Background/Purpose: SLE mice models implicate IL-21, a T cell-derived cytokine, in disease pathogenesis with cytokine over-expression promoting the development of auto-antibodies and lupus-like clinical syndromes.  IL-21 dysregulation has also been noted in human SLE with a subset of patients having an increased proportion of IL-21-producing CD4⁺ T cells. This study aims to examine the relationship between IL-21 synthesis and distinct clinical phenotypes in human SLE.

Methods: SLE patients (n = 42) fulfilling ≥ 4 ACR criteria were recruited from an established longitudinal lupus cohort. Clinical and biochemical assessment at the time of recruitment permitted calculation of disease activity (SLEDAI-2K) and SLICC damage index.  Healthy age matched controls (n = 19) were also recruited. Peripheral blood mononuclear cells were isolated over a Ficoll gradient and stimulated for 4 hours with PMA/ionomycin in the presence of GolgiStop.  Cells were analyzed by flow cytometry following cell surface (anti-CD3, -CD4) and intracellular staining (anti-IL-21, -IL-17). A Mann Whitney non-parametric test was used for comparisons between groups.  Elevated IL-21 expression for selected CD4⁺ populations was defined as values ≥ 2 standard deviations above the mean for controls.

Results: A significant proportion (26.4%) of SLE patients was found to have increased levels of CD4⁺ IL-21 producing T cells when compared to controls.  To refine this cellular population the proportion of IL-21⁺, IL-17⁺ and double positive CD4 T cells was examined.  The proportion of IL-21⁺IL-17^negCD4⁺ cells was significantly elevated in SLE patients when compared to controls (p = 0.03). The IL-17⁺IL-21^negCD4⁺ SLE compartment was also increased but did not reach statistical significance.  No differences were noted in the double positive (IL-21⁺IL-17⁺) CD4⁺ T cell populations.  To examine the relationship between the IL-21⁺IL17^negCD4⁺ population and specific clinical phenotypes patients were segregated on the basis of the proportion of IL-21⁺IL17^negCD4⁺ cells into IL-21 high patients (n = 10) with an equal number of patients with the lowest IL-21 expression selected as a comparator group. No statistically significant differences between these two groups (high vs low, mean ± SD) with regards to disease activity (5.8 ± 3.5 vs 5.7 ± 6.4), anti-dsDNA antibodies (35.6 ± 39.8 vs 44.0 ± 41.9) or complement levels (0.89 ± 0.18 vs 0.98 ± 0.38) was noted. IL-21 high patients had significantly higher disease damage index (SDI, p < 0.0001) than IL-21 low individuals.  As a corollary patients were stratified into quartiles based on their SDI score.  Patients with the highest SDI score had statistically significant higher proportion of IL-21⁺ IL17^neg CD4⁺ T cells (p = 0.02) than patients in the lowest quartile.

Conclusion: These results suggest that T cell population(s) contributing to IL-21 dysregulation in SLE reside within the IL-21⁺ IL-17^neg CD4⁺ T cell subset.  Further, as disease damage can be viewed as a surrogate marker of disease severity, this data implies that increased IL-21 synthesis may be linked to more aggressive forms of SLE.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-population-of-il-21-producing-cd4-t-cells-correlates-with-disease-damage-in-systemic-lupus-erythematosus-sle-patients/