CD27-CD38lowCD21low B-Cells Are Increased in Axial Spondyloarthritis

Abstract

B-cells have received little attention in axial spondyloarthritis (axSpA) and for this reason their role in pathogenesis remains unclear. However, there are indications that B-cells may be involved in the disease process. Our objective was to obtain insights into the composition of the peripheral B-cell compartment of axSpA patients compared to healthy donors (HD) and patients with primary Sjögren’s syndrome (pSS), a typical B-cell-associated autoimmune disease. Special emphasis was given to CD27-negative B-cells expressing low levels of CD21 (CD21low B-cells), since this subset is implicated in autoimmune diseases with strong involvement of B-cells. Transitional B-cells (CD38hi) were excluded from the analysis of the CD27-CD21low B-cell compartment. This study included 45 axSpA patients, 20 pSS patients and 30 HDs. Intriguingly, compared to HDs the frequency of CD27-CD38lowCD21low B-cells was significantly elevated in both axSpA and pSS patients (P<0.0001 for both comparisons). The frequency of CD27-CD38lowCD21low B-cells expressing the activation-induced immune markers T-bet and CD11c was decreased in axSpA patients compared to HDs. A higher proportion of CD27-CD38lowCD21low B-cells expressed the chemokine receptor CXCR3 in axSpA compared to HDs, suggestive for active involvement of these cells in an inflammatory process. The frequency of CD27-CD38lowCD21low B-cells in axSpA patients correlated positively with age and erythrocyte sedimentation rate. Furthermore, axSpA patients with extra-skeletal manifestations (ESM) showed increased frequencies of CD27-CD38lowCD21low B-cells compared to patients without ESM. In conclusion, our findings are suggestive of active B-cell involvement in the pathogenesis of axSpA, against prevailing dogma.

B Cell Involvement in the Pathogenesis of Ankylosing Spondylitis

“…In particular, plasmablasts (and plasma cells) express high levels of CD38, along with high levels of CD27 [59]. In AS patients, the majority of studies (four out of six), including our own, revealed increased frequencies of circulating plasmablasts (CD27 hi /CD38 hi cells) [20,38,46]. Thus, phenotypical analysis of circulating B cells in AS provided some evidence that there are more activated B cells and plasma cells, compared to in healthy individuals.…”

“…Similar to T cells, the expression of CXCR3 on B cells is also regulated by T-bet [34]. We have shown in AS patients that amongst CD21 low B cells (see following section), the frequency of CXCR3 + B cells is indeed strongly associated with the frequency of T-bet + B cells [20]. T-bet + B cells are postulated to represent germinal center-derived B cells destined to become antibody secreting cells [33].…”

“…In most studies, normal frequencies of total circulating B cells (CD19 + ) were seen in AS patients [20,38,[41][42][43][44][45]. In these studies, disease activity was not taken into consideration.…”

“…Furthermore, in AS patients, higher levels of CD21 low B cells were observed [38]. Recently, we also analyzed the frequency and phenotype of CD21 low cells in patients with axSpA, of whom most (80%) were diagnosed with AS [20]. Since transitional (CD38 hi ) B cells express low levels of CD21 [61], we excluded CD38 hi cells from our analysis.…”

“…This is largely due to the inability to demonstrate the presence of typical AS related autoantibodies. However, there are indications for B cell involvement in the disease pathogenesis of AS (Figure 1), demonstrated by the presence of genetic variants associated with B cell function, altered B cell subset distribution, associated (auto-) antibody formation, pathogenic B-cell-related cytokines, and the presence of B cell infiltrates in AS-affected inflammatory sites [18][19][20][21]. Furthermore, the depletion of B cells using rituximab (anti-CD20) in AS demonstrated promising results in at least a subcategory of patients naïve for anti-TNFα therapy [22].…”