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Autoimmune pulmonary alveolar proteinosis (APAP) is caused by macrophage dysfunction due to anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody. We experienced 2 cases of APAP complicated with sarcoidosis in a 42-year-old woman and a 51-year-old man (age at the sarcoidosis diagnosis). APAP preceded sarcoidosis in the woman, and both diseases were diagnosed simultaneously in the man. Sarcoidosis lesions were observed in the lung, skin, and eyes, and the pathological findings of APAP were not marked at the diagnosis of sarcoidosis in either case. Low-grade positive serum anti-GM-CSF autoantibody was suspected to be correlated with the occurrence of sarcoidosis and resolution of APAP.

Background: Sarcoidosis is a systemic granulomatous disease characterized by the combination of Th1 and Th17 responses. Recently, several arguments have suggested a potential involvement of B cells as well as T cells in the pathogenesis of sarcoidosis. Follicular helper CD4 + T (T FH ) cells are specialized in interacting with and helping B cells, and play a crucial role in the formation of germinal centers., Objective: We sought to explore the status of T FH cells and investigate their possible pathogenic role in sarcoidosis., Methods: T FH cells and B cells in peripheral blood were examined by flow cytometry, and serum samples were studied by cytokine arrays. Immunohistochemistry was performed to check for the presence of T FH cells in sarcoidosis skin lesions. Gene expression in isolated T FH cells was analyzed by quantitative RT-PCR., Results: The proportion of circulating T FH cells was decreased. CD4 + CXCR5 + T FH cells were observed in cutaneous lesions in sarcoidosis. Gene expression in circulating T FH cells and serum cytokine concentrations related to Th17 were increased in sarcoidosis patients. Gene expressions of B cell differentiation cytokines in T FH cells were not altered in sarcoidosis patients., Conclusion: We herein describe a decrease of circulating T FH cells and their migration to affected tissues. Circulating T FH cells are one of the potential cell types capable of producing IL-17 and enhancing Th17 responses, and may promote the chronic inflammation. We could not demonstrate a direct linkage between the imbalance of T FH cells and abnormal B cell differentiation in sarcoidosis., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Sarcoidosis and systemic sclerosis (SSc) are both multisystem disorders of unknown etiology. Some cases having both sarcoidosis and SSc have been reported previously. The present study was to investigate clinical features in sarcoidosis patients who possessed SSc-specific autoantibody. The pathophysiology of each disease, including shared pathways leading to the development of both conditions, is reviewed in addition to previous reports of patients with concomitant SSc and sarcoidosis. SSc-specific autoantibodies including anticentromere antibody (ACA), anti-topoisomerase I antibody, anti-RNA polymerase III antibody and anti-U1RNP antibody were examined in sarcoidosis patients. Complete medical histories, clinical examinations and laboratory tests were conducted for all patients. For reviewing previously published reports, all cases were retrieved through a PubMed search. ACA was most frequently observed in sarcoidosis patients. Plaques and papules were the most frequent as the cutaneous sarcoidosis lesions. Soluble interleukin-2 receptor was elevated in most of the cases (6/8, 75%), and thymus and activation-regulated chemokine (TARC) was elevated in all cases (6/6, 100%). Together with our two cases (cases 1 and 3), a review of previously reported cases of sarcoidosis patients concomitant with SSc showed high frequency of ACA and plaques as cutaneous lesions. We suppose that TARC may play some roles in the production of SSc-specific autoantibodies and development of concomitance with SSc in sarcoidosis, although the mechanisms remain unknown., (© 2019 Japanese Dermatological Association.)

Cutaneous lesions of sarcoidosis show varied clinical features. They are categorized into specific types; skin sarcoid, scar infiltrations with granulomas and foreign bodies, and non-specific lesions like erythema nodosum. Identification of the cutaneous lesions is important for the diagnosis of sarcoidosis, because they are an easily accessible source of tissue for histologic examination. The commonest cutaneous lesions in sarcoidosis are the nodular and plaque types of skin sarcoid, and scar infiltrations. Since the preferential sites for skin sarcoid and scar infiltrations are the face and knees, respectively, these areas should be carefully examined.

Background: Sarcoidosis is a systemic disorder characterized by the accumulation of lymphocytes and monocyte/macrophage lineage cells that results in the formation of non-caseating granulomas. Thymus- and activation-regulated chemokine (TARC)/CCL17 is an important chemokine in the amplification of Th2 responses, which are achieved by recruiting CCR4-expressing CD4 + T lymphocytes. TARC concentrations are known to increase in the serum of sarcoidosis patients; however, its role in the assessment of severity and prognosis of sarcoidosis remains unknown. The objective of this study is to elucidate the role of TARC in sarcoidosis by investigating its expression in peripheral blood and at inflammatory sites. We also examined its relationship with clinical features., Methods: Serum levels of TARC, soluble interleukin 2 receptor, angiotensin-converting enzyme, and lysozyme were measured in 82 sarcoidosis patients. The Th1 and Th2 balance in circulating CD4 + T cells was evaluated by flow cytometry. The immunohistochemical staining of TARC and CCR4 was performed in order to identify the source of TARC in affected skin tissues., Results: TARC serum levels were elevated in 78% of patients and correlated with disease severity. The percentage of CCR4 + cells and the CCR4 + /CXCR3 + cell ratios were significantly higher in sarcoidosis patients than in normal subjects (P = 0.002 and P = 0.015, respectively). Moreover, TARC was expressed by monocyte/macrophage lineage cells within granulomas. The abundancy as well as distribution of TARC staining correlated with its serum levels., Conclusions: The present results suggest that elevations in TARC drive an imbalanced Th2- weighted immune reaction and might facilitate prolonged inflammatory reactions in sarcoidosis., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Skin lesions in sarcoidosis are often the initial symptoms that enable the dermatologist to be the first to diagnose this granulomatosis. However, diagnosis is sometimes very problematic. In 2015, the diagnostic criteria for sarcoidosis were updated in Japan, with elevated serum soluble interleukin-2 receptor (sIL-2R) replacing negative tuberculin reaction. Therefore, we assessed the clinical utility of sIL-2R compared with two other common markers, angiotensin-converting enzyme (ACE) and lysozyme, in patients who visited the dermatology clinic. Data from 72 patients showed that sIL-2R was more sensitive than both ACE and lysozyme in supporting a diagnosis of sarcoidosis (52.8%) compared with ACE (29%) and lysozyme (26.4%). Additionally, the sIL-2R level was significantly higher in patients with multiple organ involvement and parenchymal infiltration. Patients with elevated sIL-2R levels had higher serum ACE and lysozyme levels, a higher incidence of pulmonary involvement, more severe chest radiographic stage and a high incidence of expression-specific signs by imaging analysis. Receiver-operator curve analysis showed that sIL-2R was a better marker at the threshold cut-off point compared with ACE and lysozyme for identifying patients with multiple organ involvement, detecting patients with pulmonary disease and parenchymal infiltration as well as predicting the presence of specific signs in the diagnosis of sarcoidosis. Moreover, the kinetics of sIL-2R levels correlated closely with clinical manifestations, in contrast to the modest changes of ACE and lysozyme levels during the follow-up period. In conclusion, sIL-2R may be considered a good marker for diagnosis and a potential indicator of disease activity., (© 2017 Japanese Dermatological Association.)

Background: Monocyte-macrophage lineage cells are the main immunocompetent cells in sarcoidosis. The main cellular elements of sarcoidal granulomas are epithelioid cells and multinucleated giant cells (MGC). MGC are also produced in vitro by human blood monocytes following various stimuli. The in vitro formation of MGC is a useful tool for understanding granulomas. CD163, a scavenger receptor for the hemoglobin-haptoglobin complex, is expressed on monocytes/macrophages and shed into blood in a soluble form (sCD163) after stimulation from Toll-like receptors and oxidative stress. sCD163 serum levels have been reported to increase in inflammatory or infectious conditions., Objective: The aim of the present study was to examine the relationship between serum levels of sCD163 and the conventional disease markers of sarcoidosis, and also to evaluate sCD163 levels in culture supernatants following the formation of MGC by human peripheral monocytes in vitro., Patients and Methods: Twenty sarcoidosis patients and twenty healthy subjects were enrolled in the study. sCD163 serum levels were evaluated using sCD163 ELISA. MGC were formed from peripheral blood monocytes by treatment with supernatant of concanavalin A-stimulated peripheral blood mononuclear cells, and sCD163 levels in the culture supernatants were measured by ELISA., Results: sCD163 serum levels were significantly higher in sarcoidosis patients than in healthy controls and correlated with ACE and soluble interleukin-2 receptor serum levels. sCD163 levels in culture supernatants increased with the production of MGC., Conclusions: sCD163 may be used as a favorable specific marker of macrophage/monocyte activity in order to more clearly understand the disease activity of sarcoidosis.

Objective: The purpose of this study was to determine serum levels of B-cell-activating factor (BAFF) and its clinical association in patients with sarcoidosis. METHODS; Serum levels of BAFF from 37 patients and 21 healthy subjects were examined by ELISA. Serum angiotensin-converting enzyme (ACE), lysozyme and IFN-γ levels in sarcoidosis patients were also measured. Isolated monocytes cultured with IFN-γ, IL-4 or IL-10 and their expression of membrane and soluble BAFF were analysed by flow cytometry or ELISA. Peripheral B cell subsets were analysed by flow cytometry. BAFF expression in the granuloma of the skin was examined by immunohistochemistry. ANAs were determined by indirect IF using HEp-2 cells as a substrate., Results: Serum BAFF levels were significantly elevated in sarcoidosis patients when compared with healthy controls. The frequency of skin and eye involvement was significantly higher in patients with elevated serum BAFF than in patients with normal levels. Serum BAFF levels were correlated with serum levels of ACE, lysozyme and IFN-γ. Immunostaining of anti-BAFF in the skin revealed BAFF expression by epithelioid cells of granuloma. In vitro, IFN-γ induced membrane-bound BAFF expression on monocytes and secretion of soluble BAFF by isolated monocytes. In the peripheral blood, sarcoidosis patients showed increased naïve B cells with a reciprocal decrease in memory B cells and plasmablasts. Seventeen of 26 (65%) sarcoidosis patients exhibited ANA positivity., Conclusion: Serum BAFF levels can be used as a surrogate marker of disease activity in sarcoidosis patients. Increased BAFF may be related to the pathogenesis of sarcoidosis.

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.

Sarcoidosis is a systemic disease of unknown etiology characterized by noncaseating granulomas, consisting mainly of epithelioid cells and multinucleated giant cells derived from monocyte-macrophage lineage cells. Monocytes fall into subpopulations comprising CD14++ CD16-, and CD14+ CD16+ cells, and expansion of the later monocytes has been reported under some pathological conditions. In this study, we examined the immunophenotype of blood monocytes in patients with sarcoidosis using two-color immunofluorescence flow cytometry. In healthy controls CD14+ CD16+ monocytes account for 5.8 +/- 2.8% of monocytes. The percentage of CD14+ CD16+ monocytes was significantly higher (p <0.02) in the sarcoidosis patients (11.8 +/- 4.9%) compared with those in healthy control subjects. The serum ACE levels were significantly correlated with the percentage of CD14+ CD16+ monocytes (p <0.05). In contrast, the percentage was not correlated with purinergic receptor expression of monocytes as estimated by LDH release from BzATP-stimulated monocytes. These findings suggest that CD14+ CD16+ monocytes represent a sensitive marker for the disease activity of sarcoidosis.

Multinucleated giant cells (MGC) are characteristic cells in granulomatous disorders such as sarcoidosis and also formed in vitro from peripheral blood mononuclear cells by stimulation with cytokines, including interferon-gamma (IFN-gamma), interleukin-3 (IL-3), IL-4, IL-13, and granulocyte-macrophage-colony stimulating factor. In addition to such inflammatory mediators, a factor derived from the pathogens of granulomatous disorders may be necessary for MGC formation. Muramyl dipeptide (MDP), a peptidoglycan portion of bacterial cell walls present in sarcoidal lesions, is one of the candidates and can preferentially induce Langhans-type cells (LGC) in in vitro MGC formation system. Although the exact mechanisms of in vitro MGC formation remains unknown, receptors such as P2X(7), integrins, CD98, and macrophage fusion protein are considered to be involved in cell-to-cell adhesion and subsequent fusion process. Monocytes from sarcoidosis patients expressed higher levels of P2X(7) and had a higher ability to induce MGC than those from healthy controls. Attributable cells for the formation were CD14(++)CD16(-) monocytes. Therefore, CD14(++)CD16(-) monocytes may infiltrate into sarcoidal lesions and be fused to form LGC by inflammatory mediators and MDP derived from the pathogens of the disorder. Effective agents for sarcoidosis such as tranilast, allopurinol, and captopril inhibited in vitro MGC formation through inhibiting the expression of adhesion molecule and purinergic receptor. Thus, an in vitro MGC formation model would be a useful tool to understand the relevance of MGC in granulomatous disorders.

Multinucleated giant cells are characteristic of a monocyte-macrophage lineage in sarcoidosis and consist of two types of cells: Langhans-type with an arcuate arrangement of nuclei and a foreign-body type with random arrangement of nuclei. To compare these cells in the cutaneous lesions of sarcoidosis, we histologically and immunohistologically examined multinucleated giant cells in 25 scar infiltrations (cutaneous sarcoidosis with foreign bodies) and 30 cutaneous lesions of sarcoidosis without foreign bodies. Regardless of the presence or absence of foreign bodies, the cutaneous lesions had both types of multinucleated giant cells, usually with a predominance of the Langhans-type, although the numbers of total multinucleated giant cells were higher in scar infiltrations than in cutaneous sarcoidosis without foreign bodies, suggesting that their frequency is influenced by the microenvironment in sarcoidal lesions such as the presence of foreign bodies. Immunohistochemical studies using surface antigens of monocyte-macrophage lineage cells and adhesion molecules indicated that both types of multinucleated giant cells are formed from monocytes rather than tissue macrophages and are phenotypically the same cells with different distributions of nuclei.

The frequency of skin involvement of sarcoidosis is 10-30% of all cases, but the prevalence of a particular type of cutaneous lesion varies among races as well as individual cases. Cutaneous involvement is divided into specific and nonspecific categories. Specific lesions include nodules, plaques, lupus pernio, subcutaneous nodules, and other rare manifestations as well as scar infiltrates. Despite the clinical importance of scar infiltrates in the diagnosis of sarcoidosis, it is often overlooked because the lesions are usually small and asymptomatic. There is some clinical importance of cutaneous sarcoidosis; the ease in obtaining lesional samples which enables a histological diagnosis of sarcoidosis, and the association of a particular type of cutaneous lesion with other organ involvement.