Antigen-specific and innate immune mechanisms in sarcoidosis
Sarcoidosis is a chronic inflammatory disease that primarily affects the lungs. In this disorder it is of great interest to better understand the immunologic mechanisms of the specific and constitutive arms of the immune system that are involved in the pathogenesis.
Our group has previously shown that a subgroup of patients with a certain HLA-type (DRB1*0301) differ radically from other sarcoidosis patients in that they have large accumulations of CD4+ T cells expressing a particular T cell receptor (TCR) for antigen in their lungs (AV2S3+ T cells) and a very good prognosis.
Our hypothesis is that a sarcoidosis-specific antigen is presented by the DRB1*0301 molecule, resulting in activation and proliferation of AV2S3+ T cells. To investigate this, immune cells from the deep airways are routinely obtained from sarcoidosis patients by means of bronchoalveolar lavage (BAL). Using mass spectrometry we recently identified peptides that bind to the DRB1*0301 molecule in the lungs of sarcoidosis patients. Thus, for the first time, we have identified HLA-bound peptides that are presented for the T-cells at the site of inflammation. These peptides, and other candidate antigens, are used for in vitro stimulation experiments to see if any of them is the long sought-after sarcoidosis antigen. T cell reactivities have been detected against the mycobacterial enzyme mKatG as well as some peptides derived from endogenous proteins, i.e. autoimmune responses. We are also investigating the antigen specificity and the function of e.g. the lung-accumulated AV2S3+ cells by studying their expression of immune-related genes and their cytokine profile upon in vitro stimulation. In an ongoing project, we are also aiming to identify which antigenic peptides are presented by HLA-DR14 and -DR15, since these HLA types are associated with chronic disease and risk of pulmonary fibrosis.
To better understand the initiation and regulation of inflammation in sarcoidosis we study receptor expression and function of cells in the innate immune system, in particular alveolar macrophages. These and other antigen-presenting cells have the capacity to initiate immune responses by reacting to stimulation of a set of receptors specific for conserved non-self molecules derived from various pathogens. Such pattern-recognition receptors are believed to be critical in determining the character of the ensuing immune response. Important examples include toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD) molecules. We study TLR expression on alveolar macrophages, and also how stimulation of these cells with TLR- and NOD-ligands affects their functional profile, e.g. their capacity to interact with T cells. Differences in these respects between patients and controls, and between patient subgroups in sarcoidosis, will help us better understand the pathogenic mechanisms in this disease.
We are also involved in projects investigating T cell function, phenotype and antigen specificity in patients with myositis and rheumatoid arthritis who have pulmonary involvement, as well as in patients with chronic obstructive pulmonary disease (COPD).