A 75-year-old female with a history of stomach cancer and depression was referred to our hospital for left cervical lymphadenopathy. The biopsy of her left cervical lymph node revealed noncaseating granulomas with multinucleated giant cells. The positron emission tomography/computed tomography (PET/CT) indicated general lymphadenopathy (left supraclavicular left axillary, hepatic lymph nodes), except for the hilar lymph node. Both histology by transbronchial lung biopsy (TBLB) and analysis of broncho alveolar lavage fluid (BALF) were indicative of sarcoidosis. C-reactive protein (CRP) and soluble interleukin-2 receptor (sIL-2R) were increased in the sera. An alternative cause of granulomatous disease was ruled out, and on follow-up, she was diagnosed with sarcoidosis. Two years later, she was hospitalized for fever, anorexia, lymph node tenderness, and erythema nodosum with significant increases in CRP and sIL-2R. After admission, the repetitive axillary lymph biopsy showed the same histological findings as before, but the G-band staining showed clonal abnormalities. Bone marrow biopsy revealed abnormal lymphocytes with petal-like nuclei. Finally, she was diagnosed with malignant lymphoma infiltrating the bone marrow. After CHOP-based chemotherapy, her laboratory data, lymphadenopathy, and clinical findings improved, and she was discharged from the hospital on the 90th day. Careful medical treatment, including genetic analysis of the lymph node, is necessary in patients with sarcoidosis if lymphadenopathy is predominant.

Rationale: Accumulating evidence has suggested that transcriptional and metabolic regulation such as mitochondrial respiration and aerobic glycolysis are key elements in the differentiation and activation of effector helper T (Th) cells. We have clarified that mitochondrial cysteinyl-tRNA synthetase (CARS2) is a principal cysteine persulfide synthase (CPERS) in vivo and regulates mitochondrial bioenergetics. We hypothesized that CARS2/CPERS and its products, reactive persulfides, may influence the differentiation of Th2 cells and allergic inflammation including asthma. Purpose: To study the roles of CARS2/CPERS in allergic inflammation in a mouse model of asthma. Methods: We used a mouse model of asthma induced by house dust mite (HDM). HDM extracts were intranasally administered in both wild-type (WT) mice and mice with heterozygous deficiency of Cars2 (Cars2^+/-). To study the roles of the CARS2/CPERS in the differentiation of Th2 cells, naive CD4⁺T cells were sorted from splenocytes and stimulated under Th2-polarized conditions. Intracellular staining for IL-4, IL-5, IL-13 and transcription factor GATA3 was analyzed by a flow cytometer. Results:Cars2^+/- mice exhibited aggravation of HDM-induced type 2 airway inflammation and increased serum IgE synthesis compared to WT mice. In vitro differentiation experiments showed that naïve CD4⁺T cells from Cars2^+/- mice accelerated differentiation into Th2 cells compared to those of WT mice. Conclusion: CARS2/CPERS and its products, reactive persulfides, may regulate the differentiation of Th2 cells during allergic inflammation.