gms | German Medical Science

Providing personalized treatments is a major challenge in the management of rheumatic diseases. Here, we investigated ex vivo phosphorylation states of blood immune cell signal transduction proteins as new biomarkers for disease progression and therapy response.

Mass cytometry was used to determine the blood immune cell fingerprint of 20 SLE patients with active disease (mean SLEDAI-2K, 8.5) and 20 age- and gender-matched controls, based on the expression of 28 cell-surface and 12 phospho-protein markers. Four patients were monitored under treatment with the JAK-inhibitor baricitinib over time. Immune cell signaling states were analyzed ex vivo, without re-stimulation.

Immune cell profiles of SLE patients were characterized by an average ~2-fold decrease in total lymphocytes, monocytes, dendritic cells and natural killer cells. By contrast, HLA-DR+ CD38+ T cells and plasmablasts (PB) were increased (3- and 2-fold, respectively). On levels of signal transducer phosphorylation, the strongest alterations were detected in the family of STAT proteins. Consistent with an activation by type I interferon, SLE patients showed increased phosphorylation of STAT1,3 and 5, with the strongest changes in memory T cells and PB (up to 4-fold). Although pSTAT1 signal intensities in innate and adaptive immune cell populations were positively correlated with anti-dsDNA autoantibody titers and associated with the number of anti-nuclear antibodies, no correlation was observed with SLEDAI-2K or monocytic SIGLEC-1 expression. Interestingly, native phosphorylation levels of STAT proteins allowed a more stringent classification of SLE patients and controls in multidimensional scaling analyses than changes in cell frequencies only.

Consistent with the successful inhibition of JAK signaling by baricitinib, clinical improvement of patients was paralleled by decreased STAT phosphorylation in CD4+ and CD8+ T cells and monocytes. One patient with improvement of skin manifestations after treatment with JAK inhibitor baricitinib was distinguished by high levels of pSTAT3 in monocytes and T cells at baseline.

In summary, single immune cell phosphorylation readouts reflect imprints of inflammation and immunological activity in SLE patients. This approach promises the discovery of new biomarkers for disease and therapy stratification in SLE and other rheumatic diseases to promote precision medicine in rheumatology.