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- Haara Löfstedt, Alexandra
(författare)
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Hemophagocytic lymphohistiocytosis and associations with malignancies
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In immune homeostasis, natural killer cells and cytotoxic T cells are responsible for clearance of virus-infected and tumor transformed cells, but also for turning off the immune response. Patients with familial hemophagocytic lymphohistiocytosis (HLH) have impaired cytotoxic function due to genetic aberrations in genes in the perforindependent cytotoxic pathway. This results in an inability to turn off the immune response and, typically, a fatal hyperinflammation, often with onset already during the first months of life. The only curative treatment is hematopoietic stem cell transplantation. Patients with hypomorphic, ‘milder’, mutations in HLH-causing genes often have later onset of disease. Notably, an increased risk of hematological malignancies has been reported in these patients. The hyperinflammation of HLH can also occur in individuals without known Mendelian genetic predisposition. In these cases, often occurring later in life, it is termed ‘secondary HLH’ and it is most often triggered by an infection or a malignancy. In paper I we established the incidence of malignancies in relatives to patients with familial HLH by combining two incidence studies of familial HLH in Sweden with the Swedish multigeneration register and the Swedish national cancer register. We report an almost three-fold increased incidence rate of all cancers in mothers of patients with HLH compared to matched controls (4.4 vs 1.6, p=0.0014). In paper II we investigated individuals diagnosed with lymphoma in a defined population in northern Sweden. We found a higher prevalence of the most common HLH-causing aberration in Sweden, an inversion of UNC13D, in patients with lymphoma (3.1% vs 1%, p=0.002). In paper III, we investigated the incidence of secondary HLH in patients with malignancies. All patients with an ICD-10 diagnosis of HLH and cancer between 1997 and 2018 were identified from the Swedish inpatient register and the Swedish cancer register. During the 22 years studied, the incidence increased 10-fold, and at least 0.6% of all patients with hematological malignancies were affected. The last seven years the incidence corresponded to 0.45 per 100 000 individuals annually in Sweden. Importantly, the shortterm survival in malignancy-associated HLH was improved. By reporting a higher risk of malignant disease in relatives of patients with familial HLH as well as a higher frequency of the HLH-causing UNC13D inversion in patients with lymphoma, the studies included in this thesis further support the notion that malignant disease and HLH are tightly linked together. A striking increase in incidence of malignancy-associated HLH is reported over the 22 years studied. This and the improved short-term survival is likely a result of increased awareness of HLH, high-lighting the value of increasing awareness even further.
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| 2. |
- 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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| 3. |
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| 4. |
- 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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