OBJECTIVE: Follicular helper T (Tfh) cells play a critical role in germinal center formation and B cell activation, both of which are hallmarks of primary Sjögren's syndrome (SS). CCR9-expressing T helper cells have "Tfh-like" characteristics and their numbers are increased at mucosa-associated sites in several inflammatory conditions. Because the characteristics of these cells are unique and evaluation has been limited, this study was undertaken to investigate the local and systemic CCL25/CCR9 axis in patients with primary SS. METHODS: Levels of CCL25 protein and messenger RNA (mRNA) and CCR9+ T helper cells were evaluated in the labial salivary glands (LSGs) of patients with primary SS and patients with sicca syndrome without a diagnosis of primary SS (non-SS sicca controls). CCL25 levels were assessed for correlation with parameters of inflammation and clinical features. Circulating CCR9+ and CXCR5+ T helper cells were compared on the basis of phenotypic and functional properties. RESULTS: CCL25 protein and mRNA levels were elevated in the LSGs of patients with primary SS as compared to non-SS sicca controls. Increased levels of CCL25 were associated with B cell hyperactivity, autoimmunity, and levels of interleukin-21 (IL-21) and soluble IL-7 receptor α-chain (IL-7Rα). Furthermore, the frequency of CCR9-expressing cells in the LSGs was increased and levels of circulating CCR9+ T helper cells expressing programmed death 1 and inducible T cell costimulator were elevated in patients with primary SS. CCR9+ T helper cells displayed higher expression of IL-7Rα and secreted higher levels of interferon-γ, IL-17, IL-4, and IL-21 as compared to CXCR5+ T helper cells, ex vivo and upon triggering with antigen or IL-7. Both CCR9+ and CXCR5+ T helper cells induced IgG production by B cells more potently than that induced in the cultures with CCR9-CXCR5- T helper cells. CONCLUSION: Enhanced expression of CCL25 in LSGs of patients with primary SS can facilitate attraction of CCR9+ T helper cells, and these cells secrete high levels of proinflammatory cytokines when triggered with antigen or IL-7. The observed associations with B cell hyperactivity, autoimmunity, and markers of lymphoid neogenesis indicate that the CCL25/CCR9 axis plays a significant role in the immunopathology of primary SS, suggesting that this axis could represent a novel therapeutic target for the disease.
OBJECTIVE:Follicular helper T (Tfh) cells play a critical role in germinal center formation and B cell activation, both of which are hallmarks of primary Sjögren's syndrome (SS). CCR9-expressing T helper cells have "Tfh-like" characteristics and their numbers are increased at mucosa-associated sites in several inflammatory conditions. Because the characteristics of these cells are unique and evaluation has been limited, this study was undertaken to investigate the local and systemic CCL25/CCR9 axis in patients with primary SS. METHODS: Levels of CCL25 protein and messenger RNA (mRNA) and CCR9+ T helper cells were evaluated in the labial salivary glands (LSGs) of patients with primary SS and patients with sicca syndrome without a diagnosis of primary SS (non-SS sicca controls). CCL25 levels were assessed for correlation with parameters of inflammation and clinical features. Circulating CCR9+ and CXCR5+ T helper cells were compared on the basis of phenotypic and functional properties. RESULTS:CCL25 protein and mRNA levels were elevated in the LSGs of patients with primary SS as compared to non-SS sicca controls. Increased levels of CCL25 were associated with B cell hyperactivity, autoimmunity, and levels of interleukin-21 (IL-21) and soluble IL-7 receptor α-chain (IL-7Rα). Furthermore, the frequency of CCR9-expressing cells in the LSGs was increased and levels of circulating CCR9+ T helper cells expressing programmed death 1 and inducible T cell costimulator were elevated in patients with primary SS. CCR9+ T helper cells displayed higher expression of IL-7Rα and secreted higher levels of interferon-γ, IL-17, IL-4, and IL-21 as compared to CXCR5+ T helper cells, ex vivo and upon triggering with antigen or IL-7. Both CCR9+ and CXCR5+ T helper cells induced IgG production by B cells more potently than that induced in the cultures with CCR9-CXCR5- T helper cells. CONCLUSION: Enhanced expression of CCL25 in LSGs of patients with primary SS can facilitate attraction of CCR9+ T helper cells, and these cells secrete high levels of proinflammatory cytokines when triggered with antigen or IL-7. The observed associations with B cell hyperactivity, autoimmunity, and markers of lymphoid neogenesis indicate that the CCL25/CCR9 axis plays a significant role in the immunopathology of primary SS, suggesting that this axis could represent a novel therapeutic target for the disease.
Authors: Judith A James; Joel M Guthridge; Hua Chen; Rufei Lu; Rebecka L Bourn; Krista Bean; Melissa E Munroe; Miles Smith; Eliza Chakravarty; Alan N Baer; Ghaith Noaiseh; Ann Parke; Karen Boyle; Lynette Keyes-Elstein; Andreea Coca; Tammy Utset; Mark C Genovese; Virginia Pascual; Paul J Utz; V Michael Holers; Kevin D Deane; Kathy L Sivils; Teresa Aberle; Daniel J Wallace; James McNamara; Nathalie Franchimont; E William St Clair Journal: Rheumatology (Oxford) Date: 2020-04-01 Impact factor: 7.580
Authors: Sofie L M Blokland; Maarten R Hillen; Fréderique M van Vliet-Moret; Angela Bikker; Wilco de Jager; Aridaman Pandit; Aike A Kruize; Timothy R D J Radstake; Joel A G van Roon Journal: RMD Open Date: 2019-01-11
Authors: Jasper C A Broen; Joel A G van Roon; Sofie L M Blokland; Maarten R Hillen; Catharina G K Wichers; Maili Zimmermann; Aike A Kruize; Timothy R D J Radstake Journal: RMD Open Date: 2019-01-11