Sarcoidosis is a multisystem inflammatory disorder of unknown aetiology. The immune pathology is characterised by dysregulated T cell (T_H1) activity, macrophage activation and granuloma formation, resulting in systemic inflammation, and organ dysfunction. I hypothesised that, as the systemic precursor to the macrophage, altered monocyte activity in sarcoidosis may contribute to the early immune pathology of the disease. In this thesis, I examined their phenotype, four key monocytic functions: cytokine production, suppression of T cell proliferation, phagocytosis and fusion (as a precursor to granulomagenesis); and their gene expression profile compared to monocytes from healthy controls. My data show that the expanded monocyte compartment comprise a greater proportion of the inflammatory (CD14⁺⁺CD16⁺) and patrolling (CD14⁺CD16⁺⁺) subsets, increased TNFα and IL-12 and decreased IL-10 and IL-4 production in sarcoidosis compared with healthy controls. The IL-10 deficit renders the monocytes less able to regulate T cell proliferation or their own fusion to multinucleate giant cells, potentially contributing to T cell expansion and granuloma formation respectively. Additionally, sarcoidosis monocytes are less able to phagocytose inert material. I also showed that previously reported deficiency in invariant NKT cells and low serum vitamin D levels in sarcoidosis may be linked to reduced IL-10 production by monocytes. Vitamin D treatment in vitro restored most of these deficiencies and provides a potential therapeutic method for manipulating monocyte function and disease genesis in sarcoidosis.

Abstract Antioxidants function as blockers of radical processes and eliminate harmful reactive oxygen species (ROS) produced during normal cellular metabolism. A complex antioxidant defence system has evolved to protect the cellular homeostasis. This system includes antioxidant enzymes (AOEs), such as superoxide dismutases (SODs), which are intracellular MnSOD and CuZnSOD and extracellular ECSOD, H2O2 scavenging enzymes catalase and glutathione peroxidase, and hemeoxygenase-1 (HO-1), an important enzyme in heme metabolism, which has also been suggested to have antioxidant capacities. ROS play an important role in the pathogenesis of interstitial lung diseases. These diseases represent a group of disorders with different etiology, histopathology, treatment and prognosis. Sarcoidosis, extrinsic allergic alveolitis and two different forms of idiopathic pulmonary fibrosis, usual interstitial pneumonia (UIP) and desquamative interstitial pneumonia (DIP) were included in this study. The purpose of this research was to evaluate the expressions of inducible nitric oxide synthase (i-NOS), endothelial nitric oxide synthase (e-NOS) and xanthine oxidase (XAO), oxidant generating enzymes commonly associated with tissue injury, and, on the other hand, the expressions of AOEs suggested to be involved in the defence of lung tissue against oxidant stress. The methods included immunohistochemistry on lung biopsies (n=48) and Western blotting, Northern blotting or reverse polymerase chain reaction (RT-PCR) on human inflammatory cells and cells obtained from bronchoalveolar lavage. I-NOS was intensively expressed in inflammatory, but not in fibrotic lesions, similar e-NOS expression was found in control lung and in all interstitial lung diseases, while XAO was mainly negative. MnSOD and HO-1 were highly expressed in the granulomas of sarcoidosis. In contrast the expressions of MnSOD and HO-1 in late fibrotic lesions of UIP were low or undetectable by immunohistochemistry. CuZnSOD and catalase showed similar immunoreactivity in healthy and diseased lung. A cell specific expression and regulation of various enzymes may play an important role during acute inflammatory diseases and also in the progression of lung fibrogenesis.

No description available.

Sarcoidosis is a multisystem, inflammatory granulomatous disease that rarely involves breast tissue. The pathophysiology of this chronic granulomatous condition is not well understood but is thought to be multifactorial, involving environmental influences causing an amplified immune response. A key histomorphology feature in sarcoidosis is the presence of non-necrotizing granulomas. In this case, we report a 41-year-old African-American man with a known history of sarcoidosis of the lung who presented with gynecomastia and bilateral breast tenderness with palpable nodules. Subsequent biopsy and microscopic examination of the breast nodules revealed diffuse involvement with non-necrotizing granulomas in both breasts. A final diagnosis of extensive sarcoidosis involving breast tissue was rendered after excluding other causes of non-necrotizing granulomas. The patient underwent a bilateral mastectomy to remove the breast nodules. This case discusses sarcoidosis involving an unusual site.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

A paracoccidioidomicose (PCM) é uma infecção sistêmica causada pelo fungo Paracoccidioides sp. A doença é endêmica na maior parte dos países da América Latina, sendo os pulmões os órgãos mais afetados. O diagnóstico de PCM é feito com base na história clínica e epidemiológica, e confirmado pela visualização microscópica das estruturas fúngicas do Paracoccidioides a partir de secreções ou tecidos. Por vezes, a apresentação clínica e os achados histopatológicos da PCM simulam os de outras doenças, como a sarcoidose, e ocasionalmente são encontradas nas lesões formas excepcionalmente pequenas do Paracoccidioides, que podem ser confundidas com outros fungos, como o Histoplasma capsulatum. O presente trabalho objetivou identificar e caracterizar os casos que simularam sarcoidose e os que apresentaram formas pequenas de Paracoccidioides dentre os 856 casos de paracoccidioidomicose diagnosticados no Laboratório de Micologia do Complexo Hospitalar Santa Casa de Porto Alegre, no período de 1981 a dezembro de 2013. Foram identificados 8 casos mimetizando a sarcoidose e 12 apresentando formas pequenas de Paracoccidoides. Dos casos que simularam a sarcoidose, todos eram fumantes do sexo masculino, com idades variando entre 27 e 59 anos (média = 42,5 anos) e apresentaram tosse produtiva, infiltrado fibronodular bilateral aos exames de imagem e granulomas sarcoides na biópsia pulmonar, recebendo prednisona como tratamento inicial. O diagnóstico de PCM, nestes casos, foi realizado por meio de cortes histológicos corados ao GMS (n=8), exame direto do escarro (n=2) e imunodifusão (n=4). Dentre os casos que apresentaram formas pequenas do Paracoccidioides, todos eram fumantes, tinham idades variando entre 33 e 68 anos (média = 55,58 anos), 10 eram do sexo masculino, e 10 apresentavam sintomas consistentes com os da PCM (dois pacientes eram assintomáticos). O diagnóstico etiológico, em todos os casos, foi realizado por meio de cortes histológicos seriados corados ao GMS (que revelaram as formas multibrotantes patognomônicas do Paracoccidioides) e corroborado por exame direto do escarro (n=3), imunodifusão (n=6) e cultura (n=1). Com isto, ressalta-se a importância da consideração dos diagnósticos diferenciais da paracoccidioidomicose. Visto que a sarcoidose é um diagnóstico de exclusão, o achado de granulomas epitelioides sem necrose deve incitar a busca ativa por agentes etiológicos com a utilização das colorações de ZN e GMS. E nos casos em que se encontram formas pequenas ou pouco usuais do Paracoccidioides, devem-se realizar cortes histológicos seriados e escalonados corados ao GMS e utilizar técnicas laboratoriais complementares, como imunodifusão e cultura, para assegurar o seu diagnóstico. / Paracoccidioidomycosis (PCM) is a systemic infection caused by the fungus Paracoccidioides sp. The disease is endemic in most Latin American countries, and the lungs are the most affected organs. The diagnosis of PCM is based on clinical and epidemiological features, and confirmed by the microscopic visualization of yeasts of Paracoccidioides from clinical specimens. Sometimes the clinical presentation and histopathological findings of PCM mimic those of other diseases, such as sarcoidosis, and occasionally exceedingly small forms of Paracoccidioides are found in lesions, which can be confused with other fungi, such as Histoplasma capsulatum. This study aimed to identify and characterize the cases that simulated sarcoidosis and those with small forms of Paracoccidioides among the 856 cases of paracoccidioidomycosis diagnosed in the Mycology Laboratory of the Hospital Complex Santa Casa de Porto Alegre, from 1981 to December 2013. 8 cases were identified mimicking sarcoidosis and 12 with small forms of Paracoccidoides. All the cases that mimicked sarcoidosis were male smokers, aged between 27 and 59 years (mean = 42.5 years) and had productive cough, bilateral fibronodular infiltrates on X-ray and sarcoid granulomas in the lung biopsy, receiving prednisone as initial treatment. The diagnosis of PCM in these cases was carried out by histological sections stained with GMS (n = 8), direct examination of sputum (n = 2) and immunodiffusion (n = 4). Among the cases with small forms of Paracoccidioides, all were smokers, aged between 33 and 68 years (mean = 55.58 years), 10 were male, and 10 had symptoms consistent with PCM (two patients were asymptomatic). The etiologic diagnosis in all the 12 cases was made by serial tissue sections stained with GMS (which revealed the multibudding pathognomonic forms of Paracoccidioides) and confirmed by direct examination of sputum (n = 3), immunodiffusion (n = 6) and culture (n = 1). In conclusion, it is emphasized the importance of considering the differential diagnosis of paracoccidioidomycosis. Since sarcoidosis is a diagnosis of exclusion, the finding of epithelioid granulomas without necrosis should encourage the active search for etiologic agents with the use of ZN and GMS stains. And in cases in which small or unusual forms of Paracoccidioides are found, serial histological sections stained with GMS and complementary laboratory techniques such as immunodiffusion and culture should be performed to ensure their diagnosis.

Habilitacijos procedūrai teikiamoje darbų apžvalgoje apibendrinti po daktaro disertacijos apgynimo (1999 m.) atliktų mokslinių tyrimų, skirtų intersticinėms plaučių ligoms, darbų rezultatai. Šioje apžvalgoje remiamasi autoriaus atliktų ir su bendraautoriais vykdytų intersticinių plaučių ligų tyrimų nuo 1999 m. iki 2008 m. Vilniaus universiteto Medicinos fakulteto Krūtinės ligų, alergologijos ir radiologijos klinikoje, Viešojoje įstaigoje Vilniaus universiteto ligoninės Santariškių klinikose, rezultatais. Svarbiausias darbo tikslas buvo nustatyti optimalią intersticinių plaučių ligų diagnostikos ir diferencinės diagnostikos seką kasdienėje klinikinėje praktikoje, pateikti praktines dažniausių intersticinių plaučių ligų diagnostikos rekomendacijas. Darbo uždaviniai buvo nustatyti klinikinių simptomų, radiologinių požymių, plaučių funkcijos rodiklių, bronchoalveolinio lavažo skysčio tyrimo ir bronchoskopinės plaučių biopsijos histologinio tyrimo diagnostinę vertę. Šioje apžvalgoje apibendrinamas 30 mokslinių straipsnių, paskelbtų 1999–2009 m. Dauguma straipsnių parengta kartu su kitais bendraautoriais (23 iš jų apžvalgos autorius buvo pirmasis autorius). Darbo rezultatų pagrindu perskaityta 14 pranešimų nacionalinėse ir 19 pranešimų tarptautinėse konferencijose (14 iš jų užsienio šalyse). / The results of scientific research published since acquisition of PhD degree in 1999 are reviewed in this survey for habilitation procedure. The interstitial lung diseases research was conducted and performed by author together with other researchers at Clinic of Chest Diseases, Allergology and Radiology of Vilnius Univesity and Vilnius University Hospital Santariškių klinikos in 1999–2008. The aim of this research was to determine optimal diagnostic pathway for interstitial lung diseases in daily clinical practice, to propose practical recommendations for diagnostic of the most common interstitial lung disorders. The tasks of the research were to evaluate diagnostic value of clinical symptoms, radiological signs, indices of respiratory function, examination of bronchoalveolar lavage fluid and bronchoscopic lung biopsy material. The review material covers 30 scientific papers published during 1999–2009. The most of papers were prepared together with co-authors, but in 23 of them the author of this survey was the first author. On the base of obtained scientific material 14 presentations at national conferences and 19 presentations at international conferences (14 of them in foreign countries) were done.

Diss. (sammanfattning) Stockholm : Karol inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Thesis (Ph.D. in Clinical Sciences) -- University of Colorado at Denver and Health Sciences Center, 2005. / Typescript. Includes bibliographical references (leaves 88-108).