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P. acnes in sarcoid granulomas detected by immunohistochemistry with PAB antibody. Hematoxylin–eosin stain and immunohistochemistry with P. acnes-specific PAB antibody are shown pairwise. PAB-reactive P. acnes (resulting in brown color) are observed in non-caseating epithelioid cell granulomas of the lymph node (A,B), lung (C,D), and ocular epiretinal membrane (E,F) from patients with sarcoidosis. Mainly small round and occasionally large ovoid positive-signals are observed in granuloma cells, irrespective of the sites at which the granuloma formed. All photos are original. Scale bar: 50 μm.
Source publication
Sarcoidosis may have more than a single causative agent, including infectious and non-infectious agents. Among the potential infectious causes of sarcoidosis, Mycobacterium tuberculosis and Propionibacterium acnes are the most likely microorganisms. Potential latent infection by both microorganisms complicates the findings of molecular and immunolo...
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Background: Studying human skin-associated bacterial communities is crucial to understanding human diseases, disease progression, and their role in maintaining human health. Objectives: This study aimed to identify normal (healthy) skin microbiome signatures of eight individuals living in Jeddah, Makkah Al-Mukarramah region, Saudi Arabia. Methods:...
Citations
... The assumed pathogenesis of sarcoidosis caused by C. acnes is as follows: 1) commensal extracellular C. acnes causes asymptomatic intracellular infection. 2) latent C. acnes can be reactivated and proliferate intracellularly, which may be triggered by certain host-or drug-induced conditions (7,(9)(10)(11). ...
A 67-year-old woman was admitted to our hospital because of a complete right bundle branch block. She had been treated with minocycline for skin sarcoidosis and her symptoms had ameliorated four years previously. Gallium scintigraphy revealed an abnormal uptake in the heart but not in the skin or lungs. She was diagnosed with cardiac sarcoidosis, although an endomyocardial biopsy could not detect any sarcoid lesions. Immunohistochemical staining for Cutibacterium acnes was positive for granulomas of the skin lesions which had been previously biopsied. One year after starting the administration of steroids, her condition improved.
... Another putative organism is Propionobacter acnes which has also been detected in upto 85% sarcoid tissue. This is also the only organism to have been cultured from sarcoid granulomas [3]. Although many studies have detected this bacteria, others have not, leaving its causative nature in doubt. ...
Sarcoidosis is a disease of immune cell dysfunction. This review serves to amalgamate the information available into a coherent hypothesis. Recent research has shown that sarcoidosis should not be considered an antigenic induced granulomatous disease alone. The contribution of activation of auto immunity also has to be recognised. The triggering antigens have been narrowed mostly to be derived from Mycobacterial tubercular proteins and Propionobacter acnes. It is possible that they may share a common particle that creates a conformational change in the receptors of Th-1 cells that drives the disease until there is switch to autoimmunity and subsequent development of fibrosis. The role of genetic and environmental factors is also reviewed in this context.
... Evidence supporting the hypothesis of microbial infection in lung sarcoidosis suggests the presence of microorganisms [12]. Members of the Mycobacterium and Cutibacterium genera as well as fungi have been linked to sarcoidosis, but not confirmed as causative agents [13,14]. Recently, Atopobium and Fusobacterium species have been suspected as etiological agents of sarcoidosis due to their identification in BAL samples from patients with pulmonary sarcoidosis [5]. ...
... Cutibacterium acnes is a skin commensal, ubiquitously distributed among healthy individuals [5]. Cutibacterium acnes produces lipases which cause inflammation of the skin and other parts of the body [14,[50][51][52]. Cutibacterium acnes has also been detected in granuloma tissue via immunohistochemistry and is believed to be involved in the pathogenesis of sarcoidosis [7]. ...
Introduction
Single microbial pathogens or host-microbiome dysbiosis are the causes of lung diseases with suspected infectious etiology. Metagenome sequencing provides an overview of the microbiome content. Due to the rarity of most granulomatous lung diseases collecting large systematic datasets is challenging. Thus, single-patient data often can only be summarized visually.
Objective
To increase the information gain from a single-case metagenome analysis we suggest a quantitative and qualitative approach.
Results
The 16S metagenomic results of 7 patients with pulmonary sarcoidosis were compared with those of 22 healthy individuals. From lysed blood, total microbial DNA was extracted and sequenced. Cleaned data reads were identified taxonomically using Kraken 2 software. Individual metagenomic data were visualized with a Sankey diagram, Krona chart, and a heat-map. We identified five genera that were exclusively present or significantly enhanced in patients with sarcoidosis - Veillonella, Prevotella, Cutibacterium, Corynebacterium, and Streptococcus.
Conclusions
Our approach can characterize the blood microbiome composition and diversity in rare diseases at an individual level. Investigation of the blood microbiome in patients with granulomatous lung diseases of unknown etiology, such as sarcoidosis could enhance our comprehension of their origin and pathogenesis and potentially uncover novel personalized therapeutics.
Keywords: Lung diseases, Sarcoidosis, Microbiome, Metagenome analysis, Visualization, Sankey diagram
... A different opinion about the key role of P. acnes in the pathogenesis of sarcoidosis is no less widespread. Endogenous infection caused by symbiotic P. acnes can lead to the formation of granulomas in individuals who are predisposed to a hypersensitive Th1 immune response against an intracellular proliferation of latent P. acnes [9]. Exposure to metals and other inorganic substances can activate the immune response and eventually trigger sarcoidosis [2]. ...
Sarcoidosis is a complex inflammatory multisystem disease of unknown etiology that is characterised by epithelioid cell granulomatous lesions affecting various organs, mainly the lungs. In general, sarcoidosis is asymptomatic, but some cases result in severe complications and organ failure. So far, no accurate and validated modelling for clinical and pathohistological manifestations of sarcoidosis is suggested. Moreover, knowledge about disease-specific diagnostic markers for sarcoidosis is scarce. For instance, pulmonary granulomatosis is associated with the upregulated production of proinflammatory molecules: TNF-α, IL-6, CXCL1, CCL2, CCL18, CD163, serum angiotensin-converting enzyme (sACE), lysozyme, neopterin, and serum amyloid A (SAA). Quantum dots (QDs) are widely applied for molecular diagnostics of various diseases. QDs are semiconductor nanoparticles of a few nanometres in size, made from ZnS, CdS, ZnSe, etc., with unique physical and chemical properties that are useful for the labelling and detection in biological experiments. QDs can conjugate with various antibodies or oligonucleotides, allowing for high-sensitivity detection of various targets in organs and cells. Our review describes existing experimental models for sarcoidosis (in vitro, in vivo, and in silico), their advantages and restrictions, as well as the physical properties of quantum dots and their potential applications in the molecular diagnostics of sarcoidosis. The most promising experimental models include mice with TSC2 deletion and an in silico multiscale computational model of sarcoidosis (SarcoidSim), developed using transcriptomics and flow cytometry of human sarcoid biopsies. Both models are most efficient to test different candidate drugs for sarcoidosis.
... It can, however, produce biofilms, leading to smoldering subacute to chronic infections of prosthetic devices. Consequently, C. acnes is known to cause surgical infections, prosthetic joint infections, and infections of implanted devices (cerebrospinal fluid shunts, deep-brain stimulators, spine hardware, prosthetic heart valves, and pacemakers) [1][2][3] ( Table 1). Cutibacterium acnes infections often produce a paucity of clinical symptoms of inflammation. ...
... Additionally, C. acnes may cause the autoinflammatory manifestations of SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) [1,2]. C. acnes infection is also associated with other autoinflammatory disorders, including chronic recurrent multifocal osteomyelitis (CRMO), and there is increasing report of an association with sarcoidosis [3,5]. SAPHO syndrome is often diagnosed late due to its overlapping manifestations with inflammatory diseases such as seronegative rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis [6][7][8]. ...
... The pathogenesis of SAPHO syndrome, CRMO, and sarcoidosis is a dysregulated innate immune response to C. acnes or other commensals [3,5]. In addition to potential impaired autophagy caused by lipoteichoic acid of the C. acnes cell membrane in tissue macrophages, C. acnes-derived circulating immune complexes may play an important role [3,[10][11]. ...
Cutibacterium acnes, previously known as Proprionobacterium, is a commensal Grampositive bacterium of the skin commonly implicated in prosthetic joint infections. However, it has been documented to play a role in other conditions, including SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), a rare autoinflammatory disorder. Diagnosing SAPHO syndrome is cumbersome, as the clinical manifestations are variable and overlap with many inflammatory joint disorders. Herein, we describe a 56-year-old female patient with a presumed diagnosis of longstanding seronegative rheumatoid arthritis and history of C. acnes prosthetic joint infection following revision arthroplasty of the right shoulder. She presented to our clinic with a rash over the upper extremities and trunk and joint symptoms involving the right shoulder. Treatment was initiated with ceftriaxone followed by doxycycline suppressive therapy, with clinical improvement of joint and skin involvement. Symptoms recurred upon brief cessation of antibiotic therapy due to adverse gastrointestinal effects; however, symptoms abated once again upon re-initiation of treatment. Given the patient’s cutaneous lesions and longstanding history of arthritis that improved with antimicrobial therapy against C. acnes, the diagnosis of SAPHO syndrome was entertained. The present case demonstrates the clinical challenges of diagnosing SAPHO syndrome and the importance of its consideration on the differential for a patient with osteoarticular and cutaneous features. Additional literature is needed to improve diagnostic criteria and treatment guidelines.
... Immunohistochemical reactions are methods based on the classic immune reaction between an antigen and an antibody, which can result in the formation of antigen-antibody immune complexes. As a result, these are techniques that are characterized by the very high sensitivity, specificity, and repeatability of the obtained results [151,152]. The reaction is revealed through the use of fluorochromes or enzymes with which the antibodies used in this method are labeled. ...
... There are two variants of this method: direct, where the labeled antibody binds directly to the desired antigen, and indirect, where first the antigen is bound by the primary antibody, and then the resulting complex is detected by binding to the labeled antibody [153]. However, determinations are carried out more frequently using the indirect method [151]. ...
Alzheimer’s disease is one of the most commonly diagnosed cases of senile dementia in the world. It is an incurable process, most often leading to death. This disease is multifactorial, and one factor of this is inflammation. Numerous mediators secreted by inflammatory cells can cause neuronal degeneration. Neuritis may coexist with other mechanisms of Alzheimer’s disease, contributing to disease progression, and may also directly underlie AD. Although much has been established about the inflammatory processes in the pathogenesis of AD, many aspects remain unexplained. The work is devoted in particular to the pathomechanism of inflammation and its role in diagnosis and treatment. An in-depth and detailed understanding of the pathomechanism of neuroinflammation in Alzheimer’s disease may help in the development of diagnostic methods for early diagnosis and may contribute to the development of new therapeutic strategies for the disease.
... The term "C. acnes-associated sarcoidosis" is applied to cases in which C. acnes is detected in granulomas via immunohistochemistry using the PAB antibody [35]. The detection sensitivity of C. acnes in sarcoid granulomas depends on the evaluation method [36,37]; an automated method of detection using a Leica system with a commercially available PAB antibody (MBL, D372-3) has been used for differential diagnosis of sarcoidosis from other granulomatous diseases. ...
... Mainly small round and occasionally large ovoid PAB antibody-positive signals can be observed in non-caseating epithelioid cell granulomas of the lung (a,b) and ocular epiretinal membrane (c,d) from patients with sarcoidosis irrespective of the sites at which the granuloma formed. All photos are original and were previously published [35]. Scale bar: 50 μm. ...
... Mainly small round and occasionally large ovoid PAB antibody-positive signals can be observed in noncaseating epithelioid cell granulomas of the lung (a,b) and ocular epiretinal membrane (c,d) from patients with sarcoidosis irrespective of the sites at which the granuloma formed. All photos are original and were previously published [35]. Scale bar: 50 µm. ...
The immunohistochemical detection of Cutibacterium acnes in sarcoid granulomas suggests its potential role in granuloma formation. C. acnes is the sole microorganism ever isolated from sarcoid lesions. Histopathologic analysis of some sarcoid lymph nodes reveals latent infection and intracellular proliferation of cell-wall-deficient C. acnes followed by insoluble immune-complex formation. Activation of T helper type 1 (Th1) immune responses by C. acnes is generally higher in sarcoidosis patients than in healthy individuals. Pulmonary granulomatosis caused by an experimental adjuvant-induced allergic immune response to C. acnes is preventable by antimicrobials, suggesting that the allergic reaction targets C. acnes commensal in the lungs. C. acnes is the most common bacterium detected intracellularly in human peripheral lungs and mediastinal lymph nodes. Some sarcoidosis patients have increased amounts of C. acnes-derived circulating immune complexes, which suggests the proliferation of C. acnes in affected organs. In predisposed individuals with hypersensitive Th1 immune responses to C. acnes, granulomas may form to confine the intracellular proliferation of latent C. acnes triggered by certain host-related or drug-induced conditions. Current clinical trials in patients with cardiac sarcoidosis are evaluating combined treatment with steroids and antimicrobials during active disease with continued antimicrobial therapy while tapering off steroids after the disease subsides.
... Immunohistochemistry against ESAT-6 antigen was found to be highly sensitive (88.6%) in humans which depicts its potential application for the diagnosis of TB [51]. The causative agent is more likely to be found in immature granulomas with a higher number of inflammatory cells than in mature caseating granulomas with fibrosis due to the degradation process in the granuloma, which is consistent with the findings of moderately intense signals in Type I lesions as opposed to mild signals in Type II and Type III lesions [52]. Previous studies also showed higher intensity of staining in cavitary lesions [53] and in the cytoplasm of macrophages and giant cells [51], which largely supported the present observations. ...
Tuberculosis (TB) is a serious zoonotic threat, impacting the human-livestock-wildlife interface globally. Here, we evaluated the status and histomorphological differentiation of TB lesions in 89 morbid cases of wild animals (bovids, cervids, carnivores, non-human primates, and pachyderms) in India. Histomorphological and molecular studies were done using Ziehl-Neelsen (ZN) staining, immunohistochemistry, and polymerase chain reaction (PCR), whereas cultural isolation was performed on selected samples. A total of 32 (35.95%) cases were confirmed as TB, comprising of 12 carnivores, 09 bovids, 06 cervids, 04 non-human primates, and a pachyderm. The TB lesions in the lungs, liver, and lymph nodes varied from the large-sized caseous nodules filled with dry cheesy material in bovids and cervids to variable-sized cavitations containing liquefied caseum in carnivores' lungs. The lungs, livers, and spleens of non-human primates exhibited small to medium-sized nodules. Histologically, lesions were divided into four categories (Types I, II, III, and IV) based on the extent of necrosis, the presence of mineralization, giant cells, and fibrous encapsulation. Extensive caseous necrosis with calcification, abundant giant cells, and thick fibroblastic encapsulation were consistent findings in the lungs, livers, and lymph nodes of bovids and cervids, whereas airway impaction with cellular exudate containing a teeming number of acid-fast bacilli and, at times, alveolar rupture leading to cavity formation was present in the lungs of carnivores. Absence of calcification and fibrous encapsulation was recorded in lungs of non-human primates. Immunohistochemical labelling with anti-early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) antibodies showed mild, moderate, and intense positive reactions in type II and III, type I, and type IV granulomatous lesions, respectively. Molecular detection by PCR revealed Mycobacterium tuberculosis (12 carnivores, 02 non-human primates and 01 pachyderm), M. bovis (02 cervids and 01 bovid) and M. orygis (02 cervids and 01 bovid). Cultural isolation confirmed M. tuberculosis in 03 carnivores and M. orygis in 02 cervids and 01 bovid. Our findings imply that TB is quite prevalent in the wildlife of India and there are considerable differences in the histomorphological lesions induced by distinct Mycobacterium species in different wild animals. The circulation of TB organisms in wild animals warrants a strict surveillance programme to identify the carrier status of these animals so that effective TB control strategies can be formulated to prevent spillover and spillback incidences at the human-livestock-wildlife interface.
... Metagenomic analysis of these strains revealed potential pathogenic factors that have not been previously reported, indicating the importance of high-resolution analysis at the strain level to unveil the pathogenesis of human diseases [24,115]. In addition to acne, C. acnes is involved in various diseases such as implant-associated infection [116,117], prostate inflammation [118], and sarcoidosis [119,120]. ...
The skin serves as the interface between the human body and the environment and interacts with the microbial community. The skin microbiota consists of microorganisms, such as bacteria, fungi, mites, and viruses, and they fluctuate depending on the microenvironment defined by anatomical location and physiological function. The balance of interactions between the host and microbiota plays a pivotal role in the orchestration of skin homeostasis; however, the disturbance of the balance due to an alteration in the microbial communities, namely, dysbiosis, leads to various skin disorders. Recent developments in sequencing technology have provided new insights into the structure and function of skin microbial communities. Based on high-throughput sequencing analysis, a growing body of evidence indicates that a new treatment using live bacteria, termed bacteriotherapy, is a feasible therapeutic option for cutaneous diseases caused by dysbiosis. In particular, the administration of specific bacterial strains has been investigated as an exclusionary treatment strategy against pathogens associated with chronic skin disorders, whereas the safety, efficacy, and sustainability of this therapeutic approach using isolated live bacteria need to be further explored. In this review, we summarize our current understanding of the skin microbiota, as well as therapeutic strategies using characterized strains of live bacteria for skin inflammatory diseases. The ecosystem formed by interactions between the host and skin microbial consortium is still largely unexplored; however, advances in our understanding of the function of the skin microbiota at the strain level will lead to the development of new therapeutic methods.
... Over the years, many possible infectious but also noninfectious agents such as metals or silica have been suggested, summarized in Table 1. Regarding infectious agents, most studies were performed addressing the possible role of either mycobacteria, aspergillus species or C. acnes as antigens in sarcoidosis [71]. ...
... However, the detection of DNA can also point to latent infection unrelated to the formation of sarcoidosis. This could be remedied with the use of a quantitative PCR, which can discriminate between a potential latent infection and a reactivated infection [71]. ...
Cutibacterium acnes (C. acnes, formerly Propionibacterium acnes) is considered to be a non-pathogenic resident of the human skin, as well as mucosal surfaces. However, it also has been demonstrated that C. acnes plays a pathogenic role in diseases such as acne vulgaris or implant infections after orthopedic surgery. Besides a role in infectious disease, this bacterium also seems to harbor immunomodulatory effects demonstrated by studies using C. acnes to enhance anti-tumor activity in various cancers or vaccination response. Sarcoidosis is a systemic inflammatory disorder of unknown causes. Cultures of C. acnes in biopsy samples of sarcoidosis patients, its presence in BAL fluid, tissue samples as well as antibodies against this bacterium found in serum of patients with sarcoidosis suggest an etiological role in this disease. In this review we address the antigenic as well as immunomodulatory potential of C. acnes with a focus on sarcoidosis. Furthermore, a potential role for antibiotic treatment in patients with sarcoidosis will be explored.
