Monogenic Inflammatory Bowel Disease: It's Never Too Late to Make a Diagnosis

Vardi, Iddo; Chermesh, Irit; Werner, Lael; Barel, Ortal; Freund, Tal; McCourt, Collin C.; Fisher, Yael; Pinsker, Marina; Javasky, Elisheva; Weiss, Batia; Rechavi, Gideon; Hagin, David; Snapper, Scott B.; Somech, Raz; Konnikova, Liza; Shouval, Dror S.

doi:10.3389/fimmu.2020.01775

Cited by 6 publications

(5 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consequently, in many of these diseases intestinal inflammation is accompanied by an immunodeficiency state, manifesting as recurrent or atypical infections. Identification of a monogenic disorder can have a marked impact on care provided for these patients through the possibility of providing targeted therapies, as we and others have shown before with anakinra for patients with IL10 receptor mutations (7) and abatacept for LPS Responsive Beige-Like Anchor Protein (LRBA) deficiency (8).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…It can represent the underpinning immune defect in cases of inflammatory bowel disease or autoimmune enteropathy with very-early onset (11,17,18). Histological features may include colonic crypt epithelium injury, chronic inflammation with remarkable increase of lymphocytes in the lamina propria and lymphocytic duodenitis resembling celiac disease (11,19,20). In our case, the main gastrointestinal complaint was a refractory erosive gastritis, without significant involvement of the remainder of the bowel apart from a lymphocytic duodenitis with villous atrophy, reminiscent of celiac disease.…”

Section: Discussionmentioning

confidence: 70%

“…With this report we would stress the importance of prompt investigations for genetic immune dysregulation disease in children with early onset gastroenterological autoimmune disorders, as recommended by several studies (20,29,35). The simultaneous presence of autoimmune FIGURE 4 | Mechanism of action of abatacept in LRBA deficiency.…”

Section: Discussionmentioning

confidence: 93%

Case Report: Refractory Autoimmune Gastritis Responsive to Abatacept in LRBA Deficiency

et al. 2021

View full text Add to dashboard Cite

Primary immunodeficiency (PID) with immune dysregulation may present with early onset gastrointestinal autoimmune disorders. When gastrointestinal autoimmunity is associated with multiple extraintestinal immune system dysfunction the diagnosis of PID is straightforward. However, with the advent of next generation sequencing technologies, genetic defects in PID genes have been increasingly recognized even when a single or no extraintestinal signs of immune dysregulation are present. A genetic diagnosis is especially important considering the expanding armamentarium of therapies designed to inhibit specific molecular pathways. We describe a boy with early-onset severe, refractory autoimmune gastritis and biallelic mutations in the LRBA gene causing a premature STOP-codon who was successfully treated with CTLA4-Ig, abatacept, with long term clinical and endoscopic remission. The case underscores the importance to consider a monogenetic defect in early onset autoimmune disorders, since the availability of targeted treatments may significantly improve patient prognosis.

show abstract

“…LRBA, a member of the BEACH-WD40 protein family, is essential for immune function. It had a role in regulating cell surface expression of CTLA4, a key inhibitor of T-cell activation and proliferation ( Vardi et al, 2020 ). Further functional enrichment analyses showed that these co-expressed genes were primarily involved in metabolism of RNA, immune system process, ncRNA processing, regulation of cell cycle, E2F pathway and transcriptional regulation by TP53.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of prognostic value, immune implication and biological function of CPNE1 in clear cell renal cell carcinoma

Zhou

Huang

et al. 2023

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Background: Elevated expression of Copine-1 (CPNE1) has been proved in various cancers; however, the underlying mechanisms by which it affects clear cell renal cell carcinoma (ccRCC) are unclear.Methods: In this study, we applied multiple bioinformatic databases to analyze the expression and clinical significance of CPNE1 in ccRCC. Co-expression analysis and functional enrichment analysis were investigated by LinkedOmics, cBioPortal and Metascape. The relationships between CPNE1 and tumor immunology were explored using ESTIMATE and CIBERSORT method. In vitro experiments, CCK-8, wound healing, transwell assays and western blotting were conducted to investigate the effects of gain- or loss-of-function of CPNE1 in ccRCC cells.Results: The expression of CPNE1 was notably elevated in ccRCC tissues and cells, and significantly correlated with grade, invasion range, stage and distant metastasis. Kaplan–Meier and Cox regression analysis displayed that CPNE1 expression was an independent prognostic factor for ccRCC patients. Functional enrichment analysis revealed that CPNE1 and its co-expressed genes mainly regulated cancer-related and immune-related pathways. Immune correlation analysis showed that CPNE1 expression was significantly related to immune and estimate scores. CPNE1 expression was positively related to higher infiltrations of immune cells, such as CD8+ T cells, plasma cells and regulatory T cells, exhibited lower infiltrations of neutrophils. Meanwhile, elevated expression of CPNE1 was characterized by high immune infiltration levels, increased expression levels of CD8+ T cell exhaustion markers (CTLA4, PDCD1 and LAG3) and worse response to immunotherapy. In vitro functional studies demonstrated that CPNE1 promoted proliferation, migration and invasion of ccRCC cells through EGFR/STAT3 pathway.Conclusion: CPNE1 is a reliable clinical predictor for the prognosis of ccRCC and promotes proliferation and migration by activating EGFR/STAT3 signaling. Moreover, CPNE1 significantly correlates with immune infiltration in ccRCC.

show abstract

Monogenic Inflammatory Bowel Disease: It's Never Too Late to Make a Diagnosis

Cited by 6 publications

References 51 publications

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

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

Case Report: Refractory Autoimmune Gastritis Responsive to Abatacept in LRBA Deficiency

Comprehensive analysis of prognostic value, immune implication and biological function of CPNE1 in clear cell renal cell carcinoma

Contact Info

Product

Resources

About