Peripheral blood responses to specific antigens and CD28 in sarcoidosis

Ahmadzai, Hasib; Cameron, Barbara; Chui, Jeanie; Lloyd, Andrew R.; Wakefield, Denis; Thomas, Paul S.

doi:10.1016/j.rmed.2012.01.012

Cited by 34 publications

(47 citation statements)

References 33 publications

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“…Vimentin-peptides were amongst the identified peptides, suggesting antigenic properties of vimentin in the sarcoidosis lung [28]. Two subsequent analyses revealed differening results with one reporting IFN-γ secretion of PBMCs in responses to the peptide in some sarcoidosis patients expressing the HLA-DRB1*0301 allele [29], but another showing no difference between non-HLA typed sarcoidosis patients and healthy volunteers [30]. We stimulated our PBMCs with whole vimentin protein but individual epitopes of the protein might have differing levels of stimulating capacity in sarcoidosis.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Kveim Reagent Identifies Targets of Cellular Immunity in Sarcoidosis

et al. 2017

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BackgroundKveim-reagent (Kv) skin testing was a historical method of diagnosing sarcoidosis. Intradermal injection of treated sarcoidosis spleen tissue resulted in a granuloma response at injection site by 4–6 weeks. Previous work indicates proteins as the possible trigger of this reaction. We aimed to identify Kv-specific proteins and characterise the ex vivo response of Peripheral Blood Mononuclear Cells (PBMCs) from sarcoidosis, tuberculosis and healthy control patients when stimulated with both Kv and selected Kv-specific proteins.MethodsKv extracts were separated by 1D-SDS-PAGE and 2D-DIGE and then underwent mass spectrometric analysis for protein identification. Sarcoidosis and control PBMCs were first stimulated with Kv and then with three selected recombinant protein candidates which were identified from the proteomic analysis. PBMC secreted cytokines were subsequently measured by Multiplex Cytokine Assay.ResultsWe observed significantly increased IFN-γ and TNF-α secretion from Kv-stimulated PBMCs of sarcoidosis patients vs. PBMCs from healthy volunteers (IFN-γ: 207.2 pg/mL vs. 3.86 pg/mL, p = 0.0018; TNF-α: 2375 pg/mL vs. 42.82 pg/mL, p = 0.0003). Through proteomic approaches we then identified 74 sarcoidosis tissue-specific proteins. Of these, 3 proteins (vimentin, tubulin and alpha-actinin-4) were identified using both 1D-SDS-PAGE and 2D-DIGE. Data are available via ProteomeXchange with identifier PXD005150. Increased cytokine secretion was subsequently observed with vimentin stimulation of sarcoidosis PBMCs vs. tuberculosis PBMCs (IFN-γ: 396.6 pg/mL vs 0.1 pg/mL, p = 0.0009; TNF-α: 1139 pg/mL vs 0.1 pg/mL, p<0.0001). This finding was also observed in vimentin stimulation of sarcoidosis PBMCs compared to PBMCs from healthy controls (IFN-γ: 396.6 pg/mL vs. 0.1 pg/mL, p = 0.014; TNF-α: 1139 pg/mL vs 42.29 pg/mL, p = 0.027). No difference was found in cytokine secretion between sarcoidosis and control PBMCs when stimulated with either tubulin or alpha-actinin-4.ConclusionsStimulation with both Kveim reagent and vimentin induces a specific pro-inflammatory cytokine secretion from sarcoidosis PBMCs. Further investigation of cellular immune responses to Kveim-specific proteins may identify novel biomarkers to assist the diagnosis of sarcoidosis.

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Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Kveim Reagent Identifies Targets of Cellular Immunity in Sarcoidosis

et al. 2017

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“…Interestingly, candidate triggers for granuloma formation in sarcoidosis Mycobacterium tuberculosis and fungal antigen P-glucan are potent stimulators of IL-6 by activating NF-kB (Ahmadzai et al, 2012; Terčelj et al, 2011). IL-6 expression correlates with disease severity and is reduced by steroid treatment (Mastorakos et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiles in granuloma tissue reveal novel diagnostic markers in sarcoidosis

Christophi

Caza

Curtiss

et al. 2014

Experimental and Molecular Pathology

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Sarcoidosis is an immune-mediated multisystem disease characterized by the formation of non-caseating granulomas. The pathogenesis of sarcoidosis is unclear, with proposed infectious or environmental antigens triggering an aberrant immune response in susceptible hosts. Multiple pro-inflammatory signaling pathways have been implicated in mediating macrophage activation and granuloma formation in sarcoidosis, including IFN-γ/STAT-1, IL-6/STAT-3, and NF-κB. It is difficult to distinguish sarcoidosis from other granulomatous diseases or assess disease severity and treatment response with histopathology alone. Therefore, development of improved diagnostic tools is imperative. Herein, we describe an efficient and reliable technique to classify granulomatous disease through selected gene expression and identify novel genes and cytokine pathways contributing to the pathogenesis of sarcoidosis. We quantified the expression of twenty selected mRNAs extracted from formalin-fixed paraffin embedded (FFPE) tissue (n=38) of normal lung, suture granulomas, sarcoid granulomas, and fungal granulomas. Utilizing quantitative real-time RT-PCR we analyzed the expression of several genes, including IL-6, COX-2, MCP-1, IFN-γ, T-bet, IRF-1, NOX2, IL-33, Eotaxin-1 and revealed differential regulation between suture, sarcoidosis, and fungal granulomas. This is the first study demonstrating that quantification of target gene expression in FFPE tissue biopsies is a potentially effective diagnostic and research tool in sarcoidosis.

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“…Two studies demonstrate the presence of circulating antibodies against mycobacterial cell culture extracts in subsets of patients with sarcoidosis [96,97]. More recently, Drake and colleagues demonstrated sarcoidosis patients have immune responses to mycobacteria-derived antigens to ESAT-6, CFP-10, antigen-85A, and superoxide dismutase while Dubaniewicz and colleagues report immune responses to mycobacterial heat shock proteins in sarcoidosis [98][99][100][101][102][103][104]. There may be a genetic basis for responses to mycobacterial antigens in sarcoidosis (Table 2).…”

Section: Role Of Mycobacterial Organisms In Sarcoidosismentioning

confidence: 99%

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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Peripheral blood responses to specific antigens and CD28 in sarcoidosis

Abstract: Patients with sarcoidosis exhibit greater PBMC responses to M. tuberculosis antigens compared to PPD-negative controls, but reduced T-cell responses to common recall antigens. One contributing mechanism may be impairment of T-cell CD28 co-stimulation.

Cited by 34 publications

References 33 publications

Proteomic Analysis of Kveim Reagent Identifies Targets of Cellular Immunity in Sarcoidosis

Proteomic Analysis of Kveim Reagent Identifies Targets of Cellular Immunity in Sarcoidosis

Gene expression profiles in granuloma tissue reveal novel diagnostic markers in sarcoidosis

Etiologies of Sarcoidosis

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