Deficiency of the protein receptor interacting serine/threonine kinase 1 (RIPK1) leads to a compromised immune system in humans that can result in autoimmune clinical features such as arthritis, according to a new study published in Science. RIPK1 is an important regulator of inflammation and cell death. Mice lacking RIPK1 have defects in multiple tissues owing to systemic inflammation and die soon after birth; however, until now the importance of RIPK1 in humans was unknown.
“We studied patients with primary immunodeficiencies and discovered four patients with biallelic loss-of-function mutations in the RIPK1 gene,” says Sergey Nejentsev, corresponding author of the study. “This, for the first time, allowed us to characterize effects of complete RIPK1 deficiency in humans.”
The four patients had lymphopenia and suffered from recurrent infections (a hallmark of immunodeficiency). Furthermore, they had early-onset inflammatory bowel disease (IBD) and progressive polyarthritis. These autoimmune features resolved in one patient who underwent haematopoietic stem cell transplantation (HSCT).
In vitro, fibroblasts derived from the patients had impaired MAPK signalling, dysregulated cytokine production and were prone to necroptosis (a regulated form of necrosis). Using whole-blood assays, the researchers revealed altered production of multiple cytokines in the absence of RIPK1. In particular, RIPK1-deficient blood cells produced more IL-1β following stimulation with phytohaemagglutinin than blood cells from healthy individuals.
The aberrant production of cytokines, including cytokines implicated in the pathogenesis of arthritis and IBD such as IL-1β, might explain the autoimmune clinical features of RIPK1-deficient patients. Although not tested in this study, the authors postulate that IL-1 inhibitors might be considered for the treatment of such patients.
RIPK1-deficient blood cells produced more IL-1β ... than blood cells from healthy individuals
“An important finding of our study is that effects of RIPK1-deficiency in humans are limited primarily to the immune system,” says Nejentsev. “Hence, HSCT can be an effective treatment for such patients if performed early in life.”
Cuchet-Lourenço, D. et al. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science. https://doi.org/10.1126/science.aar2641 (2018)
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McHugh, J. Primary immunodeficiency reveals importance of RIPK1. Nat Rev Rheumatol 14, 561 (2018). https://doi.org/10.1038/s41584-018-0075-8