IL4Rα and IL17A Blockade Rescue Autoinflammation in SOCS1 Haploinsufficiency

Abstract

By inhibition of JAK-STAT signaling, SOCS1 acts as a master regulator of the cytokine response across numerous tissue types and cytokine pathways. Haploinsufficiency of SOCS1 has recently emerged as a monogenic immunodysregulatory disease with marked clinical variability. Here, we describe a patient with severe dermatitis, recurrent skin infections, and psoriatic arthritis that harbors a novel heterozygous mutation in SOCS1. The variant, c.202_203delAC, generates a frameshift in SOCS1, p.Thr68fsAla*49, which leads to complete loss of protein expression. Unlike WT SOCS1, Thr68fs SOCS1 fails to inhibit JAK-STAT signaling when expressed in vitro. The peripheral immune signature from this patient was marked by a redistribution of monocyte sub-populations and hyper-responsiveness to multiple cytokines. Despite this broad hyper-response across multiple cytokine pathways in SOCS1 haploinsufficiency, the patient's clinical disease was markedly responsive to targeted IL4Rα- and IL17-blocking therapy. In accordance, the mutant allele was unable to regulate IL4Rα signaling. Further, patient cells were unresponsive to IL4/IL13 while on monoclonal antibody therapy. Together, this study reports a novel SOCS1 mutation and suggests that IL4Rα blockade may serve as an unexpected, but fruitful therapeutic target for some patients with SOCS1 haploinsufficiency.

Keywords: Inborn errors of immunity; JAK-STAT signaling; SOCS1; autoimmunity; autoinflammation; cytokine.

Fig. 1

Identification of a heterozygous SOCS1 mutation in a patient with severe dermatitis and psoriatic arthritis. A Clinical timeline mapping key disease features (blue) throughout time relative to treatment with dupilumab and secukinumab therapy. Labeled arrows (I–VI) indicate the timing at which photographs were taken, with roman numerals corresponding to those in B and C. B Dermatitis of the anterior thigh (I), leg (II), and chest (III) before clinical therapy. C Dermatitis of the anterior thigh (IV), leg (V), and chest (VI) after clinical therapy. D Family pedigree demonstrating the SOCS1 variant in the proband. E Sanger sequencing of the locus of interest of SOCS1 mRNA isolated from whole blood. F Linear structure of SOCS1 protein in the WT and mutant alleles. Abbreviations as follows: N-terminal domain (NTD), kinase domain (K), extended-SH2 domain (E), Src homology domain (SH2), and SOCS box (SBOX).

Fig. 2

SOCS1 T68fs fails to inhibit cytokine signaling by loss-of-expression. A SOCS1 mRNA levels by qPCR in A549 cells transduced with either empty vector (EV), WT SOCS1, or T68fs SOCS1. P-values for individual comparisons from statistical testing shown above. B Western blotting for Flag-tagged SOCS1 transfected into HEK239T cells. Immunoblotting by polyclonal SOCS1 antibodies or anti-Flag antibody. For anti-SOCS1 immunoblotting, the band present in all conditions below ~23kDa is non-specific. The horizontal arrow indicates the predicted molecular weight of T68fs SOCS1. The asterisk indicates the non-specific band. C Western blot for STAT1/2 phosphorylation by IFN-I stimulation of SOCS1-transfected HEK239T cells. D Western blot for STAT1 phosphorylation by IFN-II stimulation of SOCS1-transduced A549 cells. E Western blot for STAT6 phosphorylation by IL4 in SOCS1-transduced A549 cells. F ISRE-inducible Luciferase activity in SOCS1-transfected HEK239T cells stimulated with IFN-I. G Interferon-stimulated gene induction in SOCS1-transfected HEK239T cells stimulated with IFN-I.

Fig. 3

Mass cytometry demonstrates monocyte and γδ T-cell skewing in peripheral blood. A Relative frequency of immune cell subsets in the patient (at two time points, P_T1 and P_T2) and healthy donors (n = 10). Color intensity indicates log2 fold-change of absolute frequency over the median frequency of the healthy donors. Abbreviations: Patient (P or “SOCS1”), healthy donor (HD), effector memory (EM), class switched (CS), non-class switched (NCS), myeloid dendritic cells (mDC), classical monocytes (C monocytes), central memory (CM). B Relative frequency of total B-cells, T-regulatory cells and Th1 CD4+ T-cells. C Relative frequency of γδ T-cells and monocyte subsets.

Fig. 4

SOCS1 T68fs immune cells hyper-respond to cytokine. A Interferon-alpha stimulation (1000 IU/mL) of whole blood and analysis of STAT1 phosphorylation by mass cytometry as measured by mean signal intensity (MSI) and percent positive relative to unstimulated. B Interferon-gamma stimulation (10 ng/mL) of whole blood and analysis of STAT1 phosphorylation as above. C IL2 (10 ng/mL) of whole blood and analysis of STAT5 phosphorylation as above. D–I IL4 and IL13 stimulation (both 10 ng/mL) of the indicated whole blood subsets and analysis of STAT6 phosphorylation. Healthy donor (HD, pink) and patient samples (P or “SOCS1”, blue).