| 1. |
- Löfstedt, Alexandra, et al.
(författare)
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Haploinsufficiency of UNC13D increases the risk of lymphoma
- 2019
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Ingår i: Cancer. - : John Wiley & Sons. - 0008-543X .- 1097-0142. ; 125:11, s. 1848-1854
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Experimental models have demonstrated that immune surveillance by cytotoxic lymphocytes can protect from spontaneous neoplasms and cancer. In humans, defective lymphocyte cytotoxicity is associated with the development of hemophagocytic lymphohistiocytosis, a hyperinflammatory syndrome. However, to the best of the authors' knowledge, the degree to which human lymphocyte cytotoxicity protects from cancer remains unclear. In the current study, the authors examined the risk of lymphoma attributable to haploinsufficiency in a gene required for lymphocyte cytotoxicity.METHODS: The authors exploited a founder effect of an UNC13D inversion, which abolishes Munc13-4 expression and causes hemophagocytic lymphohistiocytosis in an autosomal recessive manner. Within 2 epidemiological screening programs in northern Sweden, an area demonstrating a founder effect of this specific UNC13D mutation, all individuals with a diagnosis of lymphoma (487 patients) and matched controls (1844 controls) were assessed using polymerase chain reaction for carrier status.RESULTS: Among 487 individuals with lymphoma, 15 (3.1%) were heterozygous carriers of the UNC13D inversion, compared with 18 controls (1.0%) (odds ratio, 3.0; P = .002). It is interesting to note that a higher risk of lymphoma was attributed to female carriers (odds ratio, 3.7; P = .004).CONCLUSIONS: Establishing a high regional prevalence of the UNC13D inversion, the authors have reported an overrepresentation of this mutation in individuals with lymphoma. Therefore, the results of the current study indicate that haploinsufficiency of a gene required for lymphocyte cytotoxicity can predispose patients to lymphoma, suggesting the importance of cytotoxic lymphocyte-mediated surveillance of cancer. Furthermore, the results of the current study suggest that female carriers are more susceptible to lymphoma.
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| 2. |
- Machaczka, Maciej, et al.
(författare)
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Development of classical Hodgkin’s lymphoma in an adult with biallelic STXBP2 mutations
- 2013
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Ingår i: Haematologica. - Stockholm : Karolinska Institutet, Dept of Medicine, Huddinge. - 0390-6078 .- 1592-8721.
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Tidskriftsartikel (refereegranskat)abstract
- Experimental model systems have delineated an important role for cytotoxic lymphocytes in the immunosurveillance of cancer. In humans, perforin-deficiency has been associated with occurrence of hematologic malignancies. Here, we describe an Epstein-Barr virus-positive classical Hodgkin's lymphoma in a patient harboring biallelic mutations in STXBP2, a gene required for exocytosis of perforin-containing lytic granules and associated with familial hemophagocytic lymphohistocytosis. Cytotoxic T lymphocytes were found infiltrating the tumor, and a high frequency of Epstein-Barr virus-specific cytotoxic T lymphocytes were detected in peripheral blood. However, lytic granule exocytosis and cytotoxicity by cytotoxic T lymphocytes, as well as natural killer cells, were severely impaired in the patient. Thus, the data suggest a link between defective lymphocyte exocytosis and development of lymphoma in STXBP2-deficient patients. Therefore, with regards to treatment of familial hemophagocytic lymphohistocytosis patients with mutations in genes required for lymphocyte exocytosis, it is important to consider both the risks of hemophagocytic lymphohistocytosis and malignancy.
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| 3. |
- Meeths, M, et al.
(författare)
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Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D
- 2011
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Ingår i: Blood. - Washington : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 118:22, s. 5783-5793
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Tidskriftsartikel (refereegranskat)abstract
- Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3'-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies.
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| 4. |
- Meeths, Marie
(författare)
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Genetic, cellular and clinical studies of hemophagocytic lymphohistiocytosis
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hemophagocytic lymphohistocytosis (HLH) is a life-threatening hyperinflammatory condition characterized by fever, cytopenia, hepatosplenomegaly, and sometimes hemophagocytosis. HLH is typically divided into two distinct groups, primary HLH and secondary HLH. Familial HLH (FHL), of autosomal recessive inheritance, is divided into type 2, 3, 4, and 5, caused by aberrations in PRF1, UNC13D, STX11, and STXBP2, respectively; all encoding proteins involved the perforin-mediated cytotoxic pathway. Consequently, patients with FHL display a defective NK cell cytotoxicity, one of the diagnostic criteria for HLH. The clinical presentation of the different forms of HLH can vary markedly, and the distinction between primary and secondary HLH is not always clear. In 1991, Henter et al. reported the first estimate of the annual incidence of FHL. Based on an increased awareness of HLH, with available diagnostic guidelines and increased clinical and biological understanding, we, in Paper I, hypothesized that the true incidence could be higher than previously estimated. However, somewhat surprisingly, the estimated annual incidence of primary HLH in Sweden was unchanged, 1.2 per million children less than 15 years of age, corresponding to 1.8 per 100 000 live born children. The annual incidence in patients aged less than 1 year was 11 per million children. The second part of Paper I aimed to provide a minimal incidence of primary HLH based on genetic findings and NK cell function consistent with primary HLH. Using these methods, twelve such patients referred to us were identified 2007-2011, giving a minimal incidence of 1.5 per million children aged less than 15 years in Sweden, corresponding to 2.2 patients per 100 000 live born children. These laboratory diagnostic tools may facilitate the diagnosis of primary HLH. In many patients with primary HLH, especially in patients of Scandinavian origin, the underlying molecular defect has not been identified. Thus, one of the major aims with this thesis was to provide a genetic diagnosis for these patients. Patients with Griscelli syndrome type 2, another autosomal recessive immunodeficiency associated with development of HLH, display a partial albinism in addition to the immunological defect. In Paper II, one out of 21 families diagnosed as having FHL, was identified with bi-allelic mutations in RAB27A, and thus instead affected by GS2. Three additional GS2 patients were also first diagnosed as having FHL and first later diagnosed with GS2, further stressing the importance of remembering GS2 among patients with HLH. The partial albinism in GS2 patients may easily be overlooked. In Paper III, Rab27a was shown to be required for NK cell cytotoxicity and degranulation induced by receptors both for natural cytotoxicity and antibody dependent cellular cytotoxicity, in contrast to what previously has been described. Furthermore, recruitment of Rab27a and Munc13-4 to perforin-containing granules was shown regulated by different receptor signals, with an inverse relationship between Rab27a and Munc13-4. In Paper IV, we describe the clinical presentation, the mutation spectrum, and NK cell function in patients with FHL type 5. Interestingly, a highly variable disease severity was observed among these patients, with an age at onset ranging from 2 months to 17 years. Furthermore, gastrointestinal symptoms, bleeding disorders, and hypogammaglobulinemia were present in about one third of the patients. Thus, we conclude that the clinical presentation of FHL type 5 can vary markedly, and that FHL5 should be considered also in patients with manifestations not typically associated with FHL. In Paper V, two non-coding aberrations in UNC13D were described to be causative of FHL type 3 in many patients of European origin, highlighting that aberrations outside the coding regions also can be a cause of disease. The first is a point mutation in intron 1 that selectively impairs UNC13D transcription in lymphocytes and the second is a 253-kb inversion straddling the UNC13D locus that affects the 3’end of the transcript. Both aberrations abolish the Munc13-4 expression. Taken together, this thesis provides genetic, cellular, and clinical findings of importance for the understanding of HLH. A genetic diagnosis, together with assessment of cytotoxic lymphocyte function, facilitates the diagnosis of patients with primary HLH and enables presymptomatic identification of affected individuals. Furthermore, a genetic diagnosis enables carrier testing and prenatal diagnosis in the affected families. Studies of cytotoxic lymphocyte function in these patients also provide fundamental insights in lymphocyte cytotoxic function and human immunology. A genetic diagnosis, together with an increased knowledge about the diverse clinical presentation, is highly valuable in the clinical management and for prompt initiation of adequate treatment in these life-threatening immunodeficiencies.
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| 5. |
- Meeths, Marie, et al.
(författare)
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Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden.
- 2015
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Ingår i: Pediatric blood & cancer. - : Wiley. - 1545-5017 .- 1545-5009. ; 62:2, s. 346-352
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Tidskriftsartikel (refereegranskat)abstract
- Primary hemophagocytic lymphohistiocytosis (HLH) represents a group of inherited hyperinflammatory immunodeficiencies, including familial HLH (FHL), Griscelli syndrome type 2 (GS2), and X-linked lymphoproliferative syndrome (XLP). We previously reported an annual incidence of suspected primary HLH in Sweden 1971-1986 of 0.12 per 100,000 children. Here, we determined if the incidence had increased with concomitant awareness.
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| 6. |
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| 7. |
- Tesi, Bianca, et al.
(författare)
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Spectrum of atypical clinical presentations in patients with biallelic PRF1 missense mutations.
- 2015
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Ingår i: Pediatric blood & cancer. - : Wiley. - 1545-5017 .- 1545-5009. ; 62:12, s. 2094-2100
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Tidskriftsartikel (refereegranskat)abstract
- Perforin, encoded by PRF1, is a pore-forming protein crucial for lymphocyte cytotoxicity. Biallelic PRF1 nonsense mutations invariably result in early-onset hemophagocytic lymphohistiocytosis (HLH), termed familial HLH type 2 (FHL2). In contrast, biallelic PRF1 missense mutations may give rise to later-onset disease and more variable manifestations.
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| 8. |
- Tesi, Bianca, et al.
(författare)
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Successful Hematopoietic Stem Cell Transplantation in a Patient with LPS-Responsive Beige-Like Anchor (LRBA) Gene Mutation
- 2016
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Ingår i: Journal of Clinical Immunology. - : Springer Science and Business Media LLC. - 0271-9142 .- 1573-2592. ; 36:5, s. 480-489
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Autosomal recessive mutations in LRBA, encoding for LPS-responsive beige-like anchor protein, were described in patients with a common variable immunodeficiency (CVID)-like disease characterized by hypogammaglobulinemia, autoimmune cytopenias, and enteropathy. Here, we detail the clinical, immunological, and genetic features of a patient with severe autoimmune manifestations. Methods: Whole exome sequencing was performed to establish a molecular diagnosis. Evaluation of lymphocyte subsets was performed for immunological characterization. Medical files were reviewed to collect clinical and immunological data. Results: A 7-year-old boy, born to consanguineous parents, presented with autoimmune hemolytic anemia, hepatosplenomegaly, autoimmune thyroiditis, and severe autoimmune gastrointestinal manifestations. Immunological investigations revealed low immunoglobulin levels and low numbers of B and NK cells. Treatment included immunoglobulin replacement and immunosuppressive therapy. Seven years after disease onset, the patient developed severe neurological symptoms resembling acute disseminated encephalomyelitis, prompting allogeneic hematopoietic stem cell transplantation (HSCT) with the HLA-identical mother as donor. Whole exome sequencing of the patient uncovered a homozygous 1 bp deletion in LRBA (c.7162delA:p.T2388Pfs*7). Importantly, during 2 years of follow-up post-HSCT, marked clinical improvement and recovery of immune function was observed. Conclusions: Our data suggest a beneficial effect of HSCT in patients with LRBA deficiency.
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