The anergic state in sarcoidosis is associated with diminished dendritic cell function

Sarcoidosis is a chronic inflammatory disease of unknown cause, characterized by granuloma formation similar to tuberculosis, but without clear evidence of a microbial infection. Because sarcoidosis is linked with clinical anergy and other evidence of diminished cellular immunity, we hypothesized that decreased skin delayed-type hypersensitivity (DTH) responses to recall Ags in affected individuals would be associated with decreased function of their blood dendritic cells (DCs). Our study involved ex vivo isolation, phenotyping, and functional testing of myeloid DCs (mDCs), plasmacytoid DCs, and T lymphocytes from blood of normal healthy volunteers and sarcoidosis subjects with active, untreated pulmonary disease. We found mDC function in the allogeneic MLR directly corresponded to the magnitude of skin DTH reactions to recall Ags in both sarcoidosis subjects and normal volunteers. However, both of these outcomes were significantly decreased in the sarcoidosis group. Diminished mDC function occurred despite up-regulated costimulatory and maturation markers. Clinical relevance is suggested by the inverse relationship between both mDC allogeneic responses and skin DTH responses with clinical disease severity as measured by chest radiograms. Because granulomas form when cellular immunity fails to clear antigenic stimuli, attenuated mDC function in sarcoidosis may contribute to susceptibility and persistence of the chronic inflammation characteristic of this disease.     

Immunoprophylaxis of respiratory syncytial virus: global experience

In sarcoidosis, host genetic factors are discussed as contributing to disease susceptibility and course. Since tumor necrosis factor (TNF)-α is a central mediator of granuloma formation and since elevated TNF-α levels are found during active phases of sarcoidosis, genetic polymorphisms correlating with influences on TNF-α levels are of special interest. The complete sequencing of the MHC region and the increase in the number of identified gene polymorphisms in this locus associated with TNF-α production offer the opportunity of detecting new genes associated with sarcoidosis and perhaps of defining disease-associated haplotypes that bear the potential of serving as predictive markers for this disease.     

Sarcoidosis and Polyarthritis

Polyarthritis is a well-recognized manifestation of sarcoidosis, but the various series of cases reported in the literature reveal considerable variation in its incidence as well as in its clinical manifestations. Three major types of sarcoid polyarthritis are defined, as distinguished by their clinical and pathological features. Two of these types are usually seen in conjunction with the subacute or transient form of sarcoidosis and, in most cases, are accompanied by erythema nodosum. They differ markedly in severity, but their prognosis is uniformly good. The third type, in contrast, is of a chronic nature and is often associated with permanent joint changes. Mild joint manifestations are a frequent finding in sarcoidosis, but more severe arthritis is relatively rare.Two cases of sarcoidosis, presenting with severe polyarthritis, are reported in detail, and cases seen in Halifax hospitals during the period 1954 to 1964 are reviewed.     

Sarcoidosis and membranous glomerulonephritis: a significant association.

Three patients were seen who had sarcoidosis associated with glomerulonephritis. Subsequent review of published reports of cases in which the two conditions occurred simultaneously showed a pattern of histological type of glomerulonephritis different from that seen in patients without associated disease. In sarcoidosis with glomerulonephritis there appeared to be a dearth of minimal-change disease and an excess of membranous glomerulonephritis compared with the prevalence that would be expected if the renal disease was merely a chance occurrence. These findings may provide evidence for an important relation between sarcoidosis and glomerulonephritis.     

Sarcoidosis in Native and Transplanted Kidneys: Incidence,Pathologic Findings,and Clinical Course

Renal involvement by sarcoidosis in native and transplanted kidneys classically presents as non caseating granulomatous interstitial nephritis. However, the incidence of sarcoidosis in native and transplant kidney biopsies, its frequency as a cause of end stage renal disease and its recurrence in renal allograft are not well defined, which prompted this study. The electronic medical records and the pathology findings in native and transplant kidney biopsies reviewed at the Johns Hopkins Hospital from 1/1/2000 to 6/30/2011 were searched. A total of 51 patients with a diagnosis of sarcoidosis and renal abnormalities requiring a native kidney biopsy were identified. Granulomatous interstitial nephritis, consistent with renal sarcoidosis was identified in kidney biopsies from 19 of these subjects (37%). This is equivalent to a frequency of 0.18% of this diagnosis in a total of 10,023 biopsies from native kidney reviewed at our institution. Follow-up information was available in 10 patients with biopsy-proven renal sarcoidosis: 6 responded to treatment with prednisone, one progressed to end stage renal disease. Renal sarcoidosis was the primary cause of end stage renal disease in only 2 out of 2,331 transplants performed. Only one biopsy-proven recurrence of sarcoidosis granulomatous interstitial nephritis was identified.

Conclusions

Renal involvement by sarcoidosis in the form of granulomatous interstitial nephritis was a rare finding in biopsies from native kidneys reviewed at our center, and was found to be a rare cause of end stage renal disease. However, our observations indicate that recurrence of sarcoid granulomatous inflammation may occur in the transplanted kidney of patients with sarcoidosis as the original kidney disease.     

Polymorphisms and haplotypes in MyD88 are associated with the development of sarcoidosis: a candidate-gene association study

Sarcoidosis is considered as a disorder of protracted immune response to an as yet unidentified causative agent that leads to granuloma formation. Material from M. tuberculosis and P. acne has been repeatedly detected in the sarcoidosis lesions, implying the involvement of the Toll-like receptor2 (TLR2) gene that responds to these intracellular pathogens. Since TLR2 association studies have produced controversial results, we sought to investigate whether the downstream signalling molecule MyD88 could be linked to disease susceptibility. We analyzed a total of 93 cases with sarcoidosis and of 89 controls for the most common MyD88 SNPs: ?938C>A (rs4988453) and 1944C>G (rs4988457). There is evidence that the genotype distributions of both variants are associated with the development of sarcoidosis (p = 0.038 for ?938C>A and p = 0.026 for 1944C>G). In particular, ?938A and 1944G carriers were associated with risk of sarcoidosis [OR = 2.48 (1.23–5.02) and OR = 0.33 (0.14–0.76)], respectively, indicating dominance of the mutant alleles; however, the adjustment of the effect size for age and sex diminished the significance. The haplotype analysis showed association for the ?938A/1944G haplotype (p < 0.001). Since genetic association studies have linked MyD88 to Hodgkin’s lymphoma it is tempting to speculate that MyD88 may contribute to the granuloma formation that characterizes sarcoidosis.     

Evidence for local dendritic cell activation in pulmonary sarcoidosis

Background

Sarcoidosis is a granulomatous disease characterized by a seemingly exaggerated immune response against a difficult to discern antigen. Dendritic cells (DCs) are pivotal antigen presenting cells thought to play an important role in the pathogenesis. Paradoxically, decreased DC immune reactivity was reported in blood samples from pulmonary sarcoidosis patients. However, functional data on lung DCs in sarcoidosis are lacking. We hypothesized that at the site of disease DCs are mature, immunocompetent and involved in granuloma formation.

Methods

We analyzed myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in broncho-alveolar lavage (BAL) and blood from newly diagnosed, untreated pulmonary sarcoidosis patients and healthy controls using 9-color flowcytometry. DCs, isolated from BAL using flowcytometric sorting (mDCs) or cultured from monocytes (mo-DCs), were functionally assessed in a mixed leukocyte reaction with naïve allogeneic CD4+ T cells. Using Immunohistochemistry, location and activation status of CD11c⁺DCs was assessed in mucosal airway biopsies.

Results

mDCs in BAL, but not in blood, from sarcoidosis patients were increased in number when compared with mDCs from healthy controls. mDCs purified from BAL of sarcoidosis patients induced T cell proliferation and differentiation and did not show diminished immune reactivity. Mo-DCs from patients induced increased TNFα release in co-cultures with naïve allogeneic CD4⁺ T cells. Finally, immunohistochemical analyses revealed increased numbers of mature CD86⁺ DCs in granuloma-containing airway mucosal biopsies from sarcoidosis patients.

Conclusion

Taken together, these finding implicate increased local DC activation in granuloma formation or maintenance in pulmonary sarcoidosis.     

Stage related morphometry of sarcoid granulomas and inflammatory cell types in broncho-alveolar lavage.

The epithelioid granulomas, interstitial and intra-alveolar mononuclear inflammatory infiltrates and the cellular compartments obtained by broncho-alveolar lavage (BAL) were measured in 40 patients with pulmonary involvement of sarcoidosis. The granulomas were divided into a central (epithelioid-cellular) zone and into a peripheral (lymphocytic-fibrotic) zone, and the density of various inflammatory cells was measured in both compartments. The cases were grouped and analyzed according to the radiological and clinical stages. The results are as follows: neutrophilic granulocytes seen in the BAL probably originate from the sarcoid granulomas in patients with stage 1 of the disease and may derive from other compartments of the lung parenchyma in patients with stage 2 or stage 3. Lymphocytes seen in the BAL of patients with stage 1 or stage 2 of the disease probably derive from intra-alveolar lymphocytic agglutinations. They originate from the sarcoid granulomas only in patients with stage 3. Macrophages seen in the BAL probably derive from the sarcoid granulomas independent from the stage of sarcoidosis. No relationship was found between the morphometric parameters and the clinical outcome of the disease.     

Effects of granuloma modulation induced by regulatory-T-lymphocyte activity on angiotensin II/III production by granuloma macrophages in murine schistosomiasis mansoni

Angiotensins are produced by granuloma macrophages in murine Schistosoma mansoni. During the course of infection, granuloma undergo a T-cell-dependent process called modulation in which their maximal size decreases. This study was undertaken to establish whether angiotensin production by granuloma macrophages is altered by immunoregulatory lymphocytes. Granuloma macrophages from modulated lesions released and contained more angiotensin II/III (AII/III) and less angiotensin I (AI) than those from the acute infection. Captopril, a specific angiotensin-converting-enzyme (ACE) inhibitor, appreciably decreased AII/III produced by macrophages from modulated granulomas. Adoptive transfer of splenic T lymphocytes from chronically infected donors into acutely infected recipients altered angiotensin production by the granuloma macrophages in a manner similar to that seen in modulated lesions. However, no difference was detected in the capacity of granuloma macrophages from acutely or chronically infected mice to metabolize 125I-AI or -AII added to cell cultures. Similarly, captopril did not alter the metabolism of exogenously administrated angiotensins. These findings suggest that regulatory T lymphocytes influence the metabolism by granuloma macrophages of endogenously produced angiotensins at least in part by induction of macrophage ACE activity. However, the degradation of extracellular AI and AII may result from the activity of enzymes other than ACE which are not inducible by modulation.     

Cysteinyl proteinases of Schistosoma mansoni eggs: purification and partial characterization

The egg stage of Schistosoma mansoni, a trematode blood fluke, is known to be responsible for an immunologically mediated granuloma formation. Proteolytic enzymes of S. mansoni eggs may be involved in the penetration of host tissue by eggs and/or may act as antigens to cause a humoral as well as a cell-mediated response leading to granuloma formation. Three acidic, thiol-dependent proteinases from the eggs of S. mansoni were isolated, and 2 major proteinases (I and II) were purified to homogeneity using chromatofocusing, AcA54 ultrogel chromatography, and thiopropyl-Sepharose 6B affinity chromatography. Proteinases I and II have molecular weights of 25,400 and 30,500, and isoelectric points of 6.0 and 5.6, respectively. These enzymes were found to be cathespin B-like cysteinyl proteinases based on similarities in molecular weight, isoelectric point, optimal assay pH, instability to neutral pH, substrate specificity, and inhibitor sensitivity. A monoclonal antibody, specific to S. mansoni egg proteinases was used in immunoblotting studies. Under native, but not under denaturing, conditions for gel electrophoresis, this monoclonal antibody reacted with egg proteinases. This antibody had previously been shown to recognize an antigen in the miracidial penetration glands of schistosome eggs.     

Sarcoidosis and tuberculosis cytokine profiles: indistinguishable in bronchoalveolar lavage but different in blood

Background

The clinical, radiological and pathological similarities between sarcoidosis and tuberculosis can make disease differentiation challenging. A complicating factor is that some cases of sarcoidosis may be initiated by mycobacteria. We hypothesised that immunological profiling might provide insight into a possible relationship between the diseases or allow us to distinguish between them.

Methods

We analysed bronchoalveolar lavage (BAL) fluid in sarcoidosis (n = 18), tuberculosis (n = 12) and healthy volunteers (n = 16). We further investigated serum samples in the same groups; sarcoidosis (n = 40), tuberculosis (n = 15) and healthy volunteers (n = 40). A cross-sectional analysis of multiple cytokine profiles was performed and data used to discriminate between samples.

Results

We found that BAL profiles were indistinguishable between both diseases and significantly different from healthy volunteers. In sera, tuberculosis patients had significantly lower levels of the Th2 cytokine interleukin-4 (IL-4) than those with sarcoidosis (p = 0.004). Additional serum differences allowed us to create a linear regression model for disease differentiation (within-sample accuracy 91%, cross-validation accuracy 73%).

Conclusions

These data warrant replication in independent cohorts to further develop and validate a serum cytokine signature that may be able to distinguish sarcoidosis from tuberculosis. Systemic Th2 cytokine differences between sarcoidosis and tuberculosis may also underly different disease outcomes to similar respiratory stimuli.     

Role of ICAM-1 in the aggregation and adhesion of human alveolar macrophages in response to TNF-alpha and INF-gamma

Intracellular adhesion molecule-1 (ICAM-1)-mediated cell-cell adhesion is thought to play an important role at sites of inflammation. Recent evidence suggests that ICAM-1 surface expression on alveolar macrophages is increased in pulmonary sarcoidosis and that inflammatory granuloma formation is characterized by the aggregation of macrophages. The present study shows that ICAM-1 expression is significantly elevated on alveolar macrophages from patients with sarcoidosis in response to tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (INF-gamma) compared with healthy controls. Aggregation and adhesion were significantly increased in alveolar macrophages treated with TNF-alpha and INF-gamma, and significantly inhibited in those pretreated with a monoclonal antibody to ICAM-1. Similarly, aggregation and adhesion were inhibited in macrophages treated with heparin, which then exhibited a wide range of biological activities relevant to inflammation. These results suggested that the surface expression of ICAM-1 on alveolar macrophages in response to TNF-alpha and INF-gamma is important in mediating aggregation and adhesion. Additionally, heparin may be useful for developing novel therapeutic agents for fibrotic lung disease.     

Bronchoalveolar cells from sarcoid patients demonstrate enhanced antigen presentation

The recognition of foreign antigens by T lymphocytes in association with lung antigen-presenting cells may be critical in the initiation of the mononuclear alveolitis and granuloma formation of pulmonary sarcoidosis. However, it has been shown that bronchoalveolar cells (BAC) from normal volunteers function poorly as antigen-presenting cells. Therefore, the ability of sarcoid BAC to serve as accessory cells for antigen-dependent autologous T cell proliferation, as measured by tritiated thymidine uptake, was compared with that of normal BAC. Although irradiated sarcoid BAC supported antigen-induced T cell proliferation, normal BAC did so poorly (p less than 0.005). Because it has been shown that sarcoid BAC produce more interleukin 1 (IL 1) than normal BAC, it was considered that the enhancement of antigen-induced proliferative responses could result from an increased amount of IL 1, and that contaminating monocytes in the peripheral blood T cell preparations displayed the antigen for T cell recognition. Therefore, it was necessary to establish that antigen-induced T cell responses required HLA-D region compatibility between the sarcoid BAC and T lymphocytes. BAC from sarcoid patients stimulated antigen-specific proliferation in T cells lines matched for at least one HLA-D-region antigen, but failed to stimulate T cell lines that were unmatched for both antigens. This finding indicates that cells in bronchoalveolar lavage fluids from sarcoid patients were fully capable of acting as antigen-presenting cells. The identification of antigen-presenting cells in the lungs of patients with sarcoidosis together with the previous findings of activated T cells, enhanced IL 1 production, and spontaneous interleukin 2 release in sarcoid patients is compatible with the hypothesis that local cell-mediated immunity is involved in the pathogenesis of pulmonary sarcoidosis.     

Neurotrophins and neurotrophin receptors in pulmonary sarcoidosis - granulomas as a source of expression

Background

Pulmonary sarcoidosis is an inflammatory disease, characterized by an accumulation of CD4⁺ lymphocytes and the formation of non-caseating epithelioid cell granulomas in the lungs. The disease either resolves spontaneously or develops into a chronic disease with fibrosis. The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) have been suggested to be important mediators of inflammation and mediate tissue remodelling. In support of this, we have recently reported enhanced NGF levels in the airways of patients with pulmonary sarcoidosis. However, less is known about levels of BDNF and NT-3, and moreover, knowledge in the cellular sources of neurotrophins and the distribution of the corresponding neurotrophin receptors in airway tissue in sarcoidosis is lacking.

Methods

The concentrations of NGF, BDNF and NT-3 in bronchoalveolar lavage fluid (BALF) of 41 patients with newly diagnosed pulmonary sarcoidosis and 27 healthy controls were determined with ELISA. The localization of neurotrophins and neurotrophin receptors were examined by immunohistochemistry on transbronchial lung biopsies from sarcoidosis patients.

Results

The sarcoidosis patients showed significantly enhanced NT-3 and NGF levels in BALF, whereas BDNF was undetectable in both patients and controls. NT-3 levels in BALF were found higher in patients with non-Löfgren sarcoidosis as compared to patients with Löfgren''s syndrome, and in more advanced disease stage. Epithelioid cells and multinucleated giant cells within the sarcoid granulomas showed marked immunoreactivity for NGF, BDNF and NT-3. Also, immunoreactivity for the neurotrophin receptor TrkA, TrkB and TrkC, was found within the granulomas. In addition, alveolar macrophages showed positive immunoreactivity for NGF, BDNF and NT-3 as well as for TrkA, TrkB and TrkC.

Conclusions

This study provides evidence of enhanced neurotrophin levels locally within the airways of patients with sarcoidosis. Findings suggest that sarcoid granuloma cells and alveolar macrophages are possible cellular sources of, as well as targets for, neurotrophins in the airways of these patients.     

Plasma Cell Granuloma of The Thyroid: Report of Case and Review of Literature

ObjectiveTo report the 12th case of a patient with a plasma cell granuloma of the thyroid, a rare cause of goiter and hypothyroidism.MethodsWe present a case report of a woman with a plasma cell granuloma of the thyroid. The clinical and pathologic features of the lesion are described, the differential diagnosis is discussed, and the relevant literature is reviewed.ResultsPlasma cell granulomas are uncommon benign lesions most typically located in the lung and only rarely identified in other organs. Only 11 cases of plasma cell granuloma of the thyroid gland have been reported previously. We describe the case of a 55-year-old woman with a long history of hypothyroidism and compressive symptoms from an enlarging neck mass. A thyroidectomy was performed. On gross examination, the thyroid had been replaced by firm, white, fibrotic tissue with a multinodular appearance. On microscopy, the infiltrate consisted predominantly of plasma cells that were polyclonal with the expression of both kappa and lambda light chains. A minor component of CD5- and CD20-positive (T and B) lymphocytes was observed. These features were important for establishing the diagnosis of a plasma cell granuloma and distinguishing the lesion from a plasmacytoma.ConclusionThis is the 12th reported case of plasma cell granuloma of the thyroid gland, a very rare cause of either a diffuse or a nodular goiter and hypothyroidism. The presence of a polyclonal plasma cell population with the expression of both kappa and lambda light chains helps to distinguish a plasma cell granuloma from a malignant plasmacytoma of the thyroid gland. (Endocr Pract. 2008; 14:611-617)     

Genitourinary Sarcoidosis

Genitourinary involvement of sarcoidosis can mimic many common urologic conditions. Although sarcoidosis is a benign inflammatory condition, it can present much like malignant or infectious conditions; thus, failed diagnosis can lead to unnecessary medications or surgical procedures. In addition, management choices for patients with scrotal findings have important implications for future fertility. Thus, this uncommon condition should be on the differential diagnosis for any urologic patient. The authors report on a patient with a scrotal mass as his presenting symptom of sarcoidosis and review the diagnosis, implications, and management of sarcoidosis involving all potential sites in the urinary tract.Key words: Sarcoidosis, Genitourinary, Scrotal mass, UrologyScrotal masses comprise a wide differential diagnosis. Although the vast majority of isolated epididymal masses are benign, solid testicular masses in adults are generally considered malignant until proven otherwise. Benign sarcoid lesions can occur in the testis, epididymis, or any other scrotal structure. In fact, sarcoidosis can involve many organs of the genitourinary (GU) system, commonly masquerading as other, more common conditions, including malignancy and infection.We present a patient with a scrotal mass as his presenting manifestation of sarcoidosis. This is followed by a concise review of the diagnosis and management of sarcoidosis, and a review of the limited literature available specifically pertaining to sarcoidosis of the GU tract. Finally, we provide initial management recommendations for each GU site of disease.     

Severe left ventricular systolic dysfunction after permanent pacemaker implantation: Should we pause before upgrading to biventricular pacing?

Left ventricular (LV) systolic dysfunction leading to heart failure (HF) is known to occur after permanent pacemaker implantation (PPI) in a subset of patients. They are often treated by upgradation of the pacemaker to cardiac resynchronisation therapy (CRT). We report a case of progressive LV dysfunction and HF after PPI. Cardiac ¹⁸FDG-PET-CT scan revealed abnormal myocardial FDG uptake suggestive of cardiac sarcoidosis (CS). Biopsy from FDG avid lymph node demonstrated non-caseating granuloma. Therapy with steroids resulted in resolution of HF symptoms accompanied by a significant improvement in LV function.     

Cutaneous silica granuloma

Cutaneous silica granuloma is a rare and fascinating cause of delayed scarring. Symptoms may arise many years after minor wounding if glass, sand, or other silica-containing particles have been embedded. Such granulomatous lesions are often nodular, indurated, and erythematous. They may respond to surgical excision or medical treatment, and in rare cases, they may spontaneously regress. We present one case in which three separate areas of cutaneous silica granulomas developed after a latent period of about 20 years and then involuted without intervention. The etiology and therapeutic options are discussed.