Background/Purpose:  Systemic lupus erythematosus (SLE) is a chronic inflammatory disease characterized by the involvement of multiple organs and systems with aberrations in T cell response, especially involving effector and regulatory lymphocytes subsets. Lupus nephritis (LN) has a significant impact on morbidity and mortality of SLE patients. Urinary markers are a potential tool for accurate assessment of LN, because they may reflect immediate local alterations in renal status. The objective of this study is to evaluate the frequency CD4⁺ T cells in urine and in peripheral blood in LN and to analyze associations with clinical and immunological parameters.

Methods:  Peripheral blood mononuclear cells (PBMC) and urinary cells from 17 patients with active LN, 20 disease controls with primary glomerulonephritis (GN) and 10 healthy controls (HC) were analyzed by flow cytometry for the frequency of Th1 (CXCR3⁺CCR5⁺), Th2 (CCR4⁺CD294⁺), Th17 (CD161⁺CCR6⁺) and regulatory T cells (T_REG cells) (CD25⁺CD127^low). In LN, CD4⁺ T-cell subtypes in PBMC were re-evaluated at six months of immunosuppressive therapy with cyclophosphamide or mycophenolate sodium. T-cell subsets were assessed in renal tissue of 12 LN patients who underwent biopsy by immunohistochemistry using the expression of transcription factors as markers: Tbet (Th1 cells), GATA3 (Th2 cells), RORᵞ (Th17 cells) and FOXP3 (T_REG cells).

Results: CD4⁺ T cells were decreased in peripheral blood from LN patients compared with primary GN and HC [38.52% ± 10.39 vs. 56.63 ± 9.59 vs. 50.69% ± 8.10; p = 0.0001) as well as a lower frequency of peripheral Th2 cells was found in LN compared with HC [2.48% (0.04-16.40) vs. 4.21% (2.98-6.38); p = 0.025]. However, no differences were observed in the frequency of urinary CD4⁺ T-cell subsets between LN and primary GN. When comparing T-cell subsets in peripheral blood from patients with and without proliferative forms of LN, no difference was found. However, a higher frequency of urinary Th17 cells was found in non-proliferative compared with proliferative LN [14.37% (4.42-57.80) vs. 3.85% (1.30-27.00); p = 0.041]. CD3⁺ and Tbet⁺ cells were found in glomeruli and interstice of LN patients, while FOXP3, RORγ and GATA-3 were present only in glomeruli. Expression of FOXP3 was significantly lower in glomeruli compared with other markers. Peripheral Th1 cells were negatively correlated with urinary Th1 cells (Rho=-0.531; p=0.028) and with Tbet in renal interstice (Rho=-0.782; p=0.004). At 6 months of treatment, LN patients showed a significant increase in peripheral Th17 cells regardless of response to immunosuppressive therapy [1.13% (0.02-8.70) vs. 5.15% (1.35-13.51); p = 0.008].

Conclusion: Associations between peripheral, urinary and renal Th1 cells indicate a potential role of Th1 response in LN. Urinary Th17 cells were associated with less severe LN, and peripheral Th17 increased at 6 months of therapy. Differences in CD4⁺ T cells between LN and primary GN or HC were found only in peripheral blood, not in urine.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd4-t-helper-cells-and-regulatory-t-cells-in-active-lupus-nephritis-an-imbalance-towards-a-predominant-th1-response/