Activation of the pentose phosphate pathway in macrophages is crucial for granuloma formation in sarcoidosis
Satoshi NakamizoYuki SugiuraYoshihiro IshidaYoko UekiSatoru YonekuraHideaki TanizakiHiroshi DateAkihiko YoshizawaTeruasa MurataKenji MinatoyaMikako KatagiriSeitaro NomuraIssei KomuroSeishi OgawaSaeko NakajimaNaotomo KambeGyohei EgawaKenji Kabashima
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Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved steroid-sparing alternatives. Here, we investigated the mechanism of granuloma formation using single-cell RNA-Seq in sarcoidosis patients. We observed that the percentages of triggering receptor expressed on myeloid cells 2-positive (TREM2-positive) macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, diagnostic makers of sarcoidosis, were increased in cutaneous sarcoidosis granulomas. Macrophages in the sarcoidosis lesion were hypermetabolic, especially in the pentose phosphate pathway (PPP). Expression of the PPP enzymes, such as fructose-1,6-bisphosphatase 1 (FBP1), was elevated in both systemic granuloma lesions and serum of sarcoidosis patients. Granuloma formation was attenuated by the PPP inhibitors in in vitro giant cell and in vivo murine granuloma models. These results suggest that the PPP may be a promising target for developing therapeutics for sarcoidosis.Relationship of tuberculosis (TB) with sarcoidosis has baffled physicians and researchers ever since the description of sarcoidosis. Not only sarcoidosis is a close clinical mimic of TB, which makes the diagnosis of sarcoidosis (vs. TB) difficult in countries with high prevalence of TB, and vice versa, but TB has also been linked to causation of sarcoidosis. All those who deal with such conditions would remember the cases, when TB, after successful treatment (or during it), is followed by a diagnosis of sarcoidosis and more commonly when patient being treated with steroids following with a diagnosis of sarcoidosis, land up with TB. In both of the clinical scenarios, the authenticity of the primary diagnosis has to be confirmed, before one can say that either of the conditions has lead to the other one. In this issue of the journal, Shah et al. present an interesting viewpoint regarding an entity called ‘tuberculous sarcoidosis’. Further, the authors have even laid down the criteria for the diagnosis of tuberculous sarcoidosis.[1] Tuberculous sarcoidosis was a term given to the patients who had features of both TB and sarcoidosis, way back in 1960.[2] However, many things have changed since then and good knowledge about the histopathological variations is observed in TB and sarcoidosis has evolved. So is there any merit in reviving this old forgotten term? For example, in the illustrative case 1 described by Shah et al. [originally by Wong et al.,[3] represents a typical presentation of sarcoidosis coexisting/following a case of bacteriologically confirmed TB, and there is no question of labeling the case as tuberculous sarcoidosis. Similarly, the case 2,[4] could be a presentation of sarcoidosis as pleural effusion with spontaneous resolution of pleural effusion[5] followed by development of typical sarcoid manifestations or could be sarcoidosis following a tuberculous pleural effusion. Cases 3 and 4 are again examples of coexisting TB and sarcoidosis with sequential and uninterrupted progression of one disease into another. Case 5 is the most typical presentation of sarcoidosis which one can encounter and just on the basis of fibrinoid necrosis resembling caseation the patient was initiated on antituberculous therapy.[6] The illustrative cases reveal only one fact: That is, the clinician should be astute to pick up the typical presentations. Finally, the diagnostic criteria laid down by Shah et al. [Table 1] are highly nonspecific and the only specific findings are those that are well known to be associated with sarcoidosis, and include typical clinical presentation with characteristic radiological and histopathological findings.Table 1: Diagnostic criteria proposed by Shah et al.Since sarcoidosis was first described, there has always been a belief that the disease is in some way related to TB.[7] Sarcoidosis is known to follow or even coexist with TB,[28] and TB following sarcoidosis is a fairly common event due to the immunosuppressive effects of glucocorticoids.[9] Thus, it is no surprise that a physician is likely to encounter situations wherein sarcoidosis may precede, follow or present concurrently with TB. Rather than coining a separate term, it would be better to recognize the typical and atypical clinical presentation of sarcoidosis and diagnose it appropriately.[1011] Of late, nucleic acid amplification of the genetic material of putative agents serves as an alternative method for isolating fastidious organisms. This method has been used successfully in identifying Tropheryma whippelli as a causative agent for Whipple's disease[12] and coronaviruses[13] as an agent for severe acute respiratory syndrome. In a recent meta-analysis, we have shown that there is a 25.6% (95% CI, 23.6 – 29.5%) prevalence of mycobacterial DNA in patients with sarcoidosis with the odds of finding mycobacteria in samples of patients with sarcoidosis versus controls being 9.67 (95% CI, 4.56 – 20.5).[14] These results indicate that there is a definite link between TB and sarcoidosis. It might be appropriate to consider that the situation of sarcoidosis is analogous to leprosy in which the tuberculoid (pauci-bacillary) and lepromatous (multi-bacillary) forms are encountered; and, sarcoidosis might represent the tuberculoid form of the pathological responses to mycobacteria.[15] Based on the current understanding, we believe that there is no merit in the term “tuberculous sarcoidosis”; and the criteria laid down by Shah et al. are neither evidence-based nor play any role in day-to-day clinical practice.
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Summary Sarcoid granulomatous dermatitis is one of the complications after tattooing. The presence of these granulomas can be produced by a foreign body reaction, a hypersensitivity phenomenon to the dye used or a sign of sarcoidosis. The histopathologic examination of the granuloma is not specific, and it is neccesary a general evaluation of the patient to discard a systemic involvement. We report a 31 years old woman who developed noncaseating epithelioid granulomas in a red tattoo. The complementary studies showed bilateral hiliar adenopathies consistent with sarcoidosis. The tattoo granulomas were the first manifestation of the disease.
Granulomatous disease
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EBUS is now used routinely in the investigation of sarcoidosis. If the pre-test CT diagnosis is sarcoidosis, it is not clear how often EBUS changes the diagnosis or management. We performed a retrospective analysis of patients referred for EBUS with possible sarcoidosis in a 24 month period.A total of 75 patients were identified. The median age was 52 years, 65% were males and 69% were white British. Patients were split into 2 groups based on the CT report - Typical of Sarcoidosis and Possible Sarcoidosis. We also looked at the number of nodes sampled. 47 patients had CT scans reported as Typical Sarcoidosis. EBUS gave results consistent with sarcoidosis in 24/47 patients (51%) and whilst 8 had other investigations, it did not change the diagnosis. The final diagnosis was sarcoid in all of this group. 28 patients were in the group with Possible Sarcoidosis. Where sarcoidosis was the most likely differential diagnosis (18/28), 8 of them had an EBUS consistent with sarcoidosis. The final diagnosis was sarcoidosis in 13 of this group (46%). In all cases diagnosed with sarcoid (n=60), the number of nodes sampled to that gave a result consistent with sarcoidosis were: 1 node - 32% (8 out of 27 patients), 2 nodes - 61% (22 out of 36 patients). 3 nodes 100% (9 out of 9 patients) EBUS has an important role in the investigation of sarcoidosis. This analysis showed greater benefit in patients with CT reported as possible rather than typical sarcoidosis. When EBUS is performed, the greater number of lymph nodes sampled improves the diagnostic yield.
Endobronchial ultrasound
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Sarcoidosis is a multi-systemic disease, the diagnosis of which depends on the presence of non-necrotising granulomas in a biopsy specimen. However, variants such as necrotising sarcoid granuloma make it difficult to differentiate the disease from other infectious processes, especially tuberculosis. Here the authors describe the case of a 58-year-old Iranian woman who developed granulomas with extensive necrosis in a systemic sarcoidosis that affected the lung, liver and spleen. These findings led to a diagnosis of tuberculosis and delayed appropriate treatment.
Caseous necrosis
Granuloma formation
Granulomatous disease
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Pentose
Transaldolase
Hexose
Metabolic pathway
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Introduction: Sarcoidosis is granulomatous disorder of unknown aetiology,predominatly manifesting in female patients. Is it the same or similar to mentioned, in patients from the Clinic for lung diseases and tuberculosis CC Serbia in Belgrade ? The Method used: retroscetive analysis were obtaine on 857 patients incoming to the Clinic (F 587-68.5% - 44,7; M 270- 31.5 % - 47,8 years) with previously obtained diagnosis of sarcoidosis. Results: Acute onset of sarcoidosis is predominatly in younger (less than 35 years) with similar gender distribution, 153 F / 132 M. The onset of sarcoidosis in oldier patients (over than 35 years) is less acute notify in more male patients, 381, than 191 female accompanying with prolonged duration of sarcoidosis (5.3 / 3.1 yrs M/F) and frequently more than one organ involved with sarcoidosis. Lung involvement were the only manifestation of sarcoidosis in 423 female/ 197 male patients. Only nonpulmonary involvement is in less numbered – 117 pts (eyes-35, skin-37,cerebri -7, spleen-5,bonnes-3,liver-9,per.lgl -57: 47F / 8 M, gl.parotis- 11, heart- 7) with male predominated: 51 pts / 30pts F. Lung and nonpulmonary sarcoidosis were notified in 134 Female and / 22 Male patients. Conclusion: Due to analysis, the numbered patients with obtained diagnosis of acute onset of sarcoidosis are female. Male patients with nonpulmonary sarcoidosis predominated over the female. Duration of sarcoidosis course is much longer in male patients.
Etiology
Pulmonary sarcoidosis
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Ocular disease is relatively common in sarcoidosis and can be the initial clinical manifestation in some instances. In this study, we retrospectively evaluated the clinical and demographic features of 9 (1.74%) patients with lacrimal gland (LG) involvement out of 516 sarcoidosis patients who were followed up at our centre over the preceding 36-years. In addition, the characteristics of patients with LG involvement were compared to those of other cases with eye involvement and to other sarcoidosis patients.In 5 subjects with LG involvement, the chest X-ray was normal. The number of stage 0 subjects among other sarcoidosis patients was significantly lower than among patients with LG involvement (p<0.001). In 2 of these cases, the diagnosis of sarcoidosis was reached by LG biopsy. The mean age of patients with LG involvement was significantly lower than that of other sarcoidosis patients (p<0.001). Also, sarcoidosis-related organ involvement--other than of the LG--was more frequent than in other sarcoidosis patients (p<0.001).It should be borne in mind that LG involvement might be the initial manifestation of sarcoidosis and the chest X-ray in these patients might be completely normal.
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Sarcoidosis is an inflammatory disorder of unknown etiology. The main characteristics of sarcoidosis are non-caseating granulomas which can be formed in affected organs. Eye and its adnexal tissues can also be involved. In the early stages of sarcoidosis, the clinical picture may be mild and not always specific. Although the early signs of sarcoidosis are lung associated, we present a clinical case with diffuse enlargement of the lacrimal glands as a first sign of systemic sarcoidosis. A 21-years-old woman presented to the ophthalmological center with a 2-weeks history of having swollen, painful upper eyelids. Primary eye examination revealed palpable tender masses in the locations of the lacrimal glands. Characteristic for sarcoidosis X-ray findings and blood tests demanded lacrimal gland and lung biopsy for diagnosis verification. In spite sarcoidosis of lacrimal glands is a rare condition, it has to be taken into consideration in the differential diagnosis of lacrimal gland masses.
Etiology
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Background: Sjögren's syndrome (SS) and sarcoidosis are diseases that can affect the salivary glands and result in the loss of salivary gland function. Most of the criteria used for the diagnosis of SS exclude sarcoidosis before establishing the diagnosis of SS. However, several reports have suggested the coexistence of both SS and sarcoidosis in the same patient. Objective: The purpose of this study was to present five cases that support a true coexistence of sarcoidosis and SS. Methods: Clinical and laboratory findings of patients with evidence of having both SS and sarcoidosis were reviewed. The diagnosis of SS was based on the European community criteria; the diagnosis of sarcoidosis was based on the presence of serological, radiographic and/or histopathologic findings that are consistent with sarcoidosis. Results: All patients fulfilled the criteria for the diagnosis of both diseases. Conclusion: Our findings appear to support a true coexistence of sarcoidosis with SS. Therefore, it is reasonable to suggest removing the exclusion of sarcoidosis from the diagnostic criteria for SS.
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The efficacy of transbronchial lung biopsy (TBLB) for the diagnosis of sarcoidosis was compared to that of scalene node biopsy (SNB). We performed both TBLB and SNB or in 336 consecutive patients with clinical features of sarcoidosis. In 270 out of 336 patients epithelioid cell granuloma was found. The frequency of granuloma in specimens obtained by TBLB was higher than that of SNB at any radiographic stage. In stage 0 and stage I diseases however, the frequency of epithelioid cell granuloma in the specimens was increased by examining both of TBLB and SNB. We concluded that SNB was useful in consecutive patients with sarcoidosis in whom the epithelioid cell granuloma could not be confirmed by TBLB.
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