The Anergic State in Sarcoidosis Is Associated with Diminished Dendritic Cell Function

Abstract

Sarcoidosis is a chronic inflammatory disease of unknown cause, characterized by granuloma formation similar to tuberculosis, but without clear evidence of a microbial infection. Because sarcoidosis is linked with clinical anergy and other evidence of diminished cellular immunity, we hypothesized that decreased skin delayed-type hypersensitivity (DTH) responses to recall Ags in affected individuals would be associated with decreased function of their blood dendritic cells (DCs). Our study involved ex vivo isolation, phenotyping, and functional testing of myeloid DCs (mDCs), plasmacytoid DCs, and T lymphocytes from blood of normal healthy volunteers and sarcoidosis subjects with active, untreated pulmonary disease. We found mDC function in the allogeneic MLR directly corresponded to the magnitude of skin DTH reactions to recall Ags in both sarcoidosis subjects and normal volunteers. However, both of these outcomes were significantly decreased in the sarcoidosis group. Diminished mDC function occurred despite up-regulated costimulatory and maturation markers. Clinical relevance is suggested by the inverse relationship between both mDC allogeneic responses and skin DTH responses with clinical disease severity as measured by chest radiograms. Because granulomas form when cellular immunity fails to clear antigenic stimuli, attenuated mDC function in sarcoidosis may contribute to susceptibility and persistence of the chronic inflammation characteristic of this disease.

Dendritic Cells in the Pathogenesis of Sarcoidosis

“…In sarcoidosis BAL fluid (34) and in blood (55), pDCs appear in similar frequency and absolute numbers as in normals. Stimulation of sarcoidosis and normal blood pDCs with TLR9 ligand CpG-A showed no difference in IFN-a protein expression.…”

“…The immunostimulatory capacity of sarcoidosis BAL fluid is inhibited with anti-CD86, suggesting that their ability to induce T cell proliferation is dependent on CD86 co-stimulatory molecule (42). Myeloid DCs from sarcoidosis peripheral blood are also less immunostimulatory than normal blood DCs, and immunostimulatory capacity is directly correlated with ability to mount a delayed-type hyper- sensitivity (DTH) response (55). Decreased DC function is a potential mechanism for sarcoidosis-induced anergy, and may suggest that reduced cellular immunity at the end organs is responsible for disease perpetuation rather than resolution.…”

Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis

“…In addition, it has recently been shown that OS9 interacts with the cytoplasmic tail of the dendritic cell-specific transmembrane protein during toll-like receptor-induced maturation of dendritic cells suggesting a role for OS9 in myeloid differentiation and cell fusion [52]. Dendritic cells have been discussed as important mediators of sarcoidosis immunology [53] and have been widely investigated with regards to various aspects of sarcoidosis [53][54][55][56].…”

Immunopathogenesis of Sarcoidosis and Risk of Malignancy: A Lost Truth?

“…Mathew et al found that mDCs from sarcoidosis subjects had, ex vivo, a significantly decreased ability to stimulate T cells, compared to mDCs from healthy controls, despite normal cell count and up-regulated co-stimulatory and maturation markers, resulting, in vivo, in a reduced skin delayedtype hypersensitivity (DTH) to recall antigens in affected individuals. Nevertheless, the function of T cells in patients with sarcoidosis remained relatively preserved (12), In sarcoidosis, mDCs dysfunction may contribute to reduce the ability to eliminate antigenic stimuli, favoring the typical chronic inflammatory state, and may contribute to reducing the tumor immune surveillance. An altered maturation of mDC has indeed been found in various tumors (e.g.…”

“…Furthermore, an anergic state (poor response to antigens in vitro and in vivo) can occur. These events, also known as the "immune paradox" of sarcoidosis, remain unexplained and have been attributed to a diminished myeloid dendritic cell (mDC) function and to a disequilibrium between effector and T-regulatory (T-reg) cells, resulting in a diminished cellular immunity (11,12). Myeloid DCs are descendants of blood myeloid hematopoietic …”