O24
AN INTERFERON TRANSCRIPTION SIGNATURE DETECTED IN PERIPHERAL
LEUCOCYTES IS A HALLMARK OF END-STAGE RENAL FAILURE
Jolly EC, Rayner TF, Carr EJ, Lee JC, Hatton A, Hollis J, Lyons PA, Smith KGC
Cambridge Institute for Medical Research, Department of Medicine, University of
Cambridge School of Clinical Medicine and NHS Department of Renal Medicine,
Addenbrooke’s Hospital, Cambridge, United Kingdom
INTRODUCTION: End-stage renal failure (ESRF) is a global healthcare concern, with
increasing patient numbers requiring renal replacement therapy annually. ESRF is associated
with abnormal immune responses conferring increased morbidity and mortality from infections
and cardiovascular disease. The immune dysregulation in ESRF remains ill-defined and no
global, cell-specific analysis has been undertaken to more precisely define potentially
pathological alterations in individual leucocyte subsets.
METHODS: We recruited 93 ESRF patients and 46 healthy controls and performed parallel
transcriptomics and immune phenotyping of separated leucocyte subsets. Analyses undertaken
included cell enumeration, flow cytometry, gene expression by microarray and serum cytokine
and immunoglobulin measurements by ELISA.
RESULTS: The most striking finding was a dominant interferon (IFN) signature affecting all
leucocyte subsets, but most pronounced in the neutrophil fraction (Figure 1A). Serum IFN-γ
was elevated in ESRF patients and correlated with an IFN score generated from gene expression
values (Fig 1B+C). We also identified that ESRF is associated with global transcriptional
alterations within all leucocyte subsets. The myeloid compartment (monocytes and neutrophils)
demonstrated the largest transcriptional shift in ESRF with up-regulation of multiple genes
involved in innate immunity, cytokine signalling and pro-inflammatory pathways. The CD4 T
cell expression data highlighted reduced expression of key molecules involved in signalling
through the T cell receptor pathway and a B cell lymphopenia was evident.
Figure 1: A: Heatmap illustrating up-regulation of interferon (IFN) genes in ESRF
neutrophils and increased serum IFN-γ in patients (B; *p<0.05), which correlated with
expression of IFN genes (C).
CONCLUSION: Our comprehensive, global analysis of leucocyte phenotype in patients with
ESRF has revealed a strong interferon-driven transcriptional response in renal disease. This may
have relevance for the high incidence of accelerated vascular disease in ESRF patients, and
could have clinical usefulness as a potential biomarker of effective preventative therapy or for
the development of therapeutic agents against ESRF-associated inflammation. Furthermore,
profound myeloid cell pro-inflammatory dysregulation with concomitant reduction in T cell
responsiveness and selective B lymphopenia was evident. These findings may help to
understand the high incidence of infectious complications and poor vaccine responses in ESRF.