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.     

Sarcoidosis and molecular mimicry—important etiopathogenetic aspects: current state and future directions

Sarcoidosis is a disease of uncertainty in terms of its cause, presentation, and clinical course. The disease has a worldwide distribution and affects all ages, races, and both sex. Sarcoidosis of the skin may have an extremely heterogeneous clinical presentation, so that the definitions of 'great imitator' and 'clinical chameleon' have long been used. The factors that influence clinical picture and severity of the disease are probably linked to the etiopathogenesis of sarcoidosis, which continues to be shrouded in mystery. The current state of the art on the pathogenesis of sarcoidosis is that it is an immunological response in a genetically susceptible individual to an as-yet undefined antigenic stimulus. How exposure occurs in genetically predisposed patients is not completely clear, but the most likely explanation is that these agents or antigens are either inhaled into the lungs or enter through contact with the skin, as these are the common target organs that are constantly in contact with the environment. An autoimmune etiology of sarcoidosis could possibly occur through a process of molecular mimicry of infectious or other environmental antigens to host antigens. This could lead to a cross-mediated immune response and induction of autoimmune disease. This molecular mimicry may probably be responsible for the heterogeneous clinical presentations of the disease. Several investigations and studies have provided valuable evidence on the etiopathogenesis of sarcoidosis, which may lead to the future development of targeted and innovative treatment strategies. Nevertheless, we are still a long way from unravelling the underlying cause of this mysterious disease.     

Uveitis and acute glaucoma as first presenting symptoms of sarcoidosis in a healthy male

Sarcoidosis is a disease that causes noncaseating granulomas in tissues such as the lungs, heart, skin, and eyes. Sarcoidosis is often found through chest x-ray or lesions in the skin and eyes. In over half of patients the disease is detected incidentally by radiographic abnormalities on a routing chest x-ray prior to development of any symptoms. The disease varies in incidence among geographic regions and can also aggregate in families. It is more common in African-Americans who have a lifetime-estimated risk of 2.4 percent compared to a lifetime risk of 0.85 percent in whites. Multiple cases have been reported on sarcoidosis with eye involvement, especially uveitis. We present a healthy 36-year-old male with no past medical who initial presentation of sarcoidosis was uveitis with acute angle closure glaucoma. To our knowledge this is the first reported case of sarcoidosis with this presentation.     

复发性结节病12例临床分析

目的 探讨结节病复发的主要临床特点.方法 将结节病复发定义为:结节病的临床和影像改变自发或经治疗完全缓解后,又出现结节病活动的证据并经影像学或病理证实.2004年至2008年在我院就诊的符合上述标准的结节病复发患者共12例,对上述患者的临床资料进行总结分析.结果 12例中11例为女性,复发时间在缓解后4～38个月.12例结节病复发患者中10例在初治时接受了口服激素治疗,复发大多发生在激素减药过程中或停药早期,病情缓解超过3年复发的2例.3例在复发时有新发脏器受损.结论 结节病复发主要发生在激素减量或停药早期,但也有病情稳定数年后复发,结节病患者应接受长期随访,并规范口服激素治疗方案,结节病复发时应进行全面检查,重新评估受累脏器.     

Serum levels of chitotriosidase as a marker of disease activity and clinical stage in sarcoidosis

BACKGROUND: Sarcoidosis is a systemic granulomatous disease characterized by T-lymphocyte activation and lymphocyte migration into involved organs, usually the lungs. The amounts of a number of biochemical markers, such as angiotensin converting enzyme (ACE) activity, increase in the serum of patients with sarcoidosis. Chitotriosidase is an enzyme secreted by activated macrophages able to catalyze the hydrolysis of both chitin and chitin-like substrates. Chitotriosidase is involved in defense against, and in degradation of chitin-containing pathogens such as fungi, nematodes, and insects. METHODS: Forty-three patients affected by chronic sarcoidosis, in active (23 patients) or inactive (20 patients) phase, were studied. Serum levels of chitotriosidase and ACE activity were evaluated and compared with those of 32 healthy subjects. Serum chitotriosidase concentration and ACE activity were also correlated with radiographic stage of disease. RESULTS: Individuals with chronic sarcoidosis have higher serum chitotriosidase concentrations and ACE activity than those of normal subjects. Sarcoidosis patients in the active phase of the disease had significantly higher chitotriosidase and ACE levels than those in the inactive phase. In contrast to serum ACE activity, a significant relationship between serum levels of chitotriosidase and the four radiographic stages of the disease was observed. CONCLUSION: Although the data need to be validated by further investigation, the observations made in this study seem to indicate that serum chitotriosidase concentrations may be a useful marker for monitoring sarcoidosis disease activity and prognosis.     

84例肺结节病临床特征分析

目的:探讨肺结节病的临床特点及诊治方法。方法:分析84例肺结节病患音的临床资料。结果:本组病例有以下临床特征:(1)以中老年女性患者为主,平均年龄48.26岁;(2)症状多样性。胸部X线检查是早期诊断的重要手段,支气管肺泡灌洗液细胞分类对诊断有帮助;(3)确诊依赖组织病理学。经纤支镜粘膜活检及经纵隔镜淋巴结活检诊断阳性率较高。结论:肺结节病临床表现多样,糖皮质激素治疗有一定疗效,但应采取个体化疗法,必要时加用其它免疫抑制剂。     

Splenic Sarcoidosis

Sarcoidosis is a multisystem granulomatous disease of unknown cause that can produce either homogeneous splenomegaly or multiple splenic nodules. Systemic symptoms can accompany splenic involvement. Although the chest radiograph may be suggestive of sarcoidosis, a normal chest radiograph is seen in one quarter to one third of patients with splenic sarcoidosis. The imaging appearance of splenic sarcoidosis can mimic more ominous neoplastic or infectious disease. Biopsy of the spleen or other involved organ may be indicated for definitive diagnosis.     

Prognosis and prognostic factors of sarcoidosis in Japan

Sarcoidosis is a systemic granulomatous disease that primarily affects the lung and lymphatic systems. Sarcoidosis patients commonly have spontaneous remission and good prognosis. But some patients show chronic, progressive and life-threatening conditions. Determination of prognosis based on the initial clinical presentation is important for the treatment. In this article, we review natural history, prognosis and the factors related prognosis of sarcoidosis patients in Japan. Shadows on chest radiograph were cleared in 76% of patients for 10 years. Approximately 15% of patients had severe organ dysfunction. In 60% of the sarcoidosis autopsy cases, the causes of death were attributed to organ involvement of sarcoidosis. Adverse prognostic factors are advanced age at onset, the presence of symptoms, extrathoracic involvement and treatment of corticosteroids.     

Spontaneously identified gastric sarcoidosis: a report of three cases

Sarcoidosis is a systemic granulomatous disease, frequently involving the lungs, lymph nodes, eyes and skin. Gastric sarcoidosis is very rare. We report three patients diagnosed initially with gastric sarcoidosis. Two had no other identified involvement, and one had involvement of the lungs and hilar lymph nodes. Gastroscopy was performed because of abdominal discomfort or as a follow-up examination for partial gastrectomy. This revealed atrophic lesions with nodular mucosal changes in the antrum and granular mucosa, and residual gastritis was found at the site of gastroduodenal anastomosis. Non-caseating epitheloid-cell granulomas were found in all patients following histological analysis. Gastroscopy and histopathological findings in gastric mucosal biopsy samples from suspicious sites are essential in establishing an accurate diagnosis of gastric sarcoidosis.     

Syphilis: a disease to exclude in diagnosing sarcoidosis.

A 37-year-old man was referred to our institution for assessment of possible sarcoidosis with involvement of the central nervous system. Before referral, he experienced a systemic illness that persisted for several months, during which time ocular and pulmonary noncaseating granulomas were identified. Sarcoidosis with involvement of the central nervous system was tentatively diagnosed. Because of several inconsistencies in the preliminary diagnosis of sarcoidosis, further assessment was pursued, and syphilis was diagnosed. Herein we emphasize the useful clinical features for distinguishing syphilis from sarcoidosis and review the clinical manifestations of pulmonary syphilis.     

The immune paradox of sarcoidosis and regulatory T cells

Sarcoidosis is characterized by extensive local inflammation (granuloma, cytokine secretion) associated with anergy (poor response to antigens in vitro and in vivo). We postulated that this paradoxical situation would correspond to a disequilibrium between effector and regulatory T lymphocytes (T reg cells). We show that CD4+CD25(bright)FoxP3+ cells accumulate at the periphery of sarcoid granulomas, in bronchoalveolar lavage fluid, and in peripheral blood of patients with active disease. These cells exhibited powerful antiproliferative activity, yet did not completely inhibit TNF-alpha production. Sarcoidosis is therefore associated with a global T reg cell subset amplification whose activity would be insufficient to control local inflammation. At the same time, peripheral T reg cells exert powerful antiproliferative activity that may account for the state of anergy. Altogether, these findings advance our conceptual understanding of immune regulation in a way that resolves the immune paradox of sarcoidosis and permit us to envisage a profound clinical impact of T reg cell manipulation on immunity.     

Renal failure and hypercalcemia as initial manifestations of extrapulmonary sarcoidosis

Sarcoidosis is a granulomatous, multisystem disease. Rarely, sarcoidosis may present with both renal failure and hypercalcemia. A 27-year-old black man presented with severe abdominal pain and renal failure. A kidney biopsy demonstrated features of both interstitial nephritis and membranous glomerulopathy thought to be secondary to nonsteroidal anti-inflammatory drugs. His renal function and symptoms improved with short-term prednisone therapy. Discontinuation of steroids led to a recurrence of renal failure and severe hypercalcemia. On the basis of an elevated angiotensin-converting enzyme level of 160 U/L and anemia, a bone marrow biopsy was performed. Acid-fast bacillus-negative, noncaseating granulomas suggested the diagnosis of sarcoidosis. The patient recovered after restarting prednisone. Sarcoidosis may cause both interstitial and membranous nephritis from direct infiltration. Hypercalcemia results from increased calcium absorption secondary to 1,25-dihydroxyvitamin D production by sarcoid granulomas. Sarcoidosis must be considered in the differential diagnosis of renal failure in black patients. Serum calcium and angiotensin-converting enzyme levels may aid the diagnosis.     

Oro-facial granulomatosis--a clinical and pathological analysis

A study of 60 patients with oro-facial granulomatosis has been conducted and the clinical presentation of this disorder defined. It encompasses the previously recognised clinical entities of Melkersson-Rosenthal syndrome and cheilitis granulomatosa. The pathological features of the disease are lymphoedema and the presence of multiple non-caseating giant cell granulomata. These granulomata are histologically indistinguishable from those found in both gastrointestinal Crohn's disease and systemic sarcoidosis. Within this series of patients, nine had evidence suggestive of gastrointestinal Crohn's disease, and in six this was confirmed. A diagnosis of sarcoidosis was made in a further two patients. The relationship of oro-facial granulomatosis to these systemic granulomatous diseases is not yet clear. Patients with oro-facial granulomatosis who have gastrointestinal symptoms should be investigated for the presence of gastrointestinal Crohn's disease. Those without symptoms should be investigated for evidence of malabsorption or serological evidence of Crohn's disease. Within the present study, the erythrocyte sedimentation rate, full blood count, corrected whole blood folate, serum albumin and calcium were the most sensitive markers of gastrointestinal involvement. Sarcoidosis should be considered in all patients with oro-facial granulomatosis. The absence of clinical signs suggestive of sarcoidosis, a normal chest radiograph and normal levels of serum angiotensin-converting enzyme makes sarcoidosis unlikely.     

Mannose-binding lectin promoter and structural gene variants in sarcoidosis

BACKGROUND: Sarcoidosis is a chronic granulomatous disease of unknown aetiology. Studies have suggested that the causative agent may be an infectious micro-organism. The mannose binding lectin (MBL) is involved in innate immunity to a wide range of micro-organisms. Mutations in the promoter region and exon 1 of the MBL gene occur with high frequency and are associated with reduced serum levels of MBL and increased susceptibility to microbial diseases. This study investigated whether MBL variants predispose to sarcoidosis by increasing their susceptibility to micro-organisms. METHODS: MBL gene promoter and exon 1 variants were detected by sequence specific primer polymerase chain reaction (SSP-PCR) in 167 UK Caucasian sarcoidosis patients and 164 control subjects. Severity of pulmonary disease outcome among patients was assessed by radiography after a minimum of 4 years from disease onset and classified as mild, moderate, and severe disease categories, accordingly. RESULTS: MBL variant frequencies were similar in patients and controls studied. Among sarcoidosis patients, the frequencies of variants were similar regardless of severity of disease outcome. The average patient ages at time of diagnosis were similar for all MBL genotypes. CONCLUSIONS: MBL gene variants do not appear to influence susceptibility to sarcoidosis, age of disease onset, or severity of disease.     

Propionibacterium acnes: an under-appreciated cause of post-neurosurgical infection

BACKGROUND: Propionibacterium acnes is increasingly recognized as a cause of post-neurosurgical infection. This review of patients with P. acnes neurosurgical infection was carried out in order to determine clinical characteristics and outcomes in relation to duration of antimicrobial treatment. METHODS: We retrospectively reviewed the charts of consecutive patients with P. acnes isolated from neurosurgical specimens from 1 January 1999 to 30 June 2005. We defined P. acnes neurosurgical infection as isolation of P. acnes alone from a sterile neurosurgical site in a patient who clinically improved following treatment with an appropriate antibiotic. RESULTS: We identified 28 patients with definite P. acnes neurosurgical infection; median age 49 years (range 23-77); 15 (54%) male. All patients had prior neurosurgical procedures: 27 (96%) post-craniotomy. The median time from surgery to presentation was 54 days (range 12-1,578). Eighteen out of 28 (64%) patients who met the definition of neurosurgical infection had Gram-positive bacilli seen in at least one surgical specimen compared with only 2/56 (4%) patients who did not meet the definition (P < 0.0001). Intravenous benzyl penicillin +/- oral penicillin VK was the most common treatment. The median duration of antibiotic treatment for intracranial infection was 29 days. Five of nine patients who had extracranial bone-flap-associated infection had 相似文献   

Propionibacterium acnes: infection beyond the skin

Propionibacterium acnes is a Gram-positive bacterium that forms part of the normal flora of the skin, oral cavity, large intestine, the conjunctiva and the external ear canal. Although primarily recognized for its role in acne, P. acnes is an opportunistic pathogen, causing a range of postoperative and device-related infections. These include infections of the bones and joints, mouth, eye and brain. Device-related infections include those of joint prostheses, shunts and prosthetic heart valves. P. acnes may play a role in other conditions, including inflammation of the prostate leading to cancer, SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome, sarcoidosis and sciatica. If an active role in these conditions is established there are major implications for diagnosis, treatment and protection. Genome sequencing of the organism has provided an insight into the pathogenic potential and virulence of P. acnes.     

Dyslipidemia and oxidative stress in sarcoidosis patients

ObjectivesSarcoidosis is an inflammatory disease characterised by enhanced production of reactive oxygen species and alterations in the circulating lipid profile. Both attributes are thought to play a role in its pathogenesis. However, current knowledge regarding the significance of blood oxidative stress/anti-oxidant defence as well as alterations in lipid status parameters in sarcoidosis is scarce. The aim of our study was to assess these parameters and their inter-relationships, as well as their potential for patient-control discrimination.Design and methodsOxidative stress status and anti-oxidant defence parameters were determined in serum and erythrocytes and lipid status parameters were assessed in the serum of 213 treated sarcoidosis patients and 90 controls.ResultsMalondialdehyde, superoxide anion, total oxidant status, prooxidant–antioxidant balance and triglycerides were significantly higher whereas total anti-oxidant status, superoxide dismutase activity and HDL-cholesterol were significantly lower in sarcoidosis patients compared with controls. Total sulfhydryl group content was higher in patients compared with controls. Serum and erythrocyte malondialdehyde exhibited the strongest ability to predict disease presence. Elevated oxidative stress was characterised by higher clinical accuracy compared with lipid status abnormality. Some oxidative stress and lipid status markers were significantly associated in sarcoidosis.ConclusionsSarcoidosis is characterised by increased oxidative stress, diminished overall anti-oxidative protection and alterations in the circulating lipid profile. Both oxidative stress and lipid status parameters demonstrated the potential to discriminate sarcoidosis from controls which was particularly evident from the point of view of oxidative stress status parameters. Association between these parameters may indicate an increased risk for atherosclerosis development.     

Non-steroid therapy for sarcoidosis

Sarcoidosis is a systemic granulomatous disease that the epidemiology remains unknown. The appropriate therapy for sarcoidosis also has not been well defined. Systemic therapy is clearly indicated for cardiac disease, neurologic disease, eye disease without response to topical therapy, hypercalcemia, and progressive symptomatic disease. Corticosteroid are very commonly used as systemic therapy for sarcoidosis. However, there are some patients who can not be controlled with corticosteroid alone and/or have adverse reactions to corticosteroid. Several cytotoxic agents, including methotrexate, azathioprine, cyclophosphamide, chlorambucil and cyclosporine A, have been used to treat sarcoidosis. There are no studies that have clearly concluded when these agents should be used for treatment. On the basis of safety and efficacy, methotrexate and azathioprine are the preferred drugs. The antimalarial agents, including chloroquine and hydroxychloroquine, most often used to treat sarcoidosis.     

Exercise intolerance and multiple conduction abnormalities as first manifestation of cardiac sarcoidosis

Sarcoidosis is a multisystem disorder of unknown cause, characterized pathologically by noncaseating granulomas. It is more commonly seen in younger adults and African Americans. Myocardial involvement occurs in at least 25% of patients with sarcoidosis and is associated with poor prognosis. In spite of recent advances in imaging modalities, early diagnosis of cardiac sarcoidosis (CS) remains very challenging. Cardiac disease as the first manifestation of sarcoidosis is rare and therefore, requires a high index of suspicion from the physician. We present a case of CS manifested initially as exercise intolerance secondary to severe cardiac conduction abnormalities.