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Activity of Childhood Lupus Nephritis is Linked to Altered T Cell and Cytokine Homeostasis

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Abstract

Purpose

Standard therapy for lupus nephritis is based on non-specific immunosuppression. We aimed to identify specific alterations in T cell and cytokine homeostasis and possible associations with disease activity in children with lupus nephritis (LN).

Methods

The phenotype of circulating T cells from children with LN and healthy controls (HC) was analyzed by flow cytometry. Intracellular expression of IL-17 and INF-γ was assessed after stimulation with anti-CD3 and anti-CD28. Serum concentrations of IP10, CCL2, TGF-β, IL-17, and IL-23 were measured by ELISA. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index 2000 update (SLEDAI-2K).

Results

Children with active LN displayed increased frequencies of effector memory CD4+CD45RO+CCR7− and terminal differentiated CD4+CD45RA+CCR7− T cells and reduced naive CD4+CD45RA+CCR7+ T cells compared to those with inactive LN or HC. Circulating CD4+CXCR3+ and CD4+CCR2+ T cells correlated inversely with the renal SLEDAI-2K, whereas IP10 and CCL2 showed a positive correlation. Reduced CD4+Foxp3+ T cells and serum TFG-β levels in active LN were associated with high serum IL-17 and IL-23 levels and correlated inversely with the renal SLEDAI-2K (r = −0.5855, p = 0.0013 and r = −0.6246, p = 0.0005, respectively), whereas IL-17 and IL-23 correlated positively (r = 0.5516, p = 0.0029 and r = 0.6116, p = 0.0007, respectively). Expansion of Th17 and Th1/Th17 cells in children with LN was significantly greater than in HC (p = 0.0304 and p = 0.0067, respectively).

Conclusion

Children with active LN display high levels of pro-inflammatory cytokines associated with an increase in effector T cells and reduction of regulatory T cells. Therapeutic regulation of the aberrant cytokine profile might specifically interrupt pathogenic mechanisms.

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Acknowledgments

This work was supported by OeNB Jubiläumsfonds Grant (13334) and Medizinischer Forschungsfonds Tirol grant to ME.

Disclosures

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pediatrics I, Innsbruck Medical University, Anichstr. 35, 6020, Innsbruck, Austria

    Monika Edelbauer, Sudhir Kshirsagar, Magdalena Riedl, Gerard Cortina & Elisabeth Steichen-Gersdorf

  2. Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Heidelberg, Heidelberg, Germany

    Heiko Billing & Burkhard Tönshoff

  3. Department of Pediatric Kidney, Liver and Metabolic Disease, Hannover Medical School, Hannover, Germany

    Dieter Haffner

  4. Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Tübingen, Tuebingen, Germany

    Oliver Amon

  5. Klinik für Kinder und Jugendliche der Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Sophia Ross

  6. Klinik und Poliklinik für Kinder- und Jugendmedizin, Uniklinik Köln, Cologne, Germany

    Jörg Dötsch

  7. Department of Plastic and Reconstructive Surgery, Innsbruck Medical University, Innsbruck, Austria

    Gottfried Wechselberger

  8. Dr. von Haunersches Kinderspital, Klinikum der Universität München, Munich, Germany

    Lutz T. Weber

  9. Institute of Medical and Chemical Laboratory Diagnostics (ZIMCL), University Hospital Innsbruck, Innsbruck, Austria

    Martin Dablander, Markus Anliker & Andrea Griesmacher

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  1. Monika Edelbauer
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Corresponding author

Correspondence to Monika Edelbauer.

Additional information

This study is dedicated in memory of Prof. Dr. Lothar Bernd Zimmerhackl.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Online Resource 1

Renal SLEDAI-2K, total SLEDAI-2K, and extra-renal manifestations of SLE at the time of sampling in children with active LN (PDF 56 kb)

Online Resource 2

Representative FACS dot plots showing the frequencies of circulating CD45RA+CCR7− (A1), CD45RA+CCR7+ (A2), CD45RA−CCR7− (A3), and CD45RA−CCR7+ (A4) cells on gated CD4+ T cells from a patient with active lupus nephritis (16.9%, 29.4%, 34.5%, and 19.2%, respectively), inactive lupus nephritis (12.7%, 39.4%, 27.5%, and 20.4%, respectively), and a control subject (5.2%, 47.4%, 22.1%, and 25.3%, respectively) (PDF 158 kb)

Online Resource 3

Increased frequency of CD69 expressing DNT cells in childhood LN. Leukocytes were stained with monoclonal antibodies to CD16/56, CD3, CD4, CD8, and CD69. Representative FACS dot plots show b) the frequencies of CD3+CD4−CD8− T cells (DNT) on gated CD3+CD16/56− cells, numbers indicate the percentage of CD3+CD4−CD8− cells and c expression of CD69 on gated DNT cells, numbers indicate the percentage of double positive cells (PDF 1.30 mb)

Online Resource 4

Reduced circulating CD4+CXCR3+ T cells in active childhood-onset LN. Representative FACS dot plots of CXCR3 expression in gated CD4+ T cells from a child with active LN, inactive LN, nephrotic syndrome (NS), and a control subject. Numbers indicate the percentage of double positive cells (PDF 493 kb)

Online Resource 5

Decrease of circulating CD4+Foxp3+ T cells in active childhood-onset LN. Representative examples of Foxp3 expression in circulating CD4+ T cells of a patient with active LN, inactive LN, nephrotic syndrome (NS), and a control subject. Numbers indicate the percentage of double positive cells (PDF 245 kb)

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Edelbauer, M., Kshirsagar, S., Riedl, M. et al. Activity of Childhood Lupus Nephritis is Linked to Altered T Cell and Cytokine Homeostasis. J Clin Immunol 32, 477–487 (2012). https://doi.org/10.1007/s10875-011-9637-0

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  • DOI: https://doi.org/10.1007/s10875-011-9637-0

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