2. Academic Validation
  3. Activation of Toll-Like Receptor 7 Signaling Pathway in Primary Sjögren's Syndrome-Associated Thrombocytopenia

Activation of Toll-Like Receptor 7 Signaling Pathway in Primary Sjögren's Syndrome-Associated Thrombocytopenia

  • Front Immunol. 2021 Mar 9:12:637659. doi: 10.3389/fimmu.2021.637659.
Shuo Zhang 1 2 3 4,  Jingge Qu 1 2 3 4,  Li Wang 1 2 3 4,  Mengtao Li 1 2 3 4,  Dong Xu 1 2 3 4,  Yan Zhao 1 2 3 4,  Fengchun Zhang 1 2 3 4,  Xiaofeng Zeng 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 2 State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 3 National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China.
  • 4 Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
PMID: 33767707 DOI: 10.3389/fimmu.2021.637659
Abstract

Objectives: To identify the importance of the Toll-like Receptor (TLR) pathway using B cell high-throughput Sequencing and to explore the participation of the TLR7 signaling pathway in primary Sjogren's syndrome (pSS)-associated thrombocytopenia in patient and mouse models. Methods: High-throughput gene Sequencing and bioinformatic analyses were performed for 9 patients: 3 patients with pSS and normal platelet counts, 3 patients with pSS-associated thrombocytopenia, and 3 healthy controls. Twenty-four patients with pSS were recruited for validation. Twenty-four non-obese diabetic (NOD) mice were divided into the TLR7 pathway inhibition (CA-4948), activation (Resiquimod), and control groups. Serum, peripheral blood, bone marrow, and submandibular glands were collected for thrombocytopenia and TLR7 pathway analysis. Results: Seven hub genes enriched in the TLR pathway were identified. Compared to that in control patients, the expression of interleukin (IL)-8 and TLR7 pathway molecules in B-cells was higher in patients with pSS-associated thrombocytopenia. Platelet counts exhibited a negative correlation with serum IL-1β and IL-8 levels. In NOD mice, CA-4948/Resiquimod treatment induced the downregulation/upregulation of the TLR7 pathway, leading to consistent elevation/reduction of platelet counts. Megakaryocyte counts in the bone marrow showed an increasing trend in the Resiquimod group, with more naked nuclei. The levels of IL-1β and IL-8 in the serum and submandibular gland tissue increased in the Resiquimod group compared with that in CA-4948 and control groups. Conclusion: pSS-associated thrombocytopenia may be a subset of the systemic inflammatory state as the TLR7 signaling pathway was upregulated in B cells of patients with pSS-associated thrombocytopenia, and activation of the TLR7 pathway led to a thrombocytopenia phenotype in NOD mice.

Keywords

B lymphcytes; Toll-like receptor 7; high-throughput nucleotide sequencing; primary Sjögren's syndrome; thrombocytopenia.

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