| 1. |
- Abolhalaj, Milad, et al.
(författare)
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Profiling dendritic cell subsets in head and neck squamous cell tonsillar cancer and benign tonsils.
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:8030
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DCs) have a key role in orchestrating immune responses and are considered important targets for immunotherapy against cancer. In order to develop effective cancer vaccines, detailed knowledge of the micromilieu in cancer lesions is warranted. In this study, flow cytometry and human transcriptome arrays were used to characterize subsets of DCs in head and neck squamous cell tonsillar cancer and compare them to their counterparts in benign tonsils to evaluate subset-selective biomarkers associated with tonsillar cancer. We describe, for the first time, four subsets of DCs in tonsillar cancer: CD123+ plasmacytoid DCs (pDC), CD1c+, CD141+, and CD1c-CD141- myeloid DCs (mDC). An increased frequency of DCs and an elevated mDC/pDC ratio were shown in malignant compared to benign tonsillar tissue. The microarray data demonstrates characteristics specific for tonsil cancer DC subsets, including expression of immunosuppressive molecules and lower expression levels of genes involved in development of effector immune responses in DCs in malignant tonsillar tissue, compared to their counterparts in benign tonsillar tissue. Finally, we present target candidates selectively expressed by different DC subsets in malignant tonsils and confirm expression of CD206/MRC1 and CD207/Langerin on CD1c+ DCs at protein level. This study descibes DC characteristics in the context of head and neck cancer and add valuable steps towards future DC-based therapies against tonsillar cancer.
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| 2. |
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| 3. |
- Hafström, Anna, et al.
(författare)
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Sentinel lymph node biopsy staging for cutaneous malignant melanoma of the head and neck.
- 2016
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 136:3
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Tidskriftsartikel (refereegranskat)abstract
- Conclusion Sentinel lymph node biopsies (SLNBs) can be performed safely and with reasonable accuracy in HNM patients. The outcome provides important prognostic information concerning DFS and further treatment. However, one must recognize that SLNB is a multidisciplinary procedure with a learning curve for all. Objectives To evaluate efficacy of performing SLNBs in a series of consecutive patients with cutaneous head and neck melanoma (HNM) ≥ T1b from introduction of the procedure and 10 years onward. Method End-points comprised of SLNB outcome, disease-free survival (DFS), and overall survival (OS). Results SNs were harvested in 128 of 160 patients (median Breslow = 2.0 mm, 29% ulcerated); success rate = 80.0%, or 92.1% if excluding patients where SLNBs were omitted due to non-localization on pre-operative imaging or because of SN-location in the parotid basin. Ten patients (7.8%) had positive SLNBs and were offered early completion neck dissections. Of the 146 patients available for follow-up (median = 27 months), 15.8% had recurrent disease. The risk of a regional nodal recurrence after a negative SLNB was 7.5%. SN-negative patients had improved DFS c.f. SN-positive patients (p < 0.001). A positive SLNB was the most important prognostic predictor of decreased DFS (hazard ratio = 5.70; p < 0.005), but had no significant impact on OS.
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| 4. |
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| 5. |
- Kirik, Ufuk, et al.
(författare)
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Antibody heavy chain variable domains of different germline gene origins diversify through different paths
- 2017
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8:NOV
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Tidskriftsartikel (refereegranskat)abstract
- B cells produce antibodies, key effector molecules in health and disease. They mature their properties, including their affinity for antigen, through hypermutation events; processes that involve, e.g., base substitution, codon insertion and deletion, often in association with an isotype switch. Investigations of antibody evolution define modes whereby particular antibody responses are able to form, and such studies provide insight important for instance for development of efficient vaccines. Antibody evolution is also used in vitro for the design of antibodies with improved properties. To better understand the basic concepts of antibody evolution, we analyzed the mutational paths, both in terms of amino acid substitution and insertions and deletions, taken by antibodies of the IgG isotype. The analysis focused on the evolution of the heavy chain variable domain of sets of antibodies, each with an origin in 1 of 11 different germline genes representing six human heavy chain germline gene subgroups. Investigated genes were isolated from cells of human bone marrow, a major site of antibody production, and characterized by next-generation sequencing and an in-house bioinformatics pipeline. Apart from substitutions within the complementarity determining regions, multiple framework residues including those in protein cores were targets of extensive diversification. Diversity, both in terms of substitutions, and insertions and deletions, in antibodies is focused to different positions in the sequence in a germline gene-unique manner. Altogether, our findings create a framework for understanding patterns of evolution of antibodies from defined germline genes.
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| 6. |
- Kirik, Ufuk, et al.
(författare)
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Data on haplotype-supported immunoglobulin germline gene inference
- 2017
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Ingår i: Data in Brief. - : Elsevier BV. - 2352-3409. ; 13, s. 620-640
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Tidskriftsartikel (refereegranskat)abstract
- Data that defines IGHV (immunoglobulin heavy chain variable) germline gene inference using sequences of IgM-encoding transcriptomes obtained by Illumina MiSeq sequencing technology are described. Such inference is used to establish personalized germline gene sets for in-depth antibody repertoire studies and to detect new antibody germline genes from widely available immunoglobulin-encoding transcriptome data sets. Specifically, the data has been used to validate (Parallel antibody germline gene and haplotype analyses support the validity of immunoglobulin germline gene inference and discovery (DOI: 10.1016/j.molimm.2017.03.012) (Kirik et al., 2017) [1]) the inference process. This was accomplished based on analysis of the inferred germline genes’ association to the donors’ different haplotypes as defined by their different, expressed IGHJ alleles and/or IGHD genes/alleles. The data is important for development of validated germline gene databases containing entries inferred from immunoglobulin-encoding transcriptome sequencing data sets, and for generation of valid, personalized antibody germline gene repertoires.
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| 7. |
- Kirik, Ufuk, et al.
(författare)
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Parallel antibody germline gene and haplotype analyses support the validity of immunoglobulin germline gene inference and discovery
- 2017
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Ingår i: Molecular Immunology. - : Elsevier BV. - 0161-5890. ; 87, s. 12-22
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Tidskriftsartikel (refereegranskat)abstract
- Analysis of antibody repertoire development and specific antibody responses important for e.g. autoimmune conditions, allergy, and protection against disease is supported by high throughput sequencing and associated bioinformatics pipelines that describe the diversity of the encoded antibody variable domains. Proper assignment of sequences to germline genes are important for many such processes, for instance in the analysis of somatic hypermutation. Germline gene inference from antibody-encoding transcriptomes, by using tools such as TIgGER or IgDiscover, has a potential to enhance the quality of such analyses. These tools may also be used to identify germline genes not previously known. In this study, we exploited such software for germline gene inference and define aspects of analysis settings and pre-existing knowledge of germline genes that affect the outcome of gene inference. Furthermore, we demonstrate the capacity of IGHJ and IGHD haplotype inference, whenever subjects are heterozygous with respect to such genes, to lend support to IGHV gene inference in general, and to the identification of novel alleles presently not recognized by germline gene reference directories. We propose that such haplotype analysis shall, whenever possible, be used in future best practice to support the outcome of germline gene inference. IGHJ-directed haplotype inference was also used to identify haplotypes not expressing some IGHV germline genes. In particular, we identified a haplotype that did not express several major germline genes such as IGHV1-8, IGHV3-9, IGHV3-15, IGHV1-18, IGHV3-21, and IGHV3-23. We envisage that haplotype analysis will provide an efficient approach to identify subjects for further studies of the link between the available immunoglobulin repertoire and outcomes of immune responses.
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| 8. |
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| 9. |
- Levin, Mattias, et al.
(författare)
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Persistence and evolution of allergen-specific IgE repertoires during subcutaneous specific immunotherapy.
- 2016
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Ingår i: The Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 1097-6825 .- 0091-6749. ; 137:5, s. 1535-1544
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Tidskriftsartikel (refereegranskat)abstract
- Specific immunotherapy (SIT) is the only treatment with proved long-term curative potential in patients with allergic disease. Allergen-specific IgE is the causative agent of allergic disease, and antibodies contribute to SIT, but the effects of SIT on aeroallergen-specific B-cell repertoires are not well understood.
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| 10. |
- Lundberg, Kristina, et al.
(författare)
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Allergen-Specific Immunotherapy Alters the Frequency, as well as the FcR and CLR Expression Profiles of Human Dendritic Cell Subsets.
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- Allergen-specific immunotherapy (AIT) induces tolerance and shifts the Th2 response towards a regulatory T-cell profile. The underlying mechanisms are not fully understood, but dendritic cells (DC) play a vital role as key regulators of T-cell responses. DCs interact with allergens via Fc receptors (FcRs) and via certain C-type lectin receptors (CLRs), including CD209/DC-SIGN, CD206/MR and Dectin-2/CLEC6A. In this study, the effect of AIT on the frequencies as well as the FcR and CLR expression profiles of human DC subsets was assessed. PBMC was isolated from peripheral blood from seven allergic donors before and after 8 weeks and 1 year of subcutaneous AIT, as well as from six non-allergic individuals. Cells were stained with antibodies against DC subset-specific markers and a panel of FcRs and CLRs and analyzed by flow cytometry. After 1 year of AIT, the frequency of CD123+ DCs was increased and a larger proportion expressed FcεRI. Furthermore, the expression of CD206 and Dectin-2 was reduced on CD141+ DCs after 1 year of treatment and CD206 as well as Dectin-1 was additionally down regulated in CD1c+ DCs. Interestingly, levels of DNGR1/CLEC9A on CD141+ DCs were increased by AIT, reaching levels similar to cells isolated from non-allergic controls. The modifications in phenotype and occurrence of specific DC subsets observed during AIT suggest an altered capacity of DC subsets to interact with allergens, which can be part of the mechanisms by which AIT induces allergen tolerance.
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