Dendritic cells (DCs) are antigen-presenting cells with the ability to induce primary immune responses necessary both for innate and adaptive immunity. Granulomatous immune responses are a form of delayed type hypersensitivity reaction, and pathologically are characterized by the recruitment and organization of activated macrophages and lymphocytes in discrete lesions laced in a network of matrix proteins. Granulomas can be part of both immune protection and disease pathology during the course of various infections and autoimmune diseases. Recently, the role of DCs in granuloma formation and granulomatous diseases has been elucidated. This review will focus on the role of DCs in granuloma formation and granulomatous diseases.

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Sarcoidosis is a systemic granulomatous disease of unknown etiology. As granulomatous uveitis is frequently observed in this disease, I discribe some characteristic changes of uveitis associated with sarcoidosis and comment on the guidelines for the diagnosis of ocular Sarcoidosis.

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Cardiac involvement is a crucial factor of death in Sarcoidosis. Thus, the early diagnosis of cardiac sarcoidosis is quite important. This study was performed to assess the current status and problems involved in the diagnosis, treatment, and prognosis of cardiac sarcoidosis, from the viewpoint of cardiologists. We analyzed 10 patients with histologically proven cardiac sarcoidosis (6 cases by myocardial specimens obtained at the left ventriculoplasty, 2 at biopsy, and 2 at autopsy). Ten patients with idiopathic dilated cardiomyopathy (DCM) served as controls. We discovered the following: 1) We frequently found cardiac sarcoidosis patients who had been diagnosed as having DCM with lack of other organ involvements, 2) These patients had some characteristic clinical features, such as non-ischemic cardiomyopathy that developed in middle-age or older, and association with or precedence by advanced atrioventricular block, local ventricular wall motion abnormalities (ventricular aneurysm formation or thinning of the interventricular septum), 3) Though the clinical course of most patients was chronic and slowly progressive, fulminant progressive cases with poor prognosis were also observed, 4) From molecular biological and immunohistochemical studies of inflammatory cytokines, the expression of helper T cell type 1 (Th1) cytokines was enhanced specifically in the myocardium of cardiac sarcoidosis patients. In conclusion, the diagnosis of cardiac sarcoidosis was difficult, particularly in cases without involvement of any other organs. These cases are frequently misdiagnosed as idiopathic DCM or unclassified cardiomyopathy. Many questions and problems still remain unresolved concerning epidemiology, etiology, pathogenesis (activity), therapy, and prognosis of cardiac sarcoidosis. Further elucidation of the etiology and the development of specific tools are anticipated for the improvement of the diagnosis and the estimation of disease activity of cardiac sarcoidosis.

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Complications in sarcoidosis patients in the Osaka area included malignant tumors such as lung cancer, malignant lymphoma, gastric and colon cancer, infectious diseases such as pulmonary tuberculosis, tuberculous pleurisy, empyema, pulmonary aspergillosis, Herpes Zoster, hepatitis C, water pox and measles pneumonia, bronchial asthma, rheumatoid arthritis, Sjogren syndrome, acute onset ITP and hyperuric acidemia. Causes of death from complications in sarcoidosis mautopsy cases included malignant tumors, infectious diseases and appoplexia, myocardial infarction.

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Left ventricular hypertrophy has been reportedly shown in cases of sarcoidosis. We investigated the frequency, and clinical and morphological characteristics of left ventricular hypertrophy in 70 patients with cardiac sarcoidosis who showed abnormalities in echocardiogram and myocardial scintigrams. Left ventricular hypertrophy was found in 20 (29%) of the 70 patients, and the most-frequently observed morphological abnormalities followed the thinning of the septum (29 cases, 41%). Asymmetrical septal hypertrophy such as hypertrophic cardiomyopathy (HCM) was found in 17 of the 20 cases. A hyperechoic area was found in the sepal wall in most of the cases. Myocardial biopsy was performed in 10 cases, and pathological findings revealed myocardial hypertrophy, fatty degeneration, and fibrosis, but there was no clear evidence of disarrangement of myocardial cells as seen in HCM. Left ventricular hypertrophy was not unusual in the patients with cardiac sarcoidosis. However, it is difficult to differentiate sarcoidosis from HCM on the basis of morphology and pathological findings.

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Refractoriness of the disease based on external and internal causes of the disease has been investigated, and elimination of the external causes has shown better prognosis, except for cases of HLA-DR8 or DR9 (Chest, 1992; JSSOG, 2000). Even so, the need for other treatment is suggested by cardiologists and others to get long-term remission. Since 1999 Minocycline (MINO) has been used for the treatment of four cases of sarcoidosis and its efficacy proven. The mechanisms of its usefulness are documented with two (ATE and IMP). However, in a comparison of MICs between three antibiotics (Table 2), the fact that tetracycline alone shows effectiveness for refractory sarcoidosis (Table 1), indicates that the external cause is indigenous Streptococcus in the upper airway and the effectiveness of minocycline is ATE.

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A 65-year-old female, complaining of exertional dyspnea was referred to our hospital for evaluation of progressive interstitial lung infiltrates predominant in the left lung and intrathoracic lymphadenopathy. Interstitial pneumonia associated with adjuvant disease could be ruled out, since she had a history of bilateral mammoplasty 36 years ago. Biopsy specimens of the enlarged paraaortic lymphnode of the mediastinum obtained by video-assisted thoracic surgery (VATS) revealed epithelioid cell granulomas typical of sarcoidosis. Foreign bodies, foreign body reactions, and hyperplasia of lymphfollicles characteristic of adjuvant disease were not observed. VATS was useful for the definite diagnosis of pulmonary sarcoidosis.

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A 51-year-old woman was admitted to our hospital because of dyspnea in May 2003. A chest X-ray picture showed bilateral pleural effusion. A CT also showed bilateral effusion and diffuse spread of micronodules in both lung fields. The bronchoscopic appearances showed endobronchial plaques characteristic of sarcoidosis. The bronchoalveolar lavage showed an increased percentage of lymphocytes with high CD4/CD8 ratio (2.82). The aspiration of effusion yielded serous fluid containing lymphocyte. A thoracoscopy was performed. Biopsy specimens of pleural and lung tissues demonstrated noncaseating epithelioid cell granulomas. Based on the histological finding, sarcoidosis was diagnosed. Pleural involvement in sarcoidosis is reportedly a rare manifestation of the disease.

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A 44-year old woman was admitted to the department of orthopedic surgery in Tsubame Rosai Hospital on the suspicion of pyogenic spondilitis in April 2003. She had suffered from blurred vision, general fatigue, and severe back pain since December 2002. Serum C-reactive protein level and spinal MRI findings were normal, although mononuclear cell numbers in the cerebrospinal fluid were slightly increased. A left inguinal lymph node biopsy revealed non-caseating epithelioid cell granuloma in the Department of Hematology, and the diagnosis of sarcoidosis was confirmed in the Department of Respirology, making reference to negative PPD test, high titer of serum angiotensin converting enzyme (ACE), bilateral uveitis, and chest radiographic findings. When facial nerve palsy appeared, she was transferred to Niigata University Hospital. She had left hypochondriac pain resistant to oral pain relievers. Physical and neurological examinations confirmed the swelling of superficial lymph nodes, bilateral parotid glands and left hemihypoesthesia, trigeminal, and facial and auditory nerve findings. Cerebrospinal fluid test showed increases in levels of protein, β 2 microglobulin and ACE. Head MRI findings were normal. ⁶⁷Ga scintigram demonstrated accumulation in the bilateral pulmonary hilum and parotid glands. From the above-mentioned results, she was diagnosed as having sarcoidosis with central nervous system involvement compatible with Heerfordts syndrome. Sarcoidosis with cranial polyneuropathy often shows high fever and can be associated with pain parallel to dermatome when radiculopathy exists.

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We report two sarcoidosis cases complicated with small fiber neuropathy. Two female patients, 71-years-old and 67-years-old, were referred to our institute, complaining of paresthesia in their extremities. Neurological examinations revealed moderate impairment of senses of warmth and pain in their distals, but no impairment in touch, joint and vibration sensation. Hypohydrosis and constipation were seen in both patients. Nerve conduction and needle electromyogram studies were normal These results were compatible with small fiber neuropathy. Immunostaining of skin biopsy specimen revealed a significant decrease in epidermal nerve fiber density, and significant increase of axonal damage. From these findings, the two cases were definitely diagnosed as having small fiber neuropathy. Diclofenac and mexiletine hydrochloride relieved paresthesia to some extent in Case 1, and amitriptyline hydrochloride was effective in Case 2.
Peripheral nerve impairment in sarcoidosis has so far been commonly thought to be represented by cranial nerve palsy and mononeutitis multiplex, but our cases suggest that small fiber neuropathy is more frequently seen among sarcoidosis patients than previously thought. Nerve conduction study and skin biopsy are useful in the diagnosis of small fiber neuropathy among a wider variation of neuropathies with sarcoidosis.

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We report a case of a 42-year-old man who had bilateral hilar lymphadenopathy and small nodular shadows in the left upper lung field detected by a health check-up at the age of 35. He was diagnosed as having Sarcoidosis by TBLB. He had a nodule on his right thigh and was diagnosed as having muscular sarcoidosis by muscle biopsy. We carefully followed-up the disease course without any treatment, and the tumor finally disappeared. At the age of 42, he suffered from back pain and went to a hospital. Because his abdominal CT revealed an irregular surface of the liver and multiple hypodense lesions in the liver and spleen, he was admitted to our hospital for further examinations. A laparoscopy revealed white plaque covering the liver. Biopsy specimens showed non-caseating granulomas. He was diagnosed as having liver sarcoidosis and treated with prednisolone (40mg/day). He died from a sudden accident after this. Here, we report a valuable case in which nodular muscular sarcoidosis and hepatic sarcoidosis were seen at different times.

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We experienced a case (an 81-years-old woman) of malignant lymphoma with uveitis, interstitial pneumonia, interstitial nephritis and elevation of serum angiotensin converting enzyme (ACE) and lysozyme level. Though sarcoidosis was suspected, she was diagnosed by autopsy as having malignant lymphoma (peripheral T cell lymphoma, unspecified). It was speculated that uveitis and tubulointerstitial nephritis could be attributed to malignant lymphoma, elevation of serum ACE level to cholestatic jaudice, and interstitial pneumonia to pneumocystis carinii and cytomegalovirus infection. This complicated case of malignant lymphoma is important for clinicians who are concerned with the medical care of sarcoidosis, so we present it here from the point of the differential diagnosis between sarcoidosis and malignant lymphoma.

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Two cases of Wegener's granulomatosis diagnosed by surgical lung biopsy are reported. A 59-year-old man was admitted to our hospital because of slight fever and cough in July 2003. Chest radiograph showed a mass shadow adjacent to the right pulmonary hilum. Although cytoplasmic-antineutrophil cytoplasmic antibody (C-ANCA) test was positive, the tumor was surgically biopsied because malignancy could not be ruled out from the radiological findings. Surgical biopsy specimens showed the geographical necrosis with granulomatous inflammation and angiitis compatible with typical findings of Wegener's granulomatosis. Oral administration of prednisolone combined with cyclophosphamide was successfully performed. Another case was a 53-year-old woman complaining of nasal obstruction and nasal discharge. Paranasal sinus CT showed a space-occupying lesion, and chest CT showed a mass in right lower lobe, suggesting Wegener's granulomatosis. However, C-ANCA test was negative. Histological specimens obtained from right lower lobe showed typical findings of Wegener's granulomatosis. Oral prednisolone and cyclophosphamide treatment markedly improved clinical symptoms.

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Sarcoidosis is a systemic, chronic disease. Various organ involvement can be found. While use of corticosteroids is a standard therapy, there continue to be questions about the timing of therapy, dose and duration, tapering and relapse, maintenance therapy, and the long term effect of corticosteroids. Immunosupressants and anticytokine agents are still under evaluation. We discussed the above-mentioned points based on recent studies and our own experience.

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There is a group of patients with chronic course in sarcoidosis, and it is this group that many of the new steroid sparing agents have been developed. In this manuscript, I will concentrate on three new agents that have been developed for sarcoidosis; antibiotic minocycline, the cytotoxic agent leflunomide, and the anti-tumor necrosis factor agent infliximab. Minocycline and doxycycline was reported as useful for sarcoidosis, and our preliminary results on 57 sarcoidosis patients indicate that at least 40% have had some sort of response, usually for skin lesions. The drug has activity against Propiniobacterium acnes, but it also has immunomodulatory effct, therefore the mechanism of action for the drug in sarcoidosis should be considered from both aspects of an antibiotic and anti-inflammatory effect.
The use of cytotoxic drugs has become a standard approach to patients with chronic sarcoidosis. Leflunomide is similar to methotrexate which have been found useful in some patients with sarcoidosis and is associated with less toxicity. We have recently reported that the response rate of the drug was slightly better for ocular disease, but the drug was effective in more than 70% of patients with pulmonary disease. We found the leflunomide was well tolerated and could be used in most patients who developed toxicity with methotrexate. Tumor necrosis factor (TNF) has been shown to be released at increased levels by alveolar macrophages by patients with active sarcoidosis. Infliximab is a chimeric monoclonal antibody which binds TNF and has been found to be effective for treatment of rheumatoid arthritis and Crohns disease. Several case reports and case series have reported the utility of infliximab for sarcoidosis. Our regimen is to give infliximab at 5mg/kg initially, week two, and then every four to six weeks. Infliximab causes lysis of cells releasing TNF, thus the effect of the drug may not be just inactivation of TNF, but also cytotoxicty of cells actively releasing TNF. Considering the increased risk for reactivation of tuberculosis, we have elected not to treat with infliximab in those tuberculosis infection was suggested on chest x-ray films.

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