Background/Purpose: In the pathogenesis of rheumatoid arthritis (RA), T helper cells can differentiate into functionally distinct subsets, leading to the persistent inflammation and immune abnormality associated with the interactive activation between T cells and B cells. However, little is known about pathological T cell subset targeted by biologic DMARD (bDMARD) therapy such as TNF inhibitor and CTLA4-Ig. We investigated association between the phenotype of CD4⁺ T helper cells and CD19⁺CD20⁺ B cells and disease activity in patients with RA, and responsiveness to bDMARD treatment.

Methods: Peripheral blood mononuclear cells were obtained from 86 patients with bio-naïve RA and 24 healthy donors (HD). The study included 25 patients treated with TNF inhibitors such infliximab, etanercept and adalimumab, and 15 patients treated with CTLA-4 Ig (abatacept). The blood samples were taken at baseline and week 24 after treatment. The phenotype of T cells and B cells was defined based on comprehensive 8-color flow cytometric analysis for human immune system termed “the Human Immunology Project” by NIH and FOCIS. The results were correlated with the clinical disease activity including the titer of RF and ACPA, CRP, ESR, MMP-3 and simplified disease activity index (SDAI).

Results: The proportion of effector memory T cells was higher in RA compared with HD, whereas the proportions of CD4⁺CXCR3⁺ Th1 cells and CD4⁺CCR6⁺ Th17 cells were not different between RA and HD. The frequency of CD4⁺CXCR5⁺ICOS⁺ activated Tfh cells was significantly increased and correlated with RF titer in patients with RA. For B cell subsets, the proportions of CD19⁺CD20⁺CD27^–IgD^– effector B cells and CD19⁺CD20^–CD38⁺ plasmablasts closely correlated with CRP, ESR and MMP-3. TNF inhibitors and abatacept markedly improved the disease activity scores such as SDAI at 24 weeks post-treatment. Abatacept significantly decreased the proportions of effector memory T cells which consisted of activated Tfh and Th17 cells, and consequently the proportion of naïve T cells increased after abatacept therapy. By contrast, the proportion of naïve T cells has decreased after TNF inhibitors, but those of effector T cells mainly Th17 cell and CD19⁺CD20⁺CD27⁺IgD⁺ IgM memory B cells has inversely increased. The percentage of CD4⁺CCR4⁺CD25⁺CD127^low regulatory T cells significantly decreased after treatment with abatacept and TNF inhibitors. 

Conclusion: These results imply that TNF blockade and CD28 co-stimulation blockade may alter contradictory changes of both T helper cell and B cell differentiation, i.e. abatacept decreases activated Tfh cells and Th17 cells whereas TNF inhibitor increases Th17 cells and memory B cells, even though both treatments improve the disease activity in patients with RA. Thus, abnormal regulation of T helper cell differentiation independent of inflammation may underlie in the pathogenesis of RA and needs to be borne in mind in the design of new therapeutic strategies for this disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinct-regulation-of-t-helper-cell-differentiation-by-biologic-dmard-therapy-in-rheumatoid-arthritis/