Immune responses in defined subgroups of patients with pulmonary sarcoidosis

This thesis focuses on inflammatory responses in the airways of sarcoidosis patients. Sarcoidosis is a T helper 1-mediated inflammatory disease with unknown aetiology. HLA-DRB1*0301pos sarcoidosis patients often present with an acute form of disease, i.e. Löfgren’s syndrome, usually with a very good prognosis. These patients also have expansions of CD4+ T cells expressing the T cell receptor AV2S3 gene segment in their lungs. The overall aim of these studies was to investigate the inflammatory and im- mune regulatory responses in sarcoidosis and in specific subgroups of patients, com- pared to healthy controls.

The cytokine profile in bronchoalveolar lavage fluid (BALF) of patients revealed that the levels of mRNA and protein expression of pro-inflammatory and Th1 associated cytokines were in general increased in sarcoidosis patients compared to healthy indi- viduals. In particular, HLA-DRB1*0301neg patients expressed significantly increased levels of pro-inflammatory and Th1 associated cytokines in their lungs as compared to HLA-DRB1*0301pos patients and controls. A tendency to a higher expression of TGF- β1 was seen in DRB1*0301pos patients.

The study of BALF CD4+ T cells in patients revealed decreased mRNA levels of the T regulatory cell-specific transcription factor, FOXP3, and of regulatory associated genes IL-10 and CCR2. Furthermore, at the protein level reduced frequencies of FOXP3- expressing BALF and blood CD4+ T cells were observed in patients. The mean fluores- cence intensity of FOXP3 expression in BALF FOXP3+ CD4+ cells of patients was also reduced. AV2S3+ CD4+ T cells expressed significantly reduced levels of FOXP3 and CCR2 compared to the other BALF CD4+ T cells. We did not find any differences in the expression of CCR2, FOXP3, IL-10 and TGF-β1 between patient subgroups. Sarcoidosis patients expressed decreased levels of T-cell immunoglobulin and mucin domain (TIM)-3 mRNA in their BALF CD4+ T cells, as compared to healthy subjects, while IL-2 expression was increased in patients. TIM molecules have been suggested to be important regulators of immune functions. In addition, our data revealed an in- creased mRNA level of IFN-γ in non-Löfgren’s patients as compared to Löfgren’s pa- tients, while the mRNA level of TIM-1 was decreased.

Analyzing alveolar macrophages, we detected a significantly lower expression of TLR2 in patients, in particular patients with Löfgren’s syndrome. We also observed that the gene expression of fibrosis-associated CCL18 was higher in patients compared to con- trols. There was a tendency to higher IL-23 levels in cultured BALF cells of patients, but upon LPS-stimulation it was markedly more upregulated in healthy controls.

In conclusion, the reduced immune regulatory response in the lungs of sarcoidosis pa- tients may result in an uncontrolled inflammation particularly in non-Löfgren’s pa- tients, contributing to the pathogenesis of this disease. AV2S3+ T cells in the lungs of Löfgren’s patients seem to have an effector function and may contribute to the eradica- tion of a postulated sarcoidosis antigen.

List of scientific papers

I. Idali F, Wikén M, Wahlström J, Mellstedt H, Eklund A, Rabbani H, Grunewald J (2006). Reduced Th1 response in the lungs of HLA-DRB1*0301 patients with pulmonary sarcoidosis. Eur Respir J. 27(3): 451-9.
https://pubmed.ncbi.nlm.nih.gov/16507843

II. Idali F, Wahlström J, Müller-Suur C, Eklund A, Grunewald J (2008). Analysis of regulatory T cell associated forkhead box P3 expression in the lungs of patients with sarcoidosis. Clin Exp Immunol. 152(1): 127-37. Epub 2008 Feb 14
https://pubmed.ncbi.nlm.nih.gov/18279440

III. Idali F, Wahlström J, Khademi M, Olsson T, Eklund A, Grunewald J (2008). Altered expression of T cell Immunoglobulin-Mucin (TIM) molecules in bronchoalveolar lavage CD4+ T cells in sarcoidosis. [Submitted]

IV. Wikén M, Idali F, Abo Al Hayja M, Grunewald J, Eklund A, Wahlström J (2008). Altered expression of TLR2 and IL-23 in bronchoalveolar lavage cells in sarcoidosis. [Submitted]