Background/Purpose:

Follicular T helper (Tfh) cells are typically located in lymphoid organs where they promote B cell differentiation and function. Circulating CD4 T cells expressing CXCR5 together with ICOS and/or PD-1 are considered as counterparts of Tfh and have B cell helper capacity (Simpson N et al, Arthritis Rheum 2010; Craft J, Nat Rev Rheumatol 2012). In addition, three subpopulations of circulating Tfh counterparts have been described: CXCR5+CXCR3+CCR6- (Tfh-Th1), CXCR5+CXCR3-CCR6+ (Tfh-Th17) and CXCR5+CXCR3-CCR6- (Tfh-Th2). Only Tfh-Th17 and Tfh-Th2, but not Tfh-Th1, display functional properties of Tfh cells (Morita et al., Immunity 2011). Altered numbers of these circulating Tfh counterparts (cTfh) and subpopulations have been associated with established RA but there are no reported studies on early RA (eRA). Furthermore, it has recently been published that CD4+CXCR5-PD-1^hi cells (“peripheral helper T cells” or Tph) also have a Tfh-like funtion, and are increased in the peripheral blood of RA patients (Rao DA et al, Nature 2017). Therefore, our objective was to study the frequency of cTfh, cTfh cell subsets, Tph cells and circulating plasmablasts (CD19+CD20-CD27+CD38^hi B cells), in patients with eRA.

Methods:

Peripheral blood was drawn from DMARD-naïve early RA patients (2010 ACR criteria) with a disease duration < 24 months (n=32), and healthy controls matched for age and gender (n=32). After isolation by Ficoll-Hypaque gradient, PBMCs were stained with antibodies to CD3, CD4, CXCR5, ICOS, PD-1, CCR6, CXCR3, CD19, CD20, CD27, and CD38, and examined by flow cytometry.

Results:

The frequency of circulating CXCR5+ cells gated for CD4+ T cells was not different among the studied groups. In contrast, eRA patients demonstrated an increased frequency of CD4+CXCR5+ICOS^hi, CD4+CXCR5+PD-1^hi and CD4+CXCR5+ ICOS^hiPD-1^hi cells. Furthermore, in eRA patients, the frequency of Tfh-Th1 cells was significantly decreased and the frequency of Tfh-Th17 and Tfh-Th2 cells was significantly increased as compared with controls. Subsequently, the ratio (Tfh-Th17+Tfh-Th2)/Tfh-Th1 was increased in eRA. That is, eRA patients demonstrate a higher proportion of Tfh cell subsets bearing a phenotype associated with B cell helping capacity. When examining seropositive (RF+ and/or ACPA+, n=17) and seronegative eRA patients (RF- and ACPA-, n=15) separately, it was evident that the above described alterations were only apparent in seropositive eRA. At the same time, the frequency of circulating plasmablasts was increased in seropositive but not in seronegative eRA. However, the frequency of Tph cells in seropositive or seronegative eRA was not different from controls.

Conclusion:

Seropositive, but not seronegative eRA patients, demonstrate an increased frequency of circulating Tfh counterparts and altered proportions of circulating Tfh subpopulations, with overrepresentation of subsets bearing a phenotype associated with B cell helping capacity. At the same time, an increased proportion of circulating plasmablasts is apparent in seropositive eRA patients. However, the frequency of Tph cells in eRA is not different from controls.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/altered-frequencies-of-circulating-follicullar-t-helper-cell-counterparts-and-their-subsets-but-not-of-peripheral-helper-t-cells-are-associated-with-increased-circulating-plasmablasts-in-seropositive/