Radiation studies in the detection of early signs of lung tissue lesion in sarcoidosis

The capacities of various radiation techniques in the study of patients with pulmonary sarcoidosis are analyzed. The sequence of their use, which ensures a high informative value, is proposed. By analyzing the X-ray semiotics in 45 patients with pulmonary sarcoidosis, the authors give the diagnostic signs of early lung parenchymal damage in this disease. Particular emphasis is placed on the procedure of lung X-ray computed tomography.     

A case of resectable lung adenocarcinoma associated with sarcoidosis

A 71-year-old woman with uveitis was referred to our hospital for further examination of the possible underlying diseases. In roentgenological examination with plain X-ray and CT scan, hilar and mediastinal lymphadenopathy and a mass shadow in the right upper lung field was observed, whereas fibrotic changes were not obvious in both lung fields. Transbronchial lung biopsy with fiberoptic bronchoscope revealed granulomatous interstitial pneumonia. CD4-positive lymphocytes were increased in bronchoalveolar lavage. The patient was diagnosed as having sarcoidosis. Subsequently, right upper lobectomy was performed, and Stage I lung adenocarcinoma was diagnosed. The patient is under follow up without medication and the disease has been stable for two years. A relationship between epithelioid granulomatosis and malignant diseases is discussed and a review of the literature is given. Since it is still controversial as to the incidence of malignant diseases in sarcoidosis patients, it is important to accumulate data on these associations.     

The Circulating Treg/Th17 Cell Ratio Is Correlated with Relapse and Treatment Response in Pulmonary Sarcoidosis Patients after Corticosteroid Withdrawal

Objectives

Pulmonary sarcoidosis is an immune-mediated disease, and some patients can be effectively treated with corticosteroids. However, nearly half of all sarcoidosis patients relapse after corticosteroid withdrawal. Different subsets of CD4+ helper T cells participate in the immunopathogenesis of sarcoidosis. Thus, the aims of our study were to investigate whether the circulating subsets of CD4+ helper T cells were associated with sarcoidosis relapse and with its remission after retreatment. Additionally, we identified a useful biomarker for predicting the relapse and remission of sarcoidosis patients.

Methods

Forty-two patients were enrolled in the present study who had previously been diagnosed with pulmonary sarcoidosis and treated with corticosteroids. The patients were allocated into either a stable group if they exhibited sustained remission (n = 22) or a relapse group if they experienced clinical or radiological recurrence after treatment withdrawal (n = 20). Peripheral blood cells were collected from these patients and analyzed to determine the frequencies of subsets of circulating CD4+ helper T cells by flow cytometry. The patients in the relapse group were retreated with corticosteroids and immunosuppressive agents and were then reevaluated to determine the frequencies of dynamic subsets of circulating CD4+ helper T cells after remission.

Results

The frequencies of circulating Tregs were significantly increased concomitant with a decrease in the circulating Th17 cell frequency in the relapsed patients compared with the stable patients. The Treg/Th17 ratio was negatively correlated with sarcoidosis activity and was sensitive to retreatment. In addition, the percentage of isolated CD45RO+Ki67+ Tregs was higher in the patients who were stable and in those who recovered after retreatment than in those who relapsed.

Conclusions

An imbalance between Tregs and Th17 cells is associated with pulmonary sarcoidosis relapse after corticosteroid withdrawal. The circulating Treg/Th17 ratio could serve as an alternative marker for monitoring pulmonary sarcoidosis relapse after the end of corticosteroid treatment and for rapidly predicting the response to retreatment.     

Sarcoidosis in coexistence with Toxoplasma gondii invasion]

Two cases of sarcoidosis with peripheral lymphatic nodes involvement and coexisting toxoplasmosis are presented. Both cases illustrate diagnostic and differentiating problems in patients with chronic lymphatic nodes enlargement and positive serological reaction to T. gondii antigen. An emphasis is on the importance of the histological examination of the lymphatic nodes for the sarcoidosis diagnosis and contribution of T. gondii to the disease. Positive serological reaction to T. gondii antigen in patients with sarcoidosis may reflect inactive toxoplasmosis; however, periodical serological tests are necessary monitoring the due immunosuppressive treatment used in patients with sarcoidosis.     

Pulmonary hypertension complicating pulmonary sarcoidosis

Pulmonary hypertension (PH) is a severe complication of sarcoidosis, with an unknown prevalence. The aetiology is multifactorial, and the exact mechanism of PH in the individual patient is often difficult to establish. The diagnostic work-up and treatment of PH in sarcoidosis is complex, and should therefore be determined by a multidisciplinary expert team in a specialised centre. It is still a major challenge to identify sarcoidosis patients at risk for developing PH. There is no validated algorithm when to refer a patient suspected for PH, and PH analysis itself is difficult. Until present, there is no established therapy for PH in sarcoidosis. Besides optimal treatment for sarcoidosis, case series evaluating new therapeutic options involving PH-targeted therapy are arising for a subgroup of patients. This review summarises the current knowledge regarding the aetiology, diagnosis and possible treatment options for PH in sarcoidosis.     

Beta-blocker use and COPD mortality: a systematic review and meta-analysis

Background

Diagnostic and treatment approaches for sarcoidosis have changed dramatically over the past decade. Yet, the most recent reports of trends in hospitalizations of sarcoidosis patients are over ten years old. The objectives of this study were to determine the incidence of sarcoidosis among hospitalized patients and to analyze recent trends and seasonality of hospitalizations in sarcoidosis patients.

Methods

We performed a retrospective cohort study of the Nationwide Inpatient Sample from 1998 through 2008. We identified all hospitalizations with a primary or secondary diagnosis of sarcoidosis (ICD-9-CM code 135). Incidence was modeled as a seasonal time series about a linear trend.

Results

Time series analysis of the monthly number of hospitalizations revealed a distinct positive linear trend. Over the study period, the number of hospitalized patients with sarcoidosis increased from 37,516 to 70,947 cases. Trends were most pronounced in patients older than 55?years (p?<?0.0001), African Americans (p?<?0.0001), females (p?=?0.0289), and non-Medicaid populations (p?<?0.0001). Hospitalizations are seasonal with highest incidence in January through March.

Conclusions

Hospitalizations among sarcoidosis patients have almost doubled during the past decade, with disproportionate rate increases in African Americans, women, and older patients. The rate also increases among patients with insurance other than Medicaid. This study indicates the need for heightened surveillance of sarcoidosis patients given the unknown consequences of evolving treatment approaches. Our results point to a need for research investigating risk factors for hospitalization, including medications, co-morbidities, demographics, and socioeconomic status.     

Prevalence of hospitalized patients with sarcoidosis in Croatia

The aim of this study was to investigate the prevalence of hospitalized patients of sarcoidosis in the Republic of Croatia, its distribution in relation to sex and age as well as its geographical distribution. The data on sarcoidosis patients hospitalized in Croatia in the last six years, from 1997 to 2002, were analyzed retrospectively. The prevalence of sarcoidosis patients hospitalised in the Republic of Croatia is 4.1/100,000. The prevalence among women is 4.7 and among men 3.5 per 100,000 persons, with a ratio of 1.4:1. The disease more frequently occurs in the regions with a continental climate than in the Mediterranean zone. The ratio of sarcoidosis patients in the continental zone to the Mediterranean zone is 1.5:1. It occurs predominantly among the adults. Over the investigated period, in our country we have not registered any case of sarcoidosis among children. It occurs more frequently at a younger age and therefore 44.5% of the patients with sarcoidosis were between 20 and 39 years of age, 40.1% were between 40 and 59 years of age and 15.3% were more than 60 years old.     

Epidemiological characteristics of sarcoidosis patients hospitalized in the Uuniversity Hospital for Lung Diseases "Jordanovac" (Zagreb, Croatia) in the 1997-2002 period

The aim of our study was to explore the characteristics of hospitalized patients with sarcoidosis concerning age, gender, clinical forms and staging, seasonality, geographical distribution, smoking habit and profession, familial clustering and mortality. We included 476 biopsy-proven sarcoidosis patients who were diagnosed at the University Hospital for Lung Diseases "Jordanovac" in the period from 1997-2002. Most of the patients (44%) were in the group of age between 20 and 40 years. The ratio of women to men was 1.4:1. The onset of the disease usually appeared in spring and summer, especially in the patients presenting with erythema nodosum, with majority of patients hospitalized in the period from May to August (51%). More patients came from urban, than from rural areas (1.5:1), and they were mostly nonsmokers (3.3:1). In 2% of sarcoidosis patients we found familial clustering. Although these data are biased regarding the selection of patients they give new insights into characteristics of sarcoidosis patients in Croatia.     

Cardiac involvement in Caucasian patients with pulmonary sarcoidosis

Background

Cardiac sarcoidosis (CS) is a potentially life-threatening condition. At present, there is no consensus with regard to the optimal non-invasive clinical evaluation and diagnostic procedures of cardiac involvement in patients with sarcoidosis. The aim of this study in a large homogenous Scandinavian sarcoidosis cohort was therefore to identify risk factors of cardiac involvement in patients with sarcoidosis, and the value of initial routine investigation with ECG and cardiac related symptoms in screening for CS.

Methods

In this retrospective study a cohort of 1017 Caucasian patients with sarcoidosis were included. They were all screened with ECG at disease onset and investigated for CS according to clinical routine.

Results

An abnormal ECG was recorded in 166 (16.3%) of the 1017 patients and CS was later diagnosed in 22 (13.2%) of them, compared to in one (0.1%) of the 851 sarcoidosis patients with a normal ECG (p < 0.0001). The risk for CS was higher in patients with a pathologic ECG combined with cardiac related symptoms (11/40) (27.5%) compared to those with pathologic ECG changes without symptoms (11/126) (8.7%) (p < 0.01). Furthermore, patients with Löfgren’s syndrome had a reduced risk for CS compared to those without (p < 0.05) the syndrome.

Conclusions

This study on an unusually large and homogenous sarcoidosis population demonstrate the importance of an abnormal ECG and cardiac related symptoms at disease onset as powerful predictors of a later diagnosis of cardiac sarcoidosis. In contrast, CS is very rare in subjects without symptoms and with a normal ECG. This knowledge is of importance, and may be used in a clinical algorithm, in identifying patients that should be followed and investigated extensively for the presence of CS.     

Circulating cytokines in sarcoidosis: Phenotype-specific alterations for fibrotic and non-fibrotic pulmonary disease

AimsSarcoidosis 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.ResultsIn 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.ConclusionsIn 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.     

Active Chronic Sarcoidosis is Characterized by Increased Transitional Blood B Cells, Increased IL-10-Producing Regulatory B Cells and High BAFF Levels

Background

Sarcoidosis is a multisystemic disease of unknown etiology characterized by a disproportionate Th1 granulomatous immune response in the organs involved. Plasmatic hypergammaglobulinemia and B cell accumulation in granulomatous lesions suggest the possible role of humoral immune responses in the pathogenesis of sarcoidosis. The purpose of this study is to describe B cell peripheral compartment in sarcoidosis.

Methodology/Principal Findings

We analyzed blood B cell subsets and BAFF levels in 33 patients with chronic sarcoidosis (active sarcoidosis n = 18; inactive sarcoidosis n = 15) and 18 healthy donors. Active chronic sarcoidosis patients had significantly less circulating memory B cells (p<0.01), more transitional (p<0.01) and increased numbers of IL-10-producing regulatory B cells (p<0.05) compared with healthy donors and patients with inactive sarcoidosis. BAFF serum levels were significantly higher in patients with active sarcoidosis (p<0.01 versus healthy donors and inactive sarcoidosis patients) and strongly correlated with serum hypergammaglobulinemia (r = 0.53, p<0.01) and angiotensin converting enzyme levels (r = 0.61, p = <0.01).

Conclusions/Significance

These data show that there is an altered B cell homeostasis in active sarcoidosis and suggest BAFF antagonist drugs as potential new treatments of this disease.     

Mycobacterium tuberculosis DNA in tissue affected by sarcoidosis.

OBJECTIVE--To investigate the prevalence of Mycobacterium tuberculosis DNA in granulomatous tissues from patients with sarcoidosis and from controls matched for age, sex, and tissue by using the polymerase chain reaction. DESIGN--Single blind control trial. SUBJECTS--16 patients with sarcoidosis who had undergone diagnostic biopsy of lung, skin, or lymph node and 16 patients with squamous cell carcinoma or Hodgkin''s disease to act as controls. In addition, four lung specimens infected with M tuberculosis were included as positive controls. RESULTS--M tuberculosis DNA was present in sarcoid tissues containing granulomas from seven of the 16 patients and one of the 16 matched controls. Two of the four specimens known to be infected with M tuberculosis were positive in the controlled experiment. CONCLUSION--These figures suggest that M tuberculosis DNA is detected as readily in patients with sarcoidosis as in patients with frankly tuberculous tissues and imply that M tuberculosis may be linked to the cause of sarcoidosis.     

Impaired survival of regulatory T cells in pulmonary sarcoidosis

Background

Impaired regulatory T cell (Treg) function is thought to contribute to ongoing inflammatory responses in sarcoidosis, but underlying mechanisms remain unclear. Moreover, it is not known if increased apoptotic susceptibility of Tregs may contribute to an impaired immunosuppressive function in sarcoidosis. Therefore, the aim of this study is to analyze proportions, phenotype, survival, and apoptotic susceptibility of Tregs in sarcoidosis.

Methods

Patients with pulmonary sarcoidosis (n = 58) were included at time of diagnosis. Tregs were analyzed in broncho-alveolar lavage fluid and peripheral blood of patients and healthy controls (HC).

Results

In sarcoidosis patients no evidence was found for a relative deficit of Tregs, neither locally nor systemically. Rather, increased proportions of circulating Tregs were observed, most prominently in patients developing chronic disease. Sarcoidosis circulating Tregs displayed adequate expression of FoxP3, CD25 and CTLA4. Remarkably, in sarcoidosis enhanced CD95 expression on circulating activated CD45RO⁺ Tregs was observed compared with HC, and proportions of these cells were significantly increased. Specifically sarcoidosis Tregs - but not Th cells - showed impaired survival compared with HC. Finally, CD95L-mediated apoptosis was enhanced in sarcoidosis Tregs.

Conclusion

In untreated patients with active pulmonary sarcoidosis, Tregs show impaired survival and enhanced apoptotic susceptibility towards CD95L. Increased apoptosis likely contributes to the insufficient immunosuppressive function of sarcoidosis Tregs. Further research into this field will help determine whether improvement of Treg survival holds a promising new therapeutic approach for chronic sarcoidosis patients.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0265-8) contains supplementary material, which is available to authorized users.     

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.     

Sarcoidosis and NOD1 variation with impaired recognition of intracellular Propionibacterium acnes

Sarcoidosis is a systemic granulomatous disease of unknown etiology. NOD2 mutations have been shown to predispose to granulomatous diseases, including Crohn's disease, Blau syndrome, and early-onset sarcoidosis, but not to adult sarcoidosis. We found that intracellular Propionibacterium acnes, a possible causative agent of sarcoidosis, activated NF-kappaB in both NOD1- and NOD2-dependent manners. Systematic search for NOD1 gene polymorphisms in Japanese sarcoidosis patients identified two alleles, 796G-haplotype (156C, 483C, 796G, 1722G) and 796A-haplotype (156G, 483T, 796A, 1722A). Allelic discrimination of 73 sarcoidosis patients and 215 healthy individuals showed that the frequency of 796A-type allele was significantly higher in sarcoidosis patients and the ORs were significantly elevated in NOD1-796G/A and 796A/A genotypes (OR [95% CI]=2.250 [1.084, 4.670] and 3.243 [1.402, 7.502], respectively) as compared to G/G genotype, showing an increasing trend across the 3 genotypes (P=0.006 for trend). A similar association was found when 52 interstitial pneumonia patients were used as disease controls. Functional studies showed that the NOD1 796A-allele was associated with reduced expression leading to diminished NF-kappaB activation in response to intracellular P. acnes. The results indicate that impaired recognition of intracellular P. acnes through NOD1 affects the susceptibility to sarcoidosis in the Japanese population.     

On the Etiology of Sarcoidosis

Bacteriophages lytic for tubercle bacilli were isolated from tuberculous patients and patients with sarcoidosis. While tuberculous patients were found to raise phage-neutralizing antibodies, those with sarcoidosis appeared unable to do so. In vitro experiments showed that in the absence of neutralizing antibodies, phagolysis and lysogenic conversion of tubercle bacilli proceed. Lysogenic conversion results in the emergence of bacilli so modified in their morphological and antigenic properties that, on the basis of the classical bacteriological criteria, they can no longer be recognized as tubercle bacilli. From six lymph node biopsies collected from patients with sarcoidosis and cultured on a variety of media, including media containing anti-phage sera, five variant strains of tubercle bacilli were isolated. These observations support the view that certain cases of sarcoidosis are due to “modified” tubercle bacilli.     

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.     

Sarcoidosis in Patients with Psoriasis: A Population-Based Cohort Study

Purpose

Psoriasis is a chronic inflammatory disease characterized by a systemic immunological response which is mainly driven by activated T helper (Th) 1 and Th17 lymphocytes. Like psoriasis, sarcoidosis is a chronic inflammatory disorder with Th1/Th17-driven inflammation. Therefore, we investigated the risk of sarcoidosis in patients with psoriasis compared to the background population in a nationwide cohort.

Methods

The study included the entire Danish population aged ≥10 years followed from 1^st January 1997 until diagnosis of sarcoidosis, death or 31^st December 2011. Patients with a history of psoriasis and/or sarcoidosis at baseline were excluded. Information on comorbidity and concomitant medication was identified by individual-level linkage of administrative registers. Incidence rates of sarcoidosis were calculated and adjusted hazard ratios (HRs) were estimated by multivariable Cox regression models adjusted for age, gender, comorbidity, medications and socioeconomic status.

Results

A total of 6,043,518 subjects were eligible for analysis. In the study period 70,125 patients with new-onset psoriasis, including 11,834 patients with severe psoriasis, were identified. The overall incidence rates of sarcoidosis were 1.18, 2.22, and 4.06 per 10,000 person-years for the reference population (9,717 cases), mild psoriasis (78 cases) and severe psoriasis (22 cases), respectively. Compared to the reference population, the age- and gender-adjusted HRs for sarcoidosis were increased in patients with psoriasis with HR 1.49 (95% confidence interval [CI] 1.18–1.87) and HR 2.51 (CI 1.64–3.85) for those with mild and severe disease, respectively.

Conclusion

In this nationwide cohort, psoriasis was associated with a disease severity-dependent increased risk of sarcoidosis.     

Relationship between mitochondria and the development of specific lipid droplets in capillary endothelial cells of the respiratory tract in patients with sarcoidosis

The aim of this study was to morphologically evaluate damage in the capillary endothelial cells of the respiratory tract in patients with sarcoidosis. We examined tissues of the bronchus and lung obtained from 16 patients with sarcoidosis consisting of 2 stage 0, 10 stage I and 4 stage II patients, and 11 controls. The morphology of capillary endothelial cells was studied using electron microscopy. In the samples from patients with sarcoidosis, lipid droplets exhibiting dark monophasic density (unsaturated fatty acids) were surrounded by abundant lysosomes in the capillary endothelial cells, and the double-membrane structure of the mitochondria attached to these lipid droplets was lost in three cases. Biphasic lipid droplets with dark and lucent (saturated fatty acids) densities were also observed, accompanied by a few lysosomes containing the residual bodies of undigested lipid-containing substances. Lucent monophasic droplets were also detected in the tissues from patients with sarcoidosis. The plasma membrane was more often damaged in capillary endothelial cells containing biphasic lipid droplets, lucent monophasic droplets as well as in those with dark monophasic droplets. However, no lipid droplets were detected in capillary endothelial cells obtained from the control subjects, except in a single case. This study demonstrated that a large number of mitochondria were mobilized and showed notable morphological changes including swelling in the capillary endothelial cells in patients with sarcoidosis. A close relationship between mitochondria and lipid droplets was observed in capillary endothelial cells of the respiratory tract, and this relation may be involved in the pathogenesis of sarcoidosis.     

TNF-alpha and HLA-DR genotyping as potential prognostic markers in pulmonary sarcoidosis.

We have analyzed the HLA-DRB1 alleles and -308 TNF-alpha gene polymorphism in 78 sarcoidosis patients and 50 controls. The sarcoidosis group as a whole did not show any significant correlation with the TNF-A or the HLA-DR alleles compared to the control group. However, the patient subgroups of L?fgren and non-L?fgren sarcoidosis exhibited significant allele associations. In the L?fgren patient group, the TNF-A2 and the HLA-DR3 alleles were represented significantly higher, with a highly significant relative risk resulting from the presence of the TNF-A2 or the HLA-DR3 allele or both. In the non-L?fgren patient group, the phenotype expressing HLA-DR2 and lacking TNF-A2 was significantly higher than in the L?fgren patient group. Due to these significant genetic differences in the subgroups of L?fgren and non-L?fgren sarcoidosis patients, we conclude that the genotyping of these two loci (-308 TNF-alpha promoter polymorphism and HLA-DR) may be of prognostic value for the course of disease in sarcoidosis.