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Longitudinal Immune Responses and Gene Expression Profiles in Type 1 Leprosy Reactions

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Abstract

Purpose

Leprosy, a chronic disease initiated by Mycobacterium leprae, is often complicated by acute inflammatory reactions. Although such episodes occur in at least 50 % of all leprosy patients and may cause irreversible nerve damage, no laboratory tests are available for early diagnosis or prediction of reactions. Since immune- and genetic host factors are critical in leprosy reactions, we hypothesize that identification of host-derived biomarkers correlated to leprosy reactions can provide the basis for new tests to facilitate timely diagnosis and treatment thereby helping to prevent tissue damage.

Methods

The longitudinal host response of a leprosy patient, who was affected by a type 1 reaction (T1R) after MDT-treatment, was studied in unprecedented detail, measuring cellular and humoral immunity and gene expression profiles to identify biomarkers specific for T1R.

Results

Cytokine analysis in response to M. leprae revealed increased production of IFN-γ, IP-10, CXCL9, IL-17A and VEGF at diagnosis of T1R compared to before T1R, whereas a simultaneous decrease in IL-10 and G-CSF was observed at T1R. Cytokines shifts coincided with a reduction in known regulatory CD39+CCL4+ and CD25high T-cell subsets. Moreover, RNA expression profiles revealed that IFN-induced genes, (V)EGF, and genes associated with cytotoxic T-cell responses (GNLY, GZMA/B, PRF1) were upregulated during T1R, whereas expression of T-cell regulation-associated genes were decreased.

Conclusions

These data show that increased inflammation, vasculoneogenesis and cytotoxicity, perturbed T-cell regulation as well as IFN-induced genes play an important role in T1R and provide potential T1R-specific host biomarkers.

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Acknowledgments

This work was supported by the Q.M. Gastmann-Wichers Foundation, the Netherlands Leprosy Relief Foundation (NLR) together with the Turing Foundation (ILEP#: 701.02.49), the Order of Malta-Grants-for-Leprosy-Research (MALTALEP), and the Heiser Program for Research in Leprosy in The New York Community Trust (P13-000392). The authors gratefully acknowledge patientD05 for his cooperation, Dr. B. Naafs for clinical details and critically reading this manuscript and Dr. K. Jordanova (Dept. of Obstetrics and Gynaecology, Free University Amsterdam) for expert-advice on confocal microscopy.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Infectious Diseases, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands

    Annemieke Geluk, Krista E. van Meijgaarden, Louis Wilson, Kidist Bobosha, Jolien J. van der Ploeg-van Schip, Susan J. F. van den Eeden, Edwin Quinten, Karin Dijkman, Kees L. M. C. Franken, Elisabeth M. Haisma, Mariëlle C. Haks & Tom H. M. Ottenhoff

  2. Armauer Hansen Research Institute, Addis Ababa, Ethiopia

    Kidist Bobosha

  3. Department of Dermatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    Colette L. M. van Hees

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  1. Annemieke Geluk
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Correspondence to Annemieke Geluk.

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Geluk, A., van Meijgaarden, K.E., Wilson, L. et al. Longitudinal Immune Responses and Gene Expression Profiles in Type 1 Leprosy Reactions. J Clin Immunol 34, 245–255 (2014). https://doi.org/10.1007/s10875-013-9979-x

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  • DOI: https://doi.org/10.1007/s10875-013-9979-x

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