Disordered Toll-like receptor 2 responses in the pathogenesis of pulmonary sarcoidosis

Gabrilovich, M. I.; Walrath, Jessica; Lunteren, Jan van; Nethery, David; Seifu, MA; Kern, Jeffrey A.; Harding, Clifford V.; Tuscano, Lori; Lee, H.; Williams, Susan; Mackay, Wilma; Tomashefski, Joseph F.; Silver, Richard F.

doi:10.1111/cei.12138

Cited by 49 publications

(39 citation statements)

References 37 publications

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“…Because of conflicting reports on the role of various TLR gene polymorphisms in human populations regarding susceptibility to sarcoidosis (21,(33)(34)(35)(36), we attempted to investigate the role of multiple TLRs simultaneously by using MyD88, a downstream adapter molecule in proinflammatory TLR/IL1R superfamily signaling (23). At least one targeted gene study has linked polymorphisms in MyD88 with susceptibility to sarcoidosis in a human population (37).…”

Section: Discussionmentioning

confidence: 99%

Induction of Pulmonary Granuloma Formation byPropionibacterium acnesIs Regulated by MyD88 and Nox2

Werner

Escolero

Hewlett

et al. 2017

Am J Respir Cell Mol Biol

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Sarcoidosis is characterized by noncaseating granulomas with an unknown cause that present primarily in the lung. Propionibacterium acnes, an immunogenic commensal skin bacterium involved in acne vulgaris, has been implicated as a possible causative agent of sarcoidosis. Here, we demonstrate that a viable strain of P. acnes isolated from a patient with sarcoidosis and instilled intratracheally into wild-type mice can generate pulmonary granulomas similar to those observed in patients with sarcoidosis. The formation of these granulomas is dependent on the administration of viable P. acnes. We also found that mice deficient in the innate immunity adapter protein MyD88 had a greater number and a larger area of granuloma lesions compared with wild-type mice administered P. acnes. Early after P. acnes administration, wild-type mice produced proinflammatory mediators and recruited neutrophils into the lung, a response that is dependent on MyD88. In addition, there was an increase in granuloma number and size after instillation with P. acnes in mice deficient in CybB, a critical component of nicotinamide adenine dinucleotide phosphate oxidase required for the production of reactive oxygen species in the phagosome. Myd882/2 or Cybb 2/2 mice both had increased persistence of P. acnes in the lung, together with enhanced granuloma formation. In conclusion, we have generated a mouse model of early granuloma formation induced by a clinically relevant strain of P. acnes isolated from a patient with sarcoidosis, and, using this model, we have shown that a deficiency in MyD88 or CybB is associated with impaired bacterial clearance and increased granuloma formation in the lung.

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Section: Discussionmentioning

confidence: 99%

Induction of Pulmonary Granuloma Formation byPropionibacterium acnesIs Regulated by MyD88 and Nox2

Werner

Escolero

Hewlett

et al. 2017

Am J Respir Cell Mol Biol

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“…Candidate gene-linkage studies have identified polymorphisms in the genes encoding TNF and its receptor to be associated with differential susceptibility to acute and chronic clinical courses in sarcoidosis [34][35][36]. Notably, studies have demonstrated enhanced responses to TLR2 stimulation, including enhanced induction of TNF, in cells from the blood and lung of sarcoidosis patients [37][38][39] (Table 1). TLR2 interacts with innate ligands as a heterodimer with other TLR subunits; an analysis of the TLR10-TLR1-TLR6 gene cluster on chromosome 4 suggests that absence of the common haplotype is associated with increased risk for developing chronic active disease in patients who initially presented with Löfgren syndrome [40].…”

Section: Genetic and Immunologic Interactions In Sarcoidosis Etiologymentioning

confidence: 99%

“…TLR2 interacts with innate ligands as a heterodimer with other TLR subunits; an analysis of the TLR10-TLR1-TLR6 gene cluster on chromosome 4 suggests that absence of the common haplotype is associated with increased risk for developing chronic active disease in patients who initially presented with Löfgren syndrome [40]. Another study examined the functional role of different TLR2 coreceptors and found that sarcoidosis BAL cells show differential responsiveness of these pathways, with increased production of TNF and IL6 in response to ligands for the TLR-2/1 heterodimer and reduced responses to TLR-2/6 ligands [39]. A role for TLR2 in sarcoidosis is further supported by animal models where experimental granulomatous inflammation is attenuated in the absence of functional TLR2 [37,39].…”

Section: Genetic and Immunologic Interactions In Sarcoidosis Etiologymentioning

confidence: 99%

“…Another study examined the functional role of different TLR2 coreceptors and found that sarcoidosis BAL cells show differential responsiveness of these pathways, with increased production of TNF and IL6 in response to ligands for the TLR-2/1 heterodimer and reduced responses to TLR-2/6 ligands [39]. A role for TLR2 in sarcoidosis is further supported by animal models where experimental granulomatous inflammation is attenuated in the absence of functional TLR2 [37,39]. Indirectly, these studies support a potential role for aberrant TLR2 responsiveness in sarcoidosis, though the genetic basis of this remains uncertain [41,42] (Table 2).…”

Section: Genetic and Immunologic Interactions In Sarcoidosis Etiologymentioning

confidence: 99%

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Etiologies of Sarcoidosis

Chen

Möller

2015

Clinic Rev Allerg Immunol

125

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Since sarcoidosis was first described more than a century ago, the etiologic determinants causing this disease remain uncertain. Studies suggest that genetic, host immunologic, and environmental factors interact together to cause sarcoidosis. Immunologic characteristics of sarcoidosis include non-caseating granulomas, enhanced local expression of T helper-1 (and often Th17) cytokines and chemokines, dysfunctional regulatory T-cell responses, dysregulated Toll-like receptor signaling, and oligoclonal expansion of CD4+ T cells consistent with chronic antigenic stimulation. Multiple environmental agents have been suggested to cause sarcoidosis. Studies from several groups implicate mycobacterial or propionibacterial organisms in the etiology of sarcoidosis based on tissue analyses and immunologic responses in sarcoidosis patients. Despite these studies, there is no consensus on the nature of a microbial pathogenesis of sarcoidosis. Some groups postulate sarcoidosis is caused by an active viable replicating infection while other groups contend there is no clinical, pathologic, or microbiologic evidence for such a pathogenic mechanism. The authors posit a novel hypothesis that proposes that sarcoidosis is triggered by a hyperimmune Th1 response to pathogenic microbial and tissue antigens associated with the aberrant aggregation of serum amyloid A within granulomas, which promotes progressive chronic granulomatous inflammation in the absence of ongoing infection.

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“…This indicates that these receptors detect PAMPs originating from intracellular pathogens (Lund et al 2003;Hemmi et al 2000) which is important in sarcoidosis where intracellular pathogens are important. However, evidence for a potential role of TLRs is suggested by evidence that BAL cells from sarcoidosis patients exhibit increased cytokine responses to the 19-kDa lipoprotein of Mycobacterium tuberculosis (LpqH), a TLR2/1 ligand, and decreased responses to the TLR-2/6 agonist fibroblast stimulating ligand-1 (FSL)-1 (Gabrilovich et al 2013).…”

Section: -Role Of Pattern Recognition Receptors In Sarcoidosismentioning

confidence: 99%