.ResultsTT genotype in MMP9 T-1702A was more frequent in sarcoidosis (p<0.0001, OR=13.71, 95% CI 7.02–26.80) and resulted in higher expression of MMP9 mRNA (p<0.0001). No differences were found between TT and AT/AA patients in terms of radiological stage, lung function test parameters, activity markers and the presence/absence of Löfgren syndrome. There were no differences in the distribution of MMP2, MMP7 and TIMP2 polymorphisms. Messenger RNAs, as well as protein concentrations of MMP2, 7, 9, and TIMP2 were elevated in patients with sarcoidosis (p<0.0001 for each).ConclusionsThe TT homozygotes of MMP9 T-1702A genotype may be predisposed to sarcoidosis. Elevated MMP2, 7, 9, and TIMP2 mRNAs suggest their inducibility.

Low Levels of NF-κB/p65 Mark Anergic CD4+T Cells and Correlate with Disease Severity in Sarcoidosis

T lymphocytes from patients with sarcoidosis respond weakly when stimulated with mitogen or antigen. However, the mechanisms responsible for this anergy are not fully understood. Here, we investigated the protein levels of nuclear transcription factor NF-κB (p50, p65, and p105), IκBα (inhibitor of NF-κB), T-cell receptor (TCR) CD3ζ-chain, tyrosine kinase p56(LCK), and nuclear factor of activated T cells c2 (NF-ATc2) in peripheral blood CD4(+) T cells from patients with sarcoidosis. Baseline expression of p65 in these lymphocytes was reduced in 50% of patients. The reduced levels of p65 in sarcoid CD4(+) T cells concurred with decreased levels of p50, p105, CD3ζ, p56(LCK), IκBα, and NF-ATc2. Polyclonal stimulation of NF-κB-deficient sarcoid T cells resulted in reduced expression of CD69 and CD154, decreased proliferation, and cytokine (i.e., interleukin 2 [IL-2] and gamma interferon [IFN-γ]) production. The clinical significance of these findings is suggested by the association between low p65 levels and the development of more severe and active sarcoidosis. Although correlative, our results support a model in which multiple intrinsic signaling defects contribute to peripheral T-cell anergy and the persistence of chronic inflammation in sarcoidosis.

Pro: The treatment of the granulomatous response is beneficial in acute sarcoidosis

Corticosteroids effectively suppress granulomatous inflammation in sarcoidosis. However, the role of corticosteroids remains unsettled nearly sixty years after the first report of their benefits. As in other contentious areas of medicine, we prioritize evidence from controlled clinical trials to guide decision-making. Despite the paucity of randomized, double-blind controlled evidence, the preponderance of data from the available trials is congruent: treatment of acute sarcoidosis is “on-balance” beneficial. To provide focus, I will limit my comments to recent-onset pulmonary sarcoidosis, defined as less than five years since diagnosis.

Proinflammatory exosomes in bronchoalveolar lavage fluid of patients with sarcoidosis

BackgroundSarcoidosis is a systemic disease of unknown aetiology characterised by granuloma formation and the presence of interferon γ (IFNγ)-producing T cells that cause inflammation and tissue damage in multiple organs,...

Dysregulation of p38 and MKP-1 in Response to NOD1/TLR4 Stimulation in Sarcoid Bronchoalveolar Cells

Sarcoidosis is a systemic inflammatory disorder characterized by distinct up-regulation of Th1 cytokines, such as tumor necrosis factor (TNF)-α and IL-12. The mechanism underlying this up-regulation remains unclear. Recognition of microbial moieties through Toll-like or Nod-like receptors evokes sequential activation of mitogen-activated protein kinases (MAPKs), which plays a role in Th1-immune response. To test the hypothesis that dysregulation in MAPK signaling in response to microbial stimulation is important in mediating Th1 response in sarcoidosis. Ex vivo cultured bronchoalveolar lavage (BAL) cells isolated from patients with sarcoidosis and control subjects were stimulated with low-dose Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain 1 (NOD1) ligands as a model of microbial stimulation, and MAPK signaling and inflammatory response were analyzed. BAL cells from patients with sarcoidosis exhibited higher basal p38 activity, greater p38 phosphorylation, and more robust production of TNF-α and IL-12/IL-23p40 on stimulation with NOD1 and TLR4 agonists than cells isolated from control subjects. In contrast, control BAL cells had greater basal extracellular signal-regulated kinase (ERK) activity and NOD1 and TLR4 agonists preferentially activated the ERK pathway. Inhibition of p38, but not ERK, attenuated production of both IL12/IL23p40 and TNF-α. Interestingly, stimulation of cells from patients with sarcoidosis with either NOD1 or TLR4 ligand failed to induce MAPK phosphatase 1 (MKP-1). Adenovirus-mediated overexpression of MKP-1 attenuated p38 activation and decreased the production of IL12/IL23p40 and TNF-α in sarcoid BAL cells. Our results suggest that enhanced p38 signaling in response to microbial products is caused by abnormal regulation of MKP-1 and contributes to heightened inflammation in sarcoidosis.

Treatment of Sarcoidosis

Sarcoidosis is an immune-mediated systemic syndrome of unknown etiology. The treatment of the granulomatous inflammation in sarcoidosis is thus dependent on nonspecific suppression of the immune response. Although steroid-sparing approaches have moved to front-line therapy for many other immune-mediated inflammatory diseases, corticosteroids remain the initial treatment of choice for most patients with sarcoidosis due in large part to the clinical variability and high rates of spontaneous remission. Given the heterogeneity of clinical phenotypes between patients, treatment approaches must be individualized. For patients with persistent disease, or for patients who are intolerant of systemic steroids, there are several steroid-sparing immune-modulating medications that have been effective for treating sarcoidosis. Besides immunosuppressives, we will also overview several sarcoidosis-related issues that contribute to patient-reported symptoms, a "sarcoidosis penumbra." Recognition and judicious therapy for these related issues are often key to optimizing outcomes and quality of life.

Serum Amyloid A Regulates Granulomatous Inflammation in Sarcoidosis through Toll-like Receptor-2

The critical innate immune mechanisms that regulate granulomatous inflammation in sarcoidosis are unknown. Because the granuloma-inducing component of sarcoidosis tissues has physicochemical properties similar to those of amyloid fibrils, we hypothesized that host proteins capable of forming poorly soluble aggregates or amyloid regulate inflammation in sarcoidosis. To determine the role of the amyloid precursor protein, serum amyloid A, as an innate regulator of granulomatous inflammation in sarcoidosis. Serum amyloid A expression was determined by immunohistochemistry in sarcoidosis and control tissues and by ELISA. The effect of serum amyloid A on nuclear factor (NF)-kappaB induction, cytokine expression, and Toll-like receptor-2 stimulation was determined with transformed human cell lines and bronchoalveolar lavage cells from patients with sarcoidosis. The effects of serum amyloid A on regulating helper T cell type 1 (Th1) granulomatous inflammation were determined in experimental models of sarcoidosis, using Mycobacterium tuberculosis catalase-peroxidase. We found that the intensity of expression and distribution of serum amyloid A within sarcoidosis granulomas was unlike that in many other granulomatous diseases. Serum amyloid A localized to macrophages and giant cells within sarcoidosis granulomas but correlated with CD3(+) lymphocytes, linking expression to local Th1 responses. Serum amyloid A activated NF-kappaB in Toll-like receptor-2-expressing human cell lines; regulated experimental Th1-mediated granulomatous inflammation through IFN-gamma, tumor necrosis factor, IL-10, and Toll-like receptor-2; and stimulated production of tumor necrosis factor, IL-10, and IL-18 in lung cells from patients with sarcoidosis, effects inhibited by blocking Toll-like receptor-2. Serum amyloid A is a constituent and innate regulator of granulomatous inflammation in sarcoidosis through Toll-like receptor-2, providing a mechanism for chronic disease and new therapeutic targets.

Antioxidant status associated with inflammation in sarcoidosis: A potential role for antioxidants

Enhanced production of reactive oxygen species (ROS), capable of reducing endogenous defense levels and enhancing inflammation, is suggested to play a role in sarcoidosis. Antioxidant supplementation might offer protection against such ROS-mediated damage. A promising candidate for antioxidant supplementation is the flavonoid quercetin. To determine the antioxidant and inflammatory status in sarcoidosis. Furthermore, the potential of quercetin to mitigate the occurring inflammation will be assessed. Non-smoking sarcoidosis patients and healthy controls matched for age, gender and dietary behavior were enrolled (NCT-00512967). Measurements included assessment of total plasma antioxidant capacity, vitamin C, uric acid, glutathione, basal and LPS-induced levels of tumor necrosis factor alpha (TNFalpha), interleukin (IL)-8 and -10 as well as the effect of quercetin on these levels. Compared to their controls, the sarcoidosis patients displayed significantly lower total plasma antioxidant capacity, decreased levels of vitamin C, uric acid and glutathione and increased levels of basal TNFalpha and IL-8. Quercetin significantly decreased ex vivo LPS-induced TNFalpha- and IL-8 production in a concentration-dependent manner in both groups. Interestingly, this quercetin effect was more pronounced in sarcoidosis patients. The endogenous antioxidant defense was significantly reduced in sarcoidosis, indicating that oxidative stress underlies the pathology of this disease. Furthermore, the inflammatory status was significantly enhanced in sarcoidosis. Finally, our results regarding the effect of quercetin on cytokine production imply that sarcoidosis patients might benefit from antioxidant supplementation not only by empowering the relatively low protection against ROS but also by reducing inflammation.

Increased levels of nerve growth factor in the airways of patients with sarcoidosis

Nerve growth factor (NGF) is a potent neuronal growth factor with inflammatory properties that recently has been proposed to be of importance in airway pathology. A role for NGF in the inflammatory granulomatous lung disease sarcoidosis is not well elucidated. The aims of this study were to investigate the secreted levels of NGF in bronchoalveolar lavage fluid (BALF) from sarcoidosis patients compared with patients with resolved disease, patients with another granulomatous disease--chronic beryllium disease (CBD)--and healthy subjects and also to investigate the relationship between NGF levels and markers of inflammation. NGF levels in BALF from 56 patients with active sarcoidosis (22 with Löfgren's syndrome), nine subjects with resolved sarcoidosis, six patients with CBD, and 31 healthy subjects were compared. A 10-fold elevation of NGF levels was found in patients with active sarcoidosis compared with subjects with clinically resolved sarcoidosis, patients with CBD and healthy subjects. In sarcoidosis patients, positive correlations between concentrations of NGF and lymphocytes, eosinophils and interferon-gamma, interleukin (IL)-4, IL-10, IL-12 were found. We demonstrate that secreted levels of NGF are markedly enhanced in the airways in active pulmonary sarcoidosis. Furthermore, a relationship between NGF and pulmonary inflammation in sarcoidosis is supported.

Monocyte heterogeneity in angiotensin-converting enzyme induction mediated by autologous T lymphocytes.

The ability of monocyte subpopulations to be induced selectively by T lymphocytes to synthesize enhanced levels of angiotensin-converting enzyme (ACE) was examined using an in vitro model employing normal peripheral blood monocytes and T lymphocytes. Separation of monocytes into subpopulations on the basis of buoyant density indicated no difference in the ability of the resulting monocyte subpopulations to produce basal levels of ACE when cultured in the absence of T lymphocytes. However, the subpopulations differed significantly in their ability to synthesize enhanced levels of ACE in response to the presence of autologous T lymphocytes; low-density monocytes were induced by T lymphocytes to synthesize three-fold more ACE than were high-density monocytes. Surface antigen labelling using MoAbs demonstrated that the low-density monocyte subpopulations also had a significantly higher percentage of Leu-M2+ monocytes compared with the high-density monocyte subpopulations. When monocytes were separated on the basis of the presence of the Leu-M2 antigen using an immune rosetting technique, T lymphocytes were able to induce significantly elevated levels of ACE in the Leu-M2+ enriched monocyte subpopulation but were unable to induce ACE beyond basal levels in the Leu-M2(+)-depleted monocyte subpopulation. These results demonstrate that monocytes are heterogeneous with respect to their ability to be induced by T lymphocytes to synthesize ACE. This raises the possibility that selective accumulation of a monocyte subpopulation in the granulomatous inflammation of sarcoidosis may be one of the factors required for elevated ACE synthesis in the resulting granuloma epithelioid cells.

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.

Tumour necrosis factor in sarcoidosis and its potential for targeted therapy.

Tumour necrosis factor (TNF)-alpha is a potent cytokine involved in the inflammatory reactions of many acute and chronic diseases. Recently, agents that block TNFalpha either directly or indirectly have been successful in the treatment of a variety of immune-mediated inflammatory disorders including rheumatoid arthritis and Crohn's disease. Sarcoidosis is an immune-mediated inflammatory disorder characterised by the formation of granulomas. TNFalpha is important in the initiation and perpetuation of inflammation in sarcoidosis, contributing to the initiation of granulomas and the progression of fibrosis, as well as to nongranulomatous inflammation. Various agents used to treat sarcoidosis affect TNF, including the most widely used drug class, corticosteroids, which are usually effective in blocking TNFalpha release from cells. Other agents that nonspecifically inhibit TNFalpha release include methotrexate, azathioprine and pentoxifylline. Specific TNF-antagonising biological agents such as infliximab and etanercept are being tested in patients with sarcoidosis, with mixed success. Infliximab has been shown to produce clinical improvement and reduce the requirement for corticosteroids in a small number of patients with sarcoidosis. However, as infliximab can be associated with reactivation of tuberculosis, which could be mistaken as worsening sarcoidosis, it should be used with caution in this patient group.

Treatment of sarcoidosis – from a basic science point of view

Progress in our understanding of the scientific basis of granulomatous inflammation in sarcoidosis provides a framework for enlightened treatment decisions. Current evidence supports the concept that the pathogenesis of sarcoidosis involves a highly polarized T-helper 1 (Th1) immune response to pathogenic tissue antigens. Conventional treatment is focused on attenuating granuloma formation with antimalarial drugs that inhibit antigen presentation or with nonspecific anti-inflammatory agents such as glucocorticosteroids, methotrexate, or azathioprine. Anti-tumour necrosis factor (TNF)-alpha agents such as pentoxifylline, thalidomide, etanercept and remicade, have recently shown some successes in sarcoidosis. Designing future therapies depends on improved knowledge of the critical immunological processes operative in different stages of disease.

In situ localization of Propionibacterium acnes DNA in lymph nodes from sarcoidosis patients by signal amplification with catalysed reporter deposition.

Sarcoidosis is a systemic granulomatous disease of unknown aetiology. Many genomes of Propionibacterium acnes and P. granulosum have been detected in lymph nodes from patients with sarcoidosis. In situ localization of propionibacterial genomes in sarcoid lymph nodes may help to establish an aetiological link between sarcoidosis and these indigenous bacteria. Formalin-fixed and paraffin-embedded biopsy samples of lymph nodes from nine patients with sarcoidosis, nine patients with tuberculosis, and nine patients with non-specific lymphadenitis as controls were examined by quantitative real-time PCR (QPCR) for P. acnes and by in situ hybridization (ISH) that used catalysed reporter deposition (CARD) for signal amplification with digoxigenin-labelled oligonucleotide probes that complemented 16S rRNA of P. acnes. The signals per 250 micro m(2) of tissue sections were counted from inside and outside the granulomas of sarcoidosis and tuberculosis and from control lymph nodes. The number of genomes by QPCR was examined for correlation with the mean signal count by ISH with CARD. In sarcoid samples, one or several signals were detected in the cytoplasm of some epithelioid cells in granulomas and of many mononuclear cells around granulomas. The mean signal counts were higher (p < 0.001) in granulomatous areas than in other areas of sarcoid lymph nodes. Even in their non-granulomatous areas, counts were higher than in granulomatous areas (p = 0.0023) and non-granulomatous areas (p < 0.001) of tuberculous lymph nodes and control lymph nodes (p = 0.0071). Correlation between the results by QPCR and ISH with CARD was significant (r = 0.86, p < 0.001). The accumulation of P. acnes genomes in and around sarcoid granulomas suggests that this indigenous bacterium may be related to the cause of granulomatous inflammation in sarcoidosis.