Sarcoidosis: immunopathogenetic concepts and their clinical application

Müller–Quernheim, Joachim

doi:10.1183/09031936.98.12030716

Cited by 214 publications

(161 citation statements)

References 254 publications

(309 reference statements)

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“…These issues have been extensively reviewed in previous papers [3,4]. However, in spite of intriguing findings, the unsuccessful attempt to isolate any given agent consistently or to create reproducible animal models failed to support the hypothesis that an infectious agent underlies sarcoidosis [4].…”

Section: Environmental Factorsmentioning

confidence: 99%

“…Nevertheless, contrasting results obtained in the search for mycobacterial deoxyribonucleic acid (DNA) in sarcoid tissues do not rule out a possible role of these agents, at least in a subset of subjects with sarcoidosis [30]. This concept fits with the oligoclonality of the disease [3]; in other words, an oligoclonal T-cell activation would be elicited by a still elusive "sarcoid agent".…”

Section: Environmental Factorsmentioning

confidence: 99%

“…Interest in the involvement of these loci in genetic susceptibility to sarcoidosis dates back to the mid 1970s and has resulted in large numbers of studies, first performed at a serological level and more recently with molecular biology techniques. The pathophysiology of sarcoidosis, implying antigen recognition, processing, and presentation to T-cells by antigen presenting cells underlies the rationale for investigating HLA, especially class 11, genes [3]. The role of HLA molecules in disease susceptibility and modulation of clinical manifestations can be summarized as follows: 1) molecular mimicry or antigenic cross-reactivity between infectious organisms and HLA sequences, producing an initial tolerance that allows an infectious organism to become invasive e.g.…”

Section: Major Histocompatibility Complex Genesmentioning

confidence: 99%

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Genetic aspects in sarcoidosis

Luisetti¹,

Beretta²,

Casali³

2000

Eur Respir J

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Sarcoidosis is an immune-mediated, multiorgan, granulomatous disorder thought to be triggered by an intricate combination of environmental and genetic factors. Two robust lines of evidence support the hypothesis of a genetic component in the pathogenesis of sarcoidosis: racial variation in its epidemiology and familial clustering of cases. The relationship between epidemiology and environmental factors affecting variations in sarcoidosis incidence/prevalence and presentation are reviewed, as well as strategies to be pursued in the search for susceptibility genes for the disorder.Pathogenic processes leading to sarcoid granuloma formation and maintenance have prompted investigators interested in the genetics of sarcoidosis to focus mainly on major histocompatibility complex genes, and indeed a remarkable amount of data has been accumulated during the last two decades. Whilst in contrast with some autoimmune disorders a clear association between human leukocyte antigen (HLA) and sarcoidosis is still a controversial issue, there is, however, a general agreement that some HLA genes are related to phenotypic variations of the disease. Some genetic investigators have focused on T-cell receptor genes, immunoglobulin genes, angiotensin converting enzyme gene, chemokine genes and others.From a review of studies performed in different racial and ethnic groups, a reasonable suggestion arises that genetic factors are the major determinant in the racial variations in the epidemiology of the disorder. This assumption is, however, so far limited by lack of studies considering both genetic and environmental factors simultaneously. Eur Respir J 2000; 16: 768±780.

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Section: Environmental Factorsmentioning

confidence: 99%

Section: Environmental Factorsmentioning

confidence: 99%

Section: Major Histocompatibility Complex Genesmentioning

confidence: 99%

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Genetic aspects in sarcoidosis

Luisetti¹,

Beretta²,

Casali³

2000

Eur Respir J

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“…Many cytokines and chemokines play an important role during the processes of sarcoid granuloma (17). On the basis of recent Th1 and Th2 paradigms, the cytokine profile of sarcoidosis is Th1 dominant when disease activity is high (17)(18)(19). Recent studies have demonstrated enhanced expression of IL-12 (20 -22) and IL-12R (23,24) in sarcoid lungs.…”

mentioning

confidence: 99%

IL-12 and IL-18 Are Increased and Stimulate IFN-γ Production in Sarcoid Lungs

Shigehara

Shijubo²,

Ohmichi

et al. 2001

The Journal of Immunology

167

101

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Sarcoidosis is a systemic chronic granulomatous disease of unknown cause. Recent investigations revealed that the cytokine profile in inflamed lesions of sarcoidosis is Th1 dominant. To obtain better immunopathologic understanding of sarcoidosis, we examined the expression of IL-12 and IL-18 and their roles in IFN-γ production in pulmonary sarcoidosis. Sarcoid cases had significantly elevated levels of IL-12 (p40 and p70) and IL-18 in bronchoalveolar lavage (BAL) fluids compared with healthy subjects. IL-12 p70 and IL-18 were immunohistochemically expressed in the epithelioid cells and giant cells of sarcoid granulomas. Significant induction of IFN-γ, IL-12 p70, and IL-18 was observed from sarcoid BAL fluid cells with LPS stimulation, whereas LPS tended to induce only IL-12 p70 in BAL fluid cells from healthy subjects. Sarcoid cases had significantly greater IFN-γ induction with LPS stimulation than healthy subjects did. IL-18 mRNA expression was observed in freshly isolated sarcoid BAL fluid cells as well as in LPS-stimulated sarcoid BAL fluid cells, but IFN-γ and IL-12 mRNA expression was observed only in LPS-stimulated BAL fluid cells. Treatment with anti-IL-12- and anti-IL-18-neutralizing Abs significantly inhibited IFN-γ production from LPS-stimulated BAL fluid cells of sarcoid cases. Coadministration of rIL-12 or rIL-18 induced greater IFN-γ production in sarcoid BAL fluid cells than in normal BAL fluid cells. We concluded that bioactive IL-12 and IL-18 were produced in sarcoid BAL fluid cells and synergistically induced IFN-γ production, indicating important cytokines in the Th1 response of sarcoidosis.

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“…Although the aetiology of sarcoidosis remains uncertain [17], extensively conducted research has revealed several of the histopathologic and immunopathogenic events which occur during the development of noncaseating granulomas and might interpret the aforementioned redox imbalance [18,19].…”

Section: Discussionmentioning

confidence: 99%

Systemic oxidative stress in patients with pulmonary sarcoidosis

Koutsokera

Papaioannou

Malli

et al. 2009

Pulmonary Pharmacology & Therapeutics

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Background: A local redox imbalance has been reported in pulmonary sarcoidosis.However, so far no study has described a systemic redox imbalance in this context.The aim of the present study was to evaluate the systemic oxidative stress in patients with sarcoidosis and determine its relationship to treatment and indices of disease severity.Methods: 35 patients with histologically proven pulmonary sarcoidosis and 13 healthy volunteers were included in the study. All patients were studied during a stable phase of their disease. Systemic oxidative stress was quantified in serum with the use of a commercially available spectrophotometric method (D-ROM test) which determines overall oxidative stress, by measuring total hydroperoxides. Oxidative stress was expressed in conventional units, i.e. Carratelli Units (UCarr), where 1UCarr corresponds to 0.8mg/L H 2 O 2 .Results: Serum oxidative stress levels were significantly higher in patients with sarcoidosis compared to those of normal subjects (390±25 vs 300±18) UCarr respectively, p=0.04). Patients not receiving systemic corticosteroids had higher levels of oxidative stress compared to steroid-treated patients (461.5±38 vs 315±20, p<0.01) and compared to controls (461.5±38 vs 300±18 UCarr, p<0.01). Oxidative stress did not correlate with diffusion lung capacity (DLCO), partial arterial oxygen tension (PaO 2 ), MRC dyspnoea scale or chest X-ray stage. Conclusions:Systemic oxidative stress is increased in patients with stable pulmonary sarcoidosis who do not receive systemic corticosteroids. This finding suggests a sustained oxidative burden even when clinical, functional and radiological criteria indicate disease stability.

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Sarcoidosis: immunopathogenetic concepts and their clinical application

Cited by 214 publications

References 254 publications

Genetic aspects in sarcoidosis

Genetic aspects in sarcoidosis

IL-12 and IL-18 Are Increased and Stimulate IFN-γ Production in Sarcoid Lungs

Systemic oxidative stress in patients with pulmonary sarcoidosis

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