Urinary mRNA and Lupus Disease Flare Dr. CC Szeto Department of - - PowerPoint PPT Presentation

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Urinary mRNA and Lupus Disease Flare Dr. CC Szeto Department of - - PowerPoint PPT Presentation

Nov 03, 2023 326 likes •546 views

Urinary mRNA and Lupus Disease Flare Dr. CC Szeto Department of Medicine & Therapeutics The Chinese University of Hong Kong Hypothetical model autoantigens lack of T cell extrinsic regulation trigger auto-reactive T cells recruitment

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Urinary mRNA and Lupus Disease Flare

  • Dr. CC Szeto

Department of Medicine & Therapeutics The Chinese University of Hong Kong

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Hypothetical model

autoantigens lack of T cell regulation extrinsic trigger auto-reactive T cells B cells produce autoantibody immune complex deposite in kidney susceptible patients renal inflammation, cell proliferation and fibrosis recruitment of bystander T lymphocyte and other mononuclear cells

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Lymphocyte subsets

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Th1 / Th2 imbalance

  • 100 patients and 10 controls

Conclusions: Patients with active lupus nephritis have increased T-bet and depressed GATA-3 expression in urinary sediment and kidney, indicating a predominant Th1 lymphocyte activation.

Chan RW, et al. Rheumatol 2006; 45; 91-957.

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Does it predict subsequent flare?

12 24 36 48

Proportion of Patients without Lupus Flare

0.0 0.2 0.4 0.6 0.8 1.0 High T-bet / GATA-3 ratio Low T-bet / GATA-3 ratio

Weeks

Conclusions: Patients with clinically quiescent lupus but increased T-bet to GATA-3 expression ratio in urinary sediment have a higher chance of disease flare, probably because of underlying Th1 lymphocyte activation.

Chan RW, et al. Rheumatol 2006; 45; 91-957.

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Validation study

  • 60 quiescent SLE patients
  • urinary mRNA expression of T-bet and GATA-3 quantified

by the RT-QPCR

  • patients were followed for 4 years for disease flare
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T-bet level is important

follow up (months) 12 24 36 48 survival free of any flare 0.0 0.2 0.4 0.6 0.8 1.0 follow up (months) 12 24 36 48 survival free of major flare 0.0 0.2 0.4 0.6 0.8 1.0 (A) (B) log rank test, p = 0.001 log rank test, p = 0.001 high T-bet high T-bet low T-bet low T-bet

Chan RW, et al. Rheumatol 2007; 46: 44-48.

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Cut-off value

1 - Specificity 0.0 0.2 0.4 0.6 0.8 1.0 Sensitivity 0.0 0.2 0.4 0.6 0.8 1.0 AUC = 0.735 1 - Specificity 0.0 0.2 0.4 0.6 0.8 1.0 Sensitivity 0.0 0.2 0.4 0.6 0.8 1.0 AUC = 0.790 (A) (B) T-bet expression = 3-fold normal T-bet expression = 3-fold normal

Chan RW, et al. Rheumatol 2007; 46: 44-48.

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Conclusion of this part

  • high urinary T-bet mRNA level was an independent

predictor of lupus flare

  • possibilities

– short term immune system (Th1) activity ? – baseline tendency of Th1 activation ?

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Other lymphocyte subsets

Kwan BC, et al. Rheumatol 2009; 48: 1491-1497.

  • 78 patients with SLE nephritis with various disease activity
  • urinary mRNA levels of Th17-related cytokines
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Regulatory T cells

  • 2 studies with 98 patients with active lupus nephritis

Wang G, et al. Rheumatol 2009; 48: 755-760. Luk CC, et al. J Rheumatol 2015; 42: 1150-1155.

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Is monitoring of urinary mRNA useful?

  • cohort of 134 adult SLE patients
  • prospectively followed for 56 weeks
  • identified 19 patients with a single disease flare
  • compared to 19 matched controls with no disease flare

during the same period

  • mRNA levels of eight pre-defined target genes in their

urinary sediment before disease flare were measured

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Change in serological markers

Szeto CC, et al. Clinica Chimica Acta 2012; 413: 448-455.

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Change in inflammatory cytokine mRNA

Szeto CC, et al. Clinica Chimica Acta 2012; 413: 448-455.

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Change in Th transcription factor mRNA

Szeto CC, et al. Clinica Chimica Acta 2012; 413: 448-455.

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Major vs minor flares

Szeto CC, et al. Clinica Chimica Acta 2012; 413: 448-455.

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Severity of flare and change in urinary mRNA

Szeto CC, et al. Clinica Chimica Acta 2012; 413: 448-455.

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Summary

  • baseline urinary T-bet mRNA level in quiescent SLE

patient is an independent risk factor of subsequent flare

  • serial monitoring of MCP-1, IL-17, GATA-3 and FOXP3

mRNA level in urinary sediment may provide an early clue for detecting disease flare

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Further research questions

  • predictive accuracy and cost-effectiveness when added on

to current serological monitoring

  • ptimal frequency of monitoring
  • role of pre-emptive treatment
  • prediction of refractory disease
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Acknowledgement

  • Nephrology: Bonnie Kwan, KM Chow, CB Leung
  • Rheumatology: LS Tam, Edmund Li
  • Pathology: Fernand Lai, Paul Choi
  • Laboratory: Rebecca Chan, G Wang, KB Lai, Cathy Luk
  • Nursing: Lee Wai Ching, Lau Miu Fong
  • These studies were supported in part by the Hong Kong

Society of Nephrology Research Grant and the Chinese University of Hong Kong (CUHK) research account 6901031.