Reduced Th1 response in the lungs of HLA-DRB1*0301 patients with pulmonary sarcoidosis

Abstract

To investigate why human leukocyte-associated antigen-DRB1*0301 (HLA-DRB1*0301) positive Scandinavian patients have a better prognosis than HLA-DRB1*0301 negative patients, the present authors examined patterns of cytokine expression in bronchoalveolar lavage (BAL) cells and BAL fluid (BALF) from patients with pulmonary sarcoidosis and controls.Using real-time PCR, the mRNA expression of selected cytokines in BAL cells from newly diagnosed, untreated nonsmoking patients (n525) and controls (n511) was quantified. Cytokine protein levels in BALF from patients (n534) and controls (n511) were assessed using cytometric bead array. The patients were evaluated and stratified into two subgroups: HLA-DRB1*0301 positive (all with an acute onset) and HLA-DRB1*0301 negative (all with an insidious onset).When comparing patients and controls, BAL cells of the patients expressed significantly higher levels of interferon (IFN)-c and interleukin (IL)-10 mRNA. There were significantly decreased IFN-c and tumour necrosis factor (TNF)-a mRNA levels, and a tendency toward higher levels of transforming growth factor-b1 mRNA in HLA-DRB1*0301 positive compared with HLA-DRB1*0301 negative patients. Protein levels of IL-1b, IL-2, IL-6, IL-12p70 and TNF-a in BALF were significantly higher in patients. HLA-DRB1*0301 positive patients exhibited tendencies to lower levels of most cytokines in BALF.In conclusion, the present data show a reduced expression of T-helper cell type-1 cytokines in human leukocyte-associated antigen-DRB1*0301 positive patients, which may relate to their good prognosis.

Specific antigen(s) in sarcoidosis: a link to autoimmunity?

“…This observation is a result of the long-lasting work of this group at the Karolinska Institut (Stockholm, Sweden) on the role of interactions between MHC-II and TCR in sarcoidosis. The authors were able to demonstrate that there are strong associations of MHC-II alleles and TCR subfamilies with the clinical course of sarcoidosis [11][12][13][14]. The second basis of this manuscript is the groundbreaking finding that the peptides fitting in this MHC-II groove could be self antigens with properties of autoantigens [15].…”

Analysis of regulatory T cell associated forkhead box P3 expression in the lungs of patients with sarcoidosis

“…More recently, we described a decreased expression of Th1-associated cytokines in HLA-DRB1*0301 pos compared with HLA-DRB1*0301 neg patients, indicating a downregulated immune response which could be an important feature of patients with resolving disease [6].…”

“…Moreover, the role of Tregs in the immunopathology of sarcoidosis may be strengthened by the fact that IL-10 and transforming growth factor (TGF)-b, two cytokines with anti-inflammatory capacities that are also produced by Tregs, have been suggested to be involved in spontaneous disease remission in sarcoidosis patients [6,[17][18][19].…”

“…Bronchoalveolar lavage fluid CD4/CD8 T lymphocyte ratio and TCR AV2S3 expression was analysed by flow cytometry as described previously [6]. For sorting, cells were stained with anti-CD4-phycoerythrin (PE) ( …”

“…Gene expression was quantified by real-time PCR using ABI Prism 7700 Sequence Detection System (Applied Biosystems, Foster City, CA, USA), as described previously [6]. RNA specimens were analysed in duplicate using primers and probes for b-actin, IL-10 and TGF-b1 [6].…”