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Doi:10.1016/j.mehy.2007.07.034

http://intl.elsevierhealth.com/journals/mehy Microbial antigen treatment in sarcoidosis – A newparadigm? ˇelj a,*, Barbara Salobir a, Ragnar Rylander b a Unit of Respiratory Diseases and Allergy, University Medical Center, Ljubljana, Sloveniab BioFact Environmental Health Research Center, Lerum, Sweden Received 19 July 2007; accepted 19 July 2007 Increasing evidence suggests that the risk for sarcoidosis is related to exposure to microbes, particularly molds. Microbial cell wall agents, even in the absence of clinical infection, could cause a late hypersensitivity reactionleading to the formation of granulomas. A few interventions studies using antimicrobial treatment demonstrateimprovement in sarcoidosis. It is suggested that diagnostic tools for the presence of microbes are used in patients withsarcoidosis and that antimicrobial treatment is considered in cases resistant to corticosteroids.
c 2007 Elsevier Ltd. All rights reserved.
and that treatment with antimicrobial agents willimprove the status of patients with the disease.
Sarcoidosis is a multi-organ disease often located inthe lung, characterised by a Th1 cytokine patterninvolving CD-4 T-cells, possibly regulated by migrat- ing dendritic cells and with increased secretionof tumor necrosis factor a (TNFa) . The clinical For the purpose of this review a distinction will be outcome is granuloma formation which is an made between studies that have found an associa- example of a delayed hypersensitivity reaction. A tion and intervention studies. The latter have a delayed hypersensitivity reaction may be caused considerably higher impact on conclusions concern- by the intracellular presence of antigens of a chem- ing causality as delineated by Bradford Hill ical or microbial origin. Regarding microbial agentsmany reports describe the presence of microbialcell wall agents (MCWA) in tissues of patients with sarcoidosis . The hypothesis can thus be formu-lated that MCWA are agents triggering sarcoidosis Several epidemiological studies have described arelation between sarcoidosis and environmentswith fungi or a high risk for fungal growth. Occupa- * Corresponding author. Address: Department of Pulmonary tional risk factors were evaluated among 273 cases Disease and Allergy, University Medical Center, Zaloska 7, 1000 of sarcoidosis and 618 siblings without the disease Ljubljana, Slovenia. Tel.: +386 1522 2342; fax: +386 1522 2347.
Specific risk exposures that imply possible c 2007 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Tercˇelj M, et al., Microbial antigen treatment in sarcoidosis – A new paradigm? MedHypotheses (2007), doi:10.1016/j.mehy.2007.07.034 fungal exposures were vegetable dusts, and indoor cant improvements of lung X-ray as well as diffu- exposure to high humidity, water damage or musty sion capacity and symptoms were found after odours. In a case-control study on 706 newly re- 6 months of treatment. At follow-up 6–58 months cruited cases of sarcoidosis and equal numbers of after cessation of anti-fungal treatment, 15 pa- age-, race-, and gender matched controls, there tients showed no signs of active disease. None of were positive associations between sarcoidosis the patients had signs of fungal infection which is and agricultural employment, and work environ- rare among patients with sarcoidosis even after long term treatment with corticosteroids .
A number of clinical case studies demonstrate the presence of microbes in patients with sarcoid-osis. Mycobacterial DNA has been detected in a high proportion of patients with cutaneous sarcoid-osis Toxoplasmosis has been related to uvea In several of the intervention studies it has been sarcoidosis and to sarcoidosis in connection suggested that the beneficial effect on granulomas with an invasive infection A case report de- of the drugs used was due to interference with the scribes a patient with corticosteroid resistant sar- immune system, decreasing or blocking the secre- coidosis that slowly developed a generalized tion of granuloma forming cytokines. Such mecha- sporotrichosis; a number of earlier reports were re- nisms have recently been reviewed and include viewed in the same paper . Cryptococcus has suppression as well as stimulation of different im- been related to sarcoidosis and Proprionibac- mune competent cells For the present con- teria nucleic acids were reported to be more com- text support for such a mechanism is found in a mon in lymph nodes of Japanese and European recent study where melatonin, an immune modu- patients with sarcoidosis . Some studies have lating drug, was found to be effective in treatment reported the presence of antigens from cell wall of 18 patients with chronic sarcoidosis .
deficient bacteria in tissue from patients with sar- An alternative interpretation is that the drugs destroy the microbial antigens responsible for the strated that such antigens were present also in granuloma reaction with a subsequent reversal of persons without the disease . Mycobacterial the lesions. A number of MCWA are known to inter- catalase–peroxidase was detected in 5 of 9 pa- fere with the functioning of the immune system tients with sarcoidosis and in none of 14 controls and cellular mechanisms related to the develop- ment of delayed hypersensitivity. Mycobacteriumtuberculosis catalase–peroxidase was found in sar-coidosis tissues and this agent will cause granuloma formation in a rat model of sarcoidosis . Thefungal cell wall agent 1,3-b-glucan persists intra- Even if relationships between microbes and sar- coidosis have been found, conclusions regarding In a rat model, injection of 1,3-b-glucan causality require a therapeutical intervention.
Such studies usually involve only a small number has also been shown to facilitate the development of patients and are mostly not double-blind which of delayed hypersensitivity caused by DNFB .
limits their impact. Antimalaria agents have been The underlying mechanism for these reactions is used to treat sarcoidosis. In one study 43 patients likely to be an influence on regulatory T-cells with were treated with improvements . Tetracyck- interference on the contact between CD4+Tcells lines were used in a study on 12 patients with cuta- and the antigen presenting dendritic cells . In neous sarcoidosis with a complete regression in 10 buildings with mouldy interiors, the secretion of patients and a partial regression in two after 1–6 TNFa from endotoxin stimulated peripheral blood months treatment In one case of sarcoidosis, monocytes was higher than among controls living the endothelial lesions present disappeared after Based on observations of three cases where pul- monary sarcoidosis improved after treatment of cutaneous and vaginal mycosis, the effects of anti-fungal treatment was evaluated in a clinical study From an environmental point of view it is likely The subjects were 18 persons with chronic that a number of different MCWA may induce a sarcoidosis resistant to corticosteroid treatment granulomatous reaction – exposure conditions will were treated with antifungal medication. Signifi- determine which agent is causative in one specific Please cite this article in press as: Tercˇelj M, et al., Microbial antigen treatment in sarcoidosis – A new paradigm? MedHypotheses (2007), doi:10.1016/j.mehy.2007.07.034 Microbial antigen treatment in sarcoidosis – A new paradigm? case, e.g. in an area with a high incidence of toxo- [3] Martin II WJ, Iannuzzi MC, Gail DB, et al. Future directions plasmosis this organism would be a dominant caus- in sarcoidosis research Summary of an NHLBI working ative agent and in another area the presence of group. Am J Resp Crit Care Med 2004;170:567–71.
[4] Marshall TG, Marshall FE. Sarcoidosis sucumbs to antibiotics mould and 1,3-b-glucan would determine the ef- – implications for autoimmune disease. Autoimmun Rev fect. It is thus not possible to talk about one or a few specific agents but rather a multitude of [5] Bradford Hill A. The environment and disease: association microbial agents in the environment that may all or causation? Proc R Soc Med 1965;58:285–300.
have the same effect on the immune system. It is [6] Newman LS, Rose CS, Bresnitz EA the ACCESS research group. A case-control etiological study of sarcoidosis – likely that this occurs at a level of exposure that environmental and occupational risk factors. Am J Respir does not cause a clinical infection. The outcome of the MCWA exposure is determined by a balance [7] Kucera GP, Rybicki BA, Kirkey KL, Coon SW, Major ML, between mechanisms for removal of the agent, Maliarik MJ, et al. Occupational risk factors for sarcoidosis inducibility of cells and cytokines and the produc- in African–American siblings. Chest 2003;123:1527–35.
[8] Li N, Bajohgli A, Kubba A, Bhawan J. Identification of tion of inflammatory controlling cytokines like mycobacterial DNA in cutaneous lesions of sarcoidosis. J IL-10. There is some evidence that when micro- organisms cause infection, the risk for formation [9] Bajoghli LN, Kubba A, Bhawan J. Identification of myco- of granulomas is decreased, probably because bacterial DNA in cutaneous lesions of sarcoidosis. J Cutan inflammation induces the production of a cytokine [10] Rizik SN. Acute anterior uveitis in a patient with sarcoidosis and toxoplasma dye test titre. Br J Ophtalmol 1965;49: [11] Kociecka W, Simon E, Pakula M, Fundowicz D. Sarcoidosis in coexistence with Toxoplasma gondii invasion. Pol Tyg Lek [12] McFarland RB, Goodman SB. Sporotrichosis and sarcoidosis.
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[14] Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of suggests that treatment with antimicrobial medica- mycobacterial and propionibacterial DNA in lymph nodes of tion could be effective by removing MCWA that Japanese and European patients with sarcoidosis. J ClinMicrobiol 2002;40:198–204.
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[18] Silzbach LE, Teirstein AS. Chloroquine therapy in 43 of MCWA in patients with sarcoidosis. It also sug- patients with intrathoracic and cutaneous sarcoidosis. Acta gests that the treatment should consider medica- [19] Bachelez H, Senet P, Cadranel J, Kaoukhov A, Dubertret L.
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Please cite this article in press as: Tercˇelj M, et al., Microbial antigen treatment in sarcoidosis – A new paradigm? MedHypotheses (2007), doi:10.1016/j.mehy.2007.07.034 [25] Song Z, Marzilli L, Greenlee BM, Chen ES, Silver RF, Askin [29] Svercek PS, Mojzisova J, Durove A, Benisek Z, Huska M. The FB. Mycobacterial catalase–peroxidase in a tissue antigen immunomodulatory effect of the soluble fungal glucan and target of the adaptive immune response in systematic (Pleurotus ostreatus) on delayed hypersensitivity and sarcoidosisi. J Exp Med 2005;201:755–67.
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relates to inflammatory markers in blood. Eur Respir J [28] Johnson KJ, Glovsky M, Schrier D. Pulmonary granuloma- tous vasculitis induced in rats by treatment with glucan. Am [32] Grutters JC, van den Bosch JMM. Corticoid treatment in sarcoidosis. Eur Resp J 2006;28:627–36.
Please cite this article in press as: Tercˇelj M, et al., Microbial antigen treatment in sarcoidosis – A new paradigm? MedHypotheses (2007), doi:10.1016/j.mehy.2007.07.034

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