RIPK1 mutations causing infantile-onset IBD with inflammatory and fistulizing features

Abstract

PurposeReceptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important regulator of necroptosis and inflammatory responses. We present the clinical features, genetic analysis and immune work-up of two patients with infantile-onset inflammatory bowel disease (IBD) resulting from RIPK1 mutations.MethodsWhole exome and Sanger sequencing was performed in two IBD patients. Mass cytometry time of flight (CyTOF) was conducted for in-depth immunophenotyping on one of the patient’s peripheral blood mononuclear cells, and compared to control subjects and patients with Crohn’s disease.ResultsThe patients presented with severe colitis and perianal fistulas in the first months of life, without severe/atypical infections. Genetic studies identified pathogenic genetic variants in RIPK1 (Patient 1, A c.1934C>T missense mutation in Exon 11; Patient 2, c.580G>A missense mutation residing in Exon 4). Protein modeling demonstrated that the mutation in Patient 1 displaces a water molecule, potentially disrupting the local environment, and the mutation in Patient 2 may lead to disruption of the packing and conformation of the kinase domain. Immunofluorescence RIPK1 staining in rectal biopsies demonstrated no expression for Patient 1 and minimal expression for Patient 2, compared to controls and patients with active Crohn’s disease. Using CyTOF unbiased clustering analysis, we identified peripheral immune dysregulation in one of these patients, characterized by an increase in IFNγ CD8+ T cells along with a decrease in monocytes, dendritic cells and B cells. Moreover, RIPK1-deficient patient’s immune cells exhibited decreased IL-6 production in response to lipopolysaccharide (LPS) across multiple cell types including T cells, B cells and innate immune cells.ConclusionsMutations in RIPK1 should be considered in very young patients presenting with colitis and perianal fistulas. Given RIPK1’s role in inflammasome activation, but also in epithelial cells, it is unclear whether IL1 blockade or allogeneic hematopoietic stem cell transplantation can suppress or cure the hyper-inflammatory response in these patients. Additional studies in humans are required to better define the role of RIPK1 in regulating intestinal immune responses, and how treatment can be optimized for patients with RIPK1 deficiency.

Very-early-onset Inflammatory Bowel Disease in an Infant with a Partial RIPK1 Deletion

“…To our knowledge, 16 patients (age at onset 1 day − 4 years old age) with autosomal recessive RIPK1 deficiency have been reported to date. They presented with colitis and recurrent infections, also some of them had polyarthritis, aphthous ulcers, and perianal disease that comparable to our patient, because of the critical role of RIPK1 in controlling human immune and intestinal homeostasis [ 7 – 9 , 15 , 19 ].…”

“…On the other hand, several patients were reported to be alive only with intravenous immunoglobulin, antifungal and antibiotic treatment. There was no relation between treatment success and age or clinical presentation of the patients [ 7 – 9 , 15 , 19 ].…”

“…The ability of HSCT to treat this disease is still unknown. Given RIPK1’s functions in regulating both immunological and epithelial responses, performing HSCT to treat these sufferers should be taken with caution since it may improve immunodeficiency [ 7 – 9 , 15 , 19 ]. Cuchet-Lourenco et al [ 7 ] reported three patients with RIPK1 deficiency who underwent HSCT.…”

RIPK1 protects naive and regulatory T cells from TNFR1-induced apoptosis

“…Furthermore, upon caspase-8 inhibition, RIPK1 can initiate the execution of necroptosis [15]. Biallelic Ripk1 mutations in humans are associated with T cell dysbiosis and autoinflammatory syndromes [16][17][18]. Patients carrying Ripk1 mutations rendering RIPK1 resistant to caspase-8 cleavage develop an autoinflammatory syndrome [19,20].…”

Blockade of IKK signaling induces RIPK1-independent apoptosis in human cells

“…Clinical studies have implicated human RIPK1 in a wide range of systemic disorders and pathologies (41)(42)(43)(44)(45)(46), leading to substantial interest in developing RIPK1 therapeutics, particularly for treating inflammatory diseases and cancer (46)(47)(48). However, whether human and murine cells similarly undergo RIPK1-dependent cell death in response to blockade of IKK signaling remains poorly understood.…”