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T follicular helper cells linked to active RA development
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DESTIN, Fla. — T follicular helper cells, which are predominantly located in splenic lymphoid follicles, and their accumulated circulation in the peripheral blood, may contribute significantly to the development of active rheumatoid arthritis, according to data presented at the North American Young Rheumatology Investigator Forum.
“T follicular helper cells are a special CD4+ T cell subset localized in the B-cell follicle,” Nitasha Kumar, MD, from Ochsner Medical Center in Jefferson, Louisiana, told attendees. “They were first reported in tonsils, where immune cells are constantly exposed to foreign antigens, resulting in the expansion of immune cells and the formation of germinal centers. T follicular helper cells can promote germinal center development and B-cell maturation, enhancing humoral responses. They bear their specific identity via signature surface markers, cytokines and transcription factors.”
“Our previous studies have shown that circulating T follicular helper cells were significantly increased in active RA patients,” she added. “This correlated with their anti-cyclic citrullinated peptide antibody titer and disease activity.”
For this study, the researchers analyzed the role of T follicular helper cells in the pathogenesis of RA among mice with collagen-induced arthritis, as well as the impact of a small molecule inhibitor selectively blocking T follicular helper cells (SMI-Tfh) and their signature transcription factor Bcl-6, Kumar said. She and colleagues established their collagen-induced arthritis model by administering type II collagen to DBA/1 mice.
Kumar and colleagues monitored disease progression daily, and made weekly notes of arthritis severity scores. Cases of clinical arthritis that arose were treated with SMI-Tfh. In addition, the researchers collected blood, spleen and affected paws at the end of the study period. They analyzed pathological changes using tissue sections stained hematoxylin and eosin. T follicular helper cells in the spleen, paw and blood were identified using immunofluorescent histochemistry staining and flow cytometry analysis. The researchers used GraphPad Prism software for statistical analysis.
According to Kumar, onset of paw-swelling occurred on days 21 to 28, and peaked on day 42 after the first immunization. Joints in the collagen-induced mice demonstrated increased inflammatory cells in the synovial tissues, and destruction of articular cartilage, compared with mice in the control group. In addition, T follicular helper cells were observed in the blood, as well as the germinal centers of the spleen, in collagen-induced mice. Meanwhile, mice treated with the small molecule inhibitor demonstrated significantly reduced paw swelling. Treatment with the small molecule inhibitor was nontoxic at 50 mg/kg.
In addition, the small molecule inhibitor appeared to reduce inflammatory cell and T follicular helper cell infiltration in inflamed joints. It also significantly reduced the frequencies of T follicular helper cells in the blood and the germinal centers of spleen among collagen-induced mice (P < .01).
“T follicular helper cells originating from splenic lymphoid follicles may contribute to the T follicular helper cells in the peripheral blood in collagen-induced arthritis, and play an important role in the development of active collagen-induced arthritis, Kumar said. “The small molecule inhibitor SMI-Tfh selectively inhibits Bcl-6, and this leads to a decrease in the T follicular helper cells in the spleen and in the inflamed joints in the collagen-induced arthritis mouse models. It appears to decrease the severity of inflammatory arthritis and may be useful as a new and additional therapeutic modality for human patients with RA.” – by Jason Laday
Reference:
Kumar N. A Distinct T follicular helper cell subset infiltrated the joints and peripheral blood in experimental inflammatory arthritis and were inhibited by a small molecule inhibitor. Presented at: North American Young Rheumatology Investigator Forum; May 1, 2019; Destin, Fla.
Disclosure: Kumar reports no relevant financial disclosures.