Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved steroid-sparing alternatives. Here, we investigated the mechanism of granuloma formation using single-cell RNA-Seq in sarcoidosis patients. We observed that the percentages of triggering receptor expressed on myeloid cells 2-positive (TREM2-positive) macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, diagnostic makers of sarcoidosis, were increased in cutaneous sarcoidosis granulomas. Macrophages in the sarcoidosis lesion were hypermetabolic, especially in the pentose phosphate pathway (PPP). Expression of the PPP enzymes, such as fructose-1,6-bisphosphatase 1 (FBP1), was elevated in both systemic granuloma lesions and serum of sarcoidosis patients. Granuloma formation was attenuated by the PPP inhibitors in in vitro giant cell and in vivo murine granuloma models. These results suggest that the PPP may be a promising target for developing therapeutics for sarcoidosis.
Abstract The pathway of homeostatic IgG extravasation is not fully understood, in spite of its importance for the maintenance of host immunity, the management of autoantibody-mediated disorders, and the use of antibody-based biologics. Here we show in a murine model of pemphigus, a prototypic cutaneous autoantibody-mediated disorder, that blood-circulating IgG extravasates into the skin in a time- and dose-dependent manner under homeostatic conditions. This IgG extravasation is unaffected by depletion of Fcγ receptors, but is largely attenuated by specific ablation of dynamin-dependent endocytic vesicle formation in blood endothelial cells (BECs). Among dynamin-dependent endocytic vesicles, IgG co-localizes well with caveolae in cultured BECs. An Abl family tyrosine kinase inhibitor imatinib, which reduces caveolae-mediated endocytosis, impairs IgG extravasation in the skin and attenuates the murine pemphigus manifestations. Our study highlights the kinetics of IgG extravasation in vivo, which might be a clue to understand the pathological mechanism of autoantibody-mediated autoimmune disorders.
It has been known that eosinophilia in the peripheral blood or tissue participate in allergic inflammatory reactions and parasitic diseases. The function of eosinophils depend on the biological activity of the granule proteins. Four of these protein-MBP, ECP, EPO, and EDN have been known. There are some assumptions that the eosinophils might cause a tissue damage on examination of their specific protein. Therefore, the measurements of these granule proteins might clarify the pathogenesis of eosinophils related diseases. In this review, we introduce a convenient method for purification, quantitative measurement in serum, BAL and detection of localization in tissue by an immunofluorescence method for specific staining of eosinophil granule proteins.
TSLP is an epithelial cell-derived cytokine synthesized in response to various stimuli, including protease allergens and microorganisms like viruses and bacteria. Biological functions of TSLP require heterodimer formation between the TSLP receptor (TSLPR) and IL-7 receptor-α, which polarize dendritic cells to induce type 2 inflammation and directly expand and/or activate Th2 cells, group 2 innate lymphoid cells, basophils, and other immune cells. TSLP is thus considered a master regulator of type 2 immune responses at the barrier surfaces of skin and the respiratory/gastrointestinal tract. Indeed, genetic, experimental, and clinical evidence suggests that the TSLP-TSLPR pathway is associated with the pathogenesis of allergic diseases such as atopic dermatitis (AD) and asthma. Tezepelumab (AMG-157/MEDI9929) is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. A phase 2 trial for moderate to severe AD showed that a greater but not statistically significant percentage of tezepelumab-treated patients showed clinical improvements compared to the placebo group. A phase 2 trial for uncontrolled, severe asthma showed significant decreases in asthma exacerbation rate and improved pulmonary function and asthma control for tezepelumab-treated patients. Levels of biomarkers of type 2 inflammation, such as blood/sputum eosinophil counts and fraction of exhaled nitric oxide decreased, however, clinical efficacy was observed irrespective of the baseline levels of these biomarkers. A blockade of the TSLP-TSLPR pathway likely will exert significant clinical effects on AD, asthma, and other allergic diseases. The efficacy of anti-TSLP antibodies compared to other biologics needs to be further examined.
