| 1. |
- Carlund, Olivia, et al.
(författare)
-
Semimethylation is a feature of diffuse large B-cell lymphoma, and subgroups with poor prognosis are characterized by global hypomethylation and short telomere length
- 2024
-
Ingår i: Clinical Epigenetics. - : BioMed Central (BMC). - 1868-7083. ; 16:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL.Results: We studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β < 0.15) was in multivariable analysis associated with worse disease-specific survival (DSS) (HR 6.920, 95% CI 1.499–31.943) and progression-free survival (PFS) (HR 4.923, 95% CI 1.286–18.849) in DLBCL and with worse DSS (HR 5.147, 95% CI 1.239–21.388) in LBCL. These cases with a high percentage of global hypomethylation also had a higher degree of CpG island methylation, including islands in promoter-associated regions, than the cases with less hypomethylation. Additionally, telomere length was heterogenous in LBCL, with a subset of the DLBCL-GC cases accounting for the longest RTL. Short RTL was independently associated with worse DSS (HR 6.011, 95% CI 1.319–27.397) and PFS (HR 4.689, 95% CI 1.102–19.963) in LBCL treated with R-CHOP-like regimens.Conclusion: We hypothesize that subclones with high global hypomethylation and hypermethylated CpG islands could have advantages in tumor progression, e.g. by inactivating tumor suppressor genes or promoting treatment resistance. Our findings suggest that cases with high global hypomethylation and thus poor prognosis could be candidates for alternative treatment regimens including hypomethylating drugs.
|
|
| 2. |
- Carrasco, Anna, et al.
(författare)
-
The Tonsil Lymphocyte Landscape in Pediatric Tonsil Hyperplasia and Obstructive Sleep Apnea
- 2021
-
Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Tonsil hyperplasia is the most common cause of pediatric obstructive sleep apnea (OSA). Despite the growing knowledge in tissue immunology of tonsils, the immunopathology driving tonsil hyperplasia and OSA remains unknown. Here we used multi-parametric flow cytometry to analyze the composition and phenotype of tonsillar innate lymphoid cells (ILCs), T cells, and B cells from pediatric patients with OSA, who had previous polysomnography. Unbiased clustering analysis was used to delineate and compare lymphocyte heterogeneity between two patient groups: children with small tonsils and moderate OSA (n = 6) or large tonsils and very severe OSA (n = 13). We detected disturbed ILC and B cell proportions in patients with large tonsils, characterized by an increase in the frequency of naive CD27(-)CD21(hi) B cells and a relative reduction of ILCs. The enrichment of naive B cells was not commensurate with elevated Ki67 expression, suggesting defective differentiation and/or migration rather than cellular proliferation to be the causative mechanism. Finally, yet importantly, we provide the flow cytometry data to be used as a resource for additional translational studies aimed at investigating the immunological mechanisms of pediatric tonsil hyperplasia and OSA.
|
|
| 3. |
- Dernstedt, Andy, 1993-
(författare)
-
Life and death of human B cells in health and disease
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- B cells provide one of the key mechanisms of immunological memory, which is theproduction of neutralising antibodies. How B cells respond to infections and vaccinationgives clues to how the development of the immunological memory is facilitated, and canthus lead to a deeper understanding of why the immune system sometimesmalfunctions. This thesis focuses on the human B cell responses in three differentsettings: Acute viral infection, mechanisms involved in germinal centre responses, andvaccination upon interrupted B cell depletion therapy in patients with multiple sclerosis(MS). We have found that during acute Puumala-orthohantavirus (PUUV) infection, Bcells activate on a large scale and derive a phenotype similar to previous observations inautoimmune diseases and chronic infections. Patients with PUUV infection also haddecreased expression of the complement regulatory protein Decay-Accelerating Factor(DAF) at an early stage in the disease. Here, we hypothesised that this might be a resultof a robust B cell response, and therefore we continued to assess B cells at the peripheralsites of their maturation. We found that B cells downregulated the complementinhibitory protein during the germinal centre reaction, which also primed the cells forphagocytosis. This finding shed light to the mechanisms that control B cell homeostasis.Finally, we assessed the B cell responses towards vaccination in patients with MS afterinterruption of their B cell depletion therapy. Here we showed that the patients yieldedexpansion of vaccination-specific memory B cells. However, these memory B cells didnot comprise expansion of DAFlo cells, in contrast to the non-MS control individuals.We speculated that the B cell depletion might have an impact on the formation of B cellmemory after interrupted treatment. Taken together, this thesis contributes to theoverall understanding of the life cycle of B cells, in the context of infection, vaccination,and homeostasis.
|
|
| 4. |
- Dernstedt, Andy, et al.
(författare)
-
Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis
- 2021
-
Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- Germinal centers (GC) are sites for extensive B cell proliferation and homeostasis is maintained by programmed cell death. The complement regulatory protein Decay Accelerating Factor (DAF) blocks complement deposition on host cells and therefore also phagocytosis of cells. Here, we show that B cells downregulate DAF upon BCR engagement and that T cell-dependent stimuli preferentially led to activation of DAF(lo) B cells. Consistent with this, a majority of light and dark zone GC B cells were DAF(lo) and susceptible to complement-dependent phagocytosis, as compared with DAF(hi) GC B cells. We could also show that the DAF(hi) GC B cell subset had increased expression of the plasma cell marker Blimp-1. DAF expression was also modulated during B cell hematopoiesis in the human bone marrow. Collectively, our results reveal a novel role of DAF to pre-prime activated human B cells for phagocytosis prior to apoptosis.
|
|
| 5. |
- Gröning, Remigius, et al.
(författare)
-
Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption
- 2023
-
Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- Peripheral B cell depletion via anti-CD20 treatment is a highly effective disease-modifying treatment for reducing new relapses in multiple sclerosis (MS) patients. A drawback of rituximab (RTX) and other anti-CD20 antibodies is a poor immune response to vaccination. While this can be mitigated by treatment interruption of at least six months prior to vaccination, the timing to resume treatment while maintaining subsequent vaccine responses remains undetermined. Here, we characterized SARS-CoV-2 S-directed antibody and B cell responses throughout three BNT162b2 mRNA vaccine doses in RTX-treated MS patients, with the first two doses given during treatment interruption. We examined B-cell mediated immune responses in blood samples from patients with RTX-treated MS throughout three BNT162b2 vaccine doses, compared to an age- and sex-matched healthy control group. The first vaccine dose was given 1.3 years (median) after the last RTX infusion, the second dose one month after the first, and the third dose four weeks after treatment re-initiation. We analyzed SARS-CoV-2 S-directed antibody levels using enzyme-linked immunosorbent assay (ELISA), and the neutralization capacity of patient serum against SARS-CoV-2 S-pseudotyped lentivirus using luciferase reporter assay. In addition, we assessed switched memory (CD19+CD20+CD27+IgD-), unswitched memory (CD19+CD20+CD27+IgD+), naïve (CD19+CD20+CD27-IgD+), and double negative (DN, CD19+CD20+CD27-IgD-) B cell frequencies, as well as their SARS-CoV-2 S-specific (CoV+) and Decay Accelerating Factor-negative (DAF-) subpopulations, using flow cytometry. After two vaccine doses, S-binding antibody levels and neutralization capacity in SARS-CoV-2-naïve MS patients were comparable to vaccinated healthy controls, albeit with greater variation. Higher antibody response levels and CoV+-DN B cell frequencies after the second vaccine dose were predictive of a boost effect after the third dose, even after re-initiation of rituximab treatment. MS patients also exhibited lower frequencies of DAF- memory B cells, a suggested proxy for germinal centre activity, than control individuals. S-binding antibody levels in RTX-treated MS patients after two vaccine doses could help determine which individuals would need to move up their next vaccine booster dose or postpone their next RTX infusion. Our findings also offer first indications on the potential importance of antigenic stimulation of DN B cells and long-term impairment of germinal centre activity in rituximab-treated MS patients.
|
|
| 6. |
|
|
| 7. |
- Kerkman, Priscilla, et al.
(författare)
-
Generation of plasma cells and CD27-IgD- B cells during hantavirus infection is associated with distinct pathological findings
- 2021
-
Ingår i: Clinical & Translational Immunology (CTI). - : John Wiley & Sons. - 2050-0068. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Human hantavirus infections can cause haemorrhagic fever with renal syndrome (HFRS). The pathogenic mechanisms arenot fully understood, nor if they affect the humoral immune system. The objective of this study was to investigate humoral immune responses to hantavirus infection and to correlate them to the typical features of HFRS: thrombocytopenia and transient kidney dysfunction.Methods: We performed a comprehensive characterisation of longitudinal antiviral B-cell responses of 26 hantavirus patients and combined this with paired clinical data. In addition, we measured extracellular adenosine triphosphate (ATP)and its breakdown products in circulation and performed in vitro stimulations to address its effect on B cells.Results: We found that thrombocytopenia was correlated to an elevated frequency of plasmablasts in circulation. In contrast, kidney dysfunction was indicative of an accumulation of CD27-IgD- B cells and CD27/low plasmablasts. Finally, we provide evidence that high levels of extracellular ATP and matrix metalloproteinase 8 can contribute to shedding of CD27 during human hantavirus infection.Conclusion: Our findings demonstrate that thrombocytopenia and kidneydysfunction associate with distinctly different effects on the humoral immune system. Moreover, hantavirus-infectedindividuals have significantly elevated levels of extracellular ATP incirculation.
|
|
| 8. |
- Kerkman, Priscilla, et al.
(författare)
-
The B cell response towards Puumala virus infection : can B cells be infected?
- 2017
-
Ingår i: Scandinavian Journal of Immunology. - : John Wiley & Sons. - 0300-9475 .- 1365-3083. ; 86:4, s. 260-260
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Hantavirus infections are rodent-borne viruses causing potential lethal infections in humans. Different hantaviruses exist worldwide, reporting a fatality rate of up to 40%. The Puumala hantavirus (PUUV) is endemic in northern Sweden. This hantavirus strain has a relatively low fatality rate but the hospitalisation rate is high. No vaccine to the virus and no treatment for the disease exist. Despite differences in severity, the immune-mediated pathogenesis of Puumala virus infection is similar to that of highly lethal strains of hantavirus. It is currently unknown how the humoral immune system is affected during hantavirus infection.The aim of this study is to characterise how the humoral immune response is affected during Puumala virus infection. A large number of longitudinal patient samples have been collected. Here, we demonstrate the longitudinal kinetics of the B cell response during Puumala virus infection and show that there is a change in B cell populations during the course of the disease. Furthermore we show that B cells carry known hantavirus receptors. This suggests that Puumala virus may directly infect B cells. Infection of the B cells could affect their function and or phenotype explaining a different immune response. Importantly, in approximately 10–15% of Puumala infected patients we could detect antibodies that could neutralise other hantaviruses in vitro. Samples from these patients could help to generate a monoclonal antibody treatment potentially treating diseases caused by several hantavirus.
|
|
| 9. |
- Kolan, Shrikant S, 1983-, et al.
(författare)
-
Growth-inhibition of cell lines derived from B cell lymphomas through antagonism of serotonin receptor signaling
- 2019
-
Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- A majority of lymphomas are derived from B cells and novel treatments are required to treat refractory disease. Neurotransmitters such as serotonin and dopamine influence activation of B cells and the effects of a selective serotonin 1A receptor (5HT1A) antagonist on growth of a number of B cell-derived lymphoma cell lines were investigated. We confirmed the expression of 5HT1A in human lymphoma tissue and in several well-defined experimental cell lines. We discovered that the pharmacological inhibition of 5HT1A led to the reduced proliferation of B cell-derived lymphoma cell lines together with DNA damage, ROS-independent caspase activation and apoptosis in a large fraction of cells. Residual live cells were found ‘locked’ in a non-proliferative state in which a selective transcriptional and translational shutdown of genes important for cell proliferation and metabolism occurred (e.g., AKT, GSK-3β, cMYC and p53). Strikingly, inhibition of 5HT1A regulated mitochondrial activity through a rapid reduction of mitochondrial membrane potential and reducing dehydrogenase activity. Collectively, our data suggest 5HT1A antagonism as a novel adjuvant to established cancer treatment regimens to further inhibit lymphoma growth.
|
|
| 10. |
|
|
