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. 2024 Sep 3:15:1447213.
doi: 10.3389/fimmu.2024.1447213. eCollection 2024.

Differential immunological profiles in seronegative versus seropositive rheumatoid arthritis: Th17/Treg dysregulation and IL-4

Baochen Li  1   2 , Rui Su  1   2 , Qiaoling Guo  1   3 , Ronghui Su  1   2 , Chong Gao  4 , Xiaofeng Li  1   2 , Caihong Wang  1   2
Affiliations

Differential immunological profiles in seronegative versus seropositive rheumatoid arthritis: Th17/Treg dysregulation and IL-4

Baochen Li et al. Front Immunol. .

Abstract

Background: Rheumatoid arthritis (RA) is an autoimmune disease with various subtypes. Among these, seronegative rheumatoid arthritis (SnRA), distinguished by its distinctive seronegative antibody phenotype, presents clinical diagnosis and treatment challenges. This study aims to juxtapose the immunological features of SnRA with seropositive rheumatoid arthritis (SpRA) to investigate potential mechanisms contributing to differences in antibody production.

Methods: This study included 120 patients diagnosed with RA and 78 patients diagnosed with psoriatic arthritis (PsA), comprising 41 cases of SnRA and 79 cases of SpRA. Clinical, serological, and immune data were collected from all participants to systematically identify and confirm the most pivotal immunological distinctions between SnRA and SpRA.

Results: (1) SpRA demonstrates more pronounced T-helper 17 cells (Th17)/Regulatory T cells (Treg) dysregulation, vital immunological differences from SnRA. (2) SpRA exhibits higher inflammatory cytokine levels than SnRA and PsA. (3) Lymphocyte subset ratios and cytokine overall distribution in SnRA close to PsA. (4) Interleukin-4 (IL-4) emerges as the central immunological disparity marker between SnRA and SpRA.

Conclusion: Th17/Treg imbalance is one of the vital immunological disparities between SnRA and SpRA. Interestingly, PsA and SnRA display similar peripheral blood immunological profiles, providing immunological evidence for these two diseases' clinical and pathological similarities. Furthermore, IL-4 emerges as the central immunological disparity marker between SnRA and SpRA, suggesting its potential role as a triggering mechanism for differential antibody production.

Keywords: T-helper 17 cells; biomarker; interleukin-4; regulatory T cells; seronegative rheumatoid arthritis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic of the gating for flow cytometric analysis of lymphocyte subsets (A) Representative flow cytometry analysis of peripheral lymphocytes.T: CD45+CD3+; CD4+T: CD45+CD3+CD4+; CD8+T: CD45+CD3+CD8+; B: CD45+CD3-CD19+; NK: CD45+CD3-CD16+CD56+ (B) Representative flow cytometry analysis of CD4+ T cell subsets. Th1: CD4+INF-γ+; Th2: CD4+IL-4+; Th17: CD4+IL-17+; Treg: CD4+CD25+Foxp3+.
Figure 2
Figure 2
Peripheral blood lymphocyte subpopulation levels in each study group (A) Comparison of peripheral blood lymphocyte subsets and CD4+ T cell counts among each study group (B) Comparison of the proportion of peripheral blood lymphocyte subsets and CD4+ T cells among each study group (*p < 0.05, **p < 0.01, ***p < 0.001; by ANOVA analysis).
Figure 3
Figure 3
PsA and SnRA display similar peripheral blood immunological profiles (A) Differences in CD4+T/CD8+T, Th1/Th2, and Th17/Treg ratios in each study group (B) Differences in serum levels of IL-2, IL-4, IL-6, IL-10, IL-17, INF-γ, and TNF-α in each study group (*p < 0.05, **p < 0.01, ***p < 0.001; by ANOVA analysis).
Figure 4
Figure 4
Univariate logistic regression analyses for factors associated with SpRA patients (*p < 0.05, **p < 0.01, ***p < 0.001).
Figure 5
Figure 5
Stepwise selection of key immunological differential factors between SnRA and SpRA (A) Variable importance plot using RF model between SnRA and SpRA (B) Stepwise Random Forest calculates the out-of-bag estimation error rate corresponding to the number of variables (C) Receiver operating curves (ROC) for IL-4, TNF-α, and IL-2.
Figure 6
Figure 6
IL-4 as the central immunological difference between SnRA and SpRA (A) ROC curves for IL-4 alone and IL-4 in combination with TNF-α and IL-2 (B) ROC curves for IL-4 in the modeling group and validation group (C) Correlation analysis between serum IL-4 and RF in patients with SpRA.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (grant no. 81971543), Four“Batches”Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province (NO 2022XM05), The Central Guidance Special Funds for Local Science and Technology Development (YDZJSX20231A061), Shanxi Province Higher "Billion Project " Science Technology Guidance Project (BYJL042).