Exploring the transcription profile of fixed drug eruption lesions

Elisa Schunkert, MD
Department of Dermatology
Division of Rheumatology, Immunology, and Allergy
Poster Overview

Fixed Drug Eruptions (FDE) are a unique type of allergic reaction to drug manifesting as round red skin lesions that recur at the same site on the body with each repeat exposure to the causative drug. They are therefore immunologically one of the most intriguing diseases to study and to date, underlying mechanism of disease is unknown. We initiated a retrospective study using skin specimens from FDE patients and healthy controls that were formalin-fixed paraffin embedded, a method that preserves proteins and messenger RNA within the tissue. This allowed us to perform gene expression analysis of over 200 genes. The analysis supported a role for CD8+ T cells, and T cell effector function favored T-helper cell 1/cytotoxic T cell activity, as cytotoxic molecules were upregulated. The data further suggested that central memory T cells seemed to migrate into FDE skin lesions, characterized by increased levels of cell surface markers (CD45RO, CD62L and CD127). Against the current paradigm, natural killer cells and multiple types of antigen presenting cells appeared to be heavily involved in disease. Lastly, we identified a pathway involved in disease (called JAK/STAT), that could offer an alternative option for treatment.

Scientific Abstract

Fixed Drug Eruptions (FDE) are an intriguing disease as lesions uniquely reappear at the same anatomic site upon re-exposure to a culprit drug. Disease pathogenesis is poorly understood. To illuminate the immunobiology of FDE, we began by performing transcriptional profiling of skin specimens from FDE patients and healthy controls. Analysis of over 200 genes supported a role for cytotoxic CD8+ T cells, producing TNF╬▒ and cytotoxic granules (perforin and granzymes), but not granulysin or Fas/FasL. Activating NK cell receptor pathway was upregulated, suggesting a potential alternative to standard MHC:TCR signaling. Transcriptional profiling further supported recruitment of central memory T cells into FDE skin lesions, characterized by increased expression of CD45RO, CD62L and CD127, rather than mediation by resident memory T cells. Moreover, findings suggested previously unappreciated roles for NK cells and several antigen presenting cell subsets in disease, confirmed via immunofluorescence tissue staining. Lastly, JAK3/STAT1 pathway was upregulated, identifying a possible alternative approach to steroids for targeted treatment. This study highlights the immunologic complexity of FDE and provides a strong foundation for future immunologic studies.

Clinical Implications
The pathobiology of Fixed Drug Eruptions (FDE) remains enigmatic. This study helps us better understand disease etiology, including potential pathways involved that may offer alternative, more targeted treatment approaches to the current steroid regimens.
Research Areas
Authors
Schunkert, E., Romar, G.A., Hsieh, P.-C., Foreman, R.K., Barrera Burgos, V., Divito, S.J.
Principal Investigator
Sherrie Divito, MD, PhD

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