Treatment of an HLH-mimic disease based on HAVCR2 variants with absent TIM-3 expression

Tromp, Samantha A.M.; Gillissen, Marijn A.; Moens, Sophie J. Bernelot; Leeuwen, Ester M. M. van; Jansen, Machiel H.; Koens, Lianne; Rutten, Caroline E.; Kuijpers, Taco W.

doi:10.1182/bloodadvances.2022007450

Cited by 7 publications

(8 citation statements)

References 23 publications

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“…As a limitation of the retrospective study, we could not exclude the presence of internal organ panniculitis in our six patients with idiopathic HLH/HLH-like systemic illnesses since the computed tomography scan of the whole abdomen was not performed among those without abdominal symptoms, although omental panniculitis has been reported in a patient with a germline HAVCR2 mutation presenting with HLH without skin lesion. 17 Additionally, we could not demonstrate any factors associated with disease relapse or mortality, possibly due to the heterogeneity of the treatments among cohorts. WES was not performed in the patients with no HAVCR2 mutation to identify other potential genetic alterations contributing to HLH/HLH-like systemic illnesses.…”

Section: Discussionmentioning

confidence: 62%

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Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis

et al. 2023

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Germline HAVCR2 mutations are frequently detected in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients with/without hemophagocytic lymphohistiocytosis (HLH) but factors associated with variable manifestations remain undetermined. To evaluate clinical variations and associated factors in SPTCL and/or HLH with/without HAVCR2 mutations, we performed direct sequencing of HAVCR2 exon 2 using DNA from patients with SPTCL or idiopathic HLH/HLH-like systemic illnesses, defined by HLH alone without secondary causes. The systematic review and individual patient data (IPD) level meta-analysis which included the present and previously published studies reporting HAVCR2 mutations in SPTCL with/without HLH populations was subsequently conducted using random-effects meta-analysis and multivariate logistic regression. Among 34 patients enrolled, 10 of 28 SPTCL patients developed HLH/HLH-like systemic illnesses. Six cases with HAVCR2Y82C mutation manifested with HLH without panniculitis. Male gender (p=0.03) and age

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Section: Discussionmentioning

confidence: 62%

“…Thirteen studies (6 cohorts and 7 case reports) were eli- gible for the systematic review (Table 3). [1][2][3][9][10][11][12][13][14][15][16][17] The PRISMA flow diagram for study screening and the selection process is illustrated in the Online Supplementary Figure S5.…”

Section: Systematic Review and Conventional Meta-analysismentioning

confidence: 99%

Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis

et al. 2023

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“…This variant has previously been demonstrated to encode a loss of function allele and has, in homozygous but also in heterozygous states, been shown to cause subcutaneous panniculitis-like T cell lymphoma (SPTCL) and autoin ammatory disease(18). However, also cases of autoin ammation in the absence of SPTCL have been recently linked to HAVCR2 germline mutations (19,20). The I97M missense mutation causes TIM-3 missfolding, aggregation in the Golgi apparatus and lack of surface expression(18).…”

Section: Resultsmentioning

confidence: 99%

Post-transplant inflammatory bowel disease associated with donor-derived TIM-3 deficiency

Baldrich,

Althaus,

Menter

et al. 2023

Preprint

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Purpose Inflammatory bowel disease (IBD) occurring following allogenic stem cell transplantation (aSCT) is a very rare condition. The underlying pathogenesis is poorly defined. There is currently no systematic effort to exclude loss- or gain-of-function mutations in immune-related genes in stemcell donors. Methods Whole exome sequencing of hematopoietic cell-intrinsic, donor-derived vs. skin-derived germline DNA was performed in an index patient with post-aSCT IBD. Expression of the immune checkpoint protein TIM-3 and T cell-edrived cytokines/chemokines was assessed in in vitro activated patient-derived T cells by flow-cytometry and by performing immune-histology on sections from inflamed vs. non-inflamed intestinal tissue. Results We have molecularly characterized a patient who developed fulminant inflammatory bowel disease following aSCT with stable 100% donor-derived hematopoiesis. A pathogenic c.A291G; p.I97M HAVCR2 mutation encoding the immune checkpoint protein TIM-3 was identified in the patient’s blood-derived DNA, while being absent in DNA derived from the skin. TIM-3 expression was much decreased in in vitro activated patient-derived T cells, while effector cytokines and Foxp3 expression were preserved. TIM-3 expression was barely detectable in the patient’s intestinal mucosa, while being detected unambiguously in inflamed and non-inflamed colon from unrelated individuals. Conclusion We report the first case of acquired, ‘transplanted’ insufficiency of the regulatory TIM-3 checkpoint linked to post-aSCT IBD.

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“…The c.A291G; p.I97M HAVCR2 /TIM-3 mutation has been demonstrated to encode a loss of function allele and has, in homozygous but also in heterozygous states, been shown to cause subcutaneous panniculitis-like T cell lymphoma (SPTCL) and autoinflammatory disease [ 19 ]. Also, cases of autoinflammation in the absence of SPTCL have been recently linked to HAVCR2 germline mutations [ 25 , 26 ]. The I97M missense mutation causes TIM-3 misfolding, aggregation in the Golgi apparatus, and lack of surface expression [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency

Baldrich,

Althaus,

Menter

et al. 2024

J Clin Immunol

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Inflammatory bowel disease (IBD) occurring following allogeneic stem cell transplantation (aSCT) is a very rare condition. The underlying pathogenesis needs to be better defined. There is currently no systematic effort to exclude loss- or gain-of-function mutations in immune-related genes in stem cell donors. This is despite the fact that more than 100 inborn errors of immunity may cause or contribute to IBD. We have molecularly characterized a patient who developed fulminant inflammatory bowel disease following aSCT with stable 100% donor-derived hematopoiesis. A pathogenic c.A291G; p.I97M HAVCR2 mutation encoding the immune checkpoint protein TIM-3 was identified in the patient’s blood-derived DNA, while being absent in DNA derived from the skin. TIM-3 expression was much decreased in the patient’s serum, and in vitro-activated patient-derived T cells expressed reduced TIM-3 levels. In contrast, T cell-intrinsic CD25 expression and production of inflammatory cytokines were preserved. TIM-3 expression was barely detectable in the immune cells of the patient’s intestinal mucosa, while being detected unambiguously in the inflamed and non-inflamed colon from unrelated individuals. In conclusion, we report the first case of acquired, “transplanted” insufficiency of the regulatory TIM-3 checkpoint linked to post-aSCT IBD.

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Treatment of an HLH-mimic disease based on HAVCR2 variants with absent TIM-3 expression

Cited by 7 publications

References 23 publications

Germline <i>HAVCR2</i> mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis

Germline <i>HAVCR2</i> mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis

Post-transplant inflammatory bowel disease associated with donor-derived TIM-3 deficiency

Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency

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