Defining SOCS1 haploinsufficiency in Human – SOCSIMMUNITY

Tumor genetic mapping has changed the way to cure cancers. Similar revolution is now ongoing in autoimmune diseases, as shown in recent identification of monogenic causes of autoimmunité.

Cytokines are essential effectors of immune responses and signal through the JAK-STAT pathway. Inducible suppressors of cytokine signaling (SOCS)-1 is the most potent inhibitor of cytokine signaling. We have recently identified a new dominant cause of systemic autoimmunity caused by SOCS1 haploinsufficiency (SOCS1-HA) in 9 patients from 5 kindreds. The spectrum of the disease is broad from asymptomatic carriers to severe lupus and / or lymphoproliferation, including lymphoma. Interestingly SOCS1 somatic mutations were also reported in haematological malignancies.

We believe that SOCS1 is a critical immune checkpoint preventing both autoimmunity and lymphoprolifération.

SOCS1 has a conserved central Src-homology 2 (SH2) domain (binding to JAKs’ phosphotyrosine-containing sequences) and a short C-terminal SOCS box (causing the ubiquitination and proteasomal degradation of captured substrates). In addition, SOCS1 directly inhibits JAK kinase activity through its kinase inhibitory region (KIR domain). The SH2 domain is the most conserved domain in the SOCS1 protein and determines the SOCS target specificity. SOCS1 is also the only SOCS to have a nuclear localization signal capable to inhibit NF-kB induced inflammation.
SOCS1 thus exerts a double regulation on both cytokine signaling via JAK / STAT and NF-kB nuclear expression and the site of a given mutation may drive the functional impact of the genetic anomalies.

In SOCSIMMUNITY, we will
1/ identify additional patients with lupus or haematological malignancies carrying germline or somatic SOCS1 mutations;
2/ analyze the impact of SOCS-1-HA on the development, activation and function of immune subsets and dissect the mechanism of action of individual SOCS1 variants in cytokine signal transduction cascades,
3/ screen a library of JAK inhibitors to identify personalized treatments for each patient.

The exploration of this new genetic disease will lead to understanding the role of SOCS1 in human pathologies and open the possibility of reversing this deficit through targeted therapies.