Frode Vartdal

• Polak, Justyna; Wagnerberger, Johanna Henny; Torsetnes, Silje Bøen; Lindeman, Ida; Høglund, Rune Alexander Aamodt & Vartdal, Frode [Show all 8 contributors for this article] (2023). Single-cell transcriptomics combined with proteomics of intrathecal IgG reveal transcriptional heterogeneity of oligoclonal IgG-secreting cells in multiple sclerosis. Frontiers in Cellular Neuroscience. 17. doi: 10.3389/fncel.2023.1189709. Full text in Research Archive Show summary

  The phenotypes of B lineage cells that produce oligoclonal IgG in multiple sclerosis have not been unequivocally determined. Here, we utilized single-cell RNA-seq data of intrathecal B lineage cells in combination with mass spectrometry of intrathecally synthesized IgG to identify its cellular source. We found that the intrathecally produced IgG matched a larger fraction of clonally expanded antibody-secreting cells compared to singletons. The IgG was traced back to two clonally related clusters of antibody-secreting cells, one comprising highly proliferating cells, and the other consisting of more differentiated cells expressing genes associated with immunoglobulin synthesis. These findings suggest some degree of heterogeneity among cells that produce oligoclonal IgG in multiple sclerosis.

• Lindeman, Ida; Polak, Justyna; Qiao, Shuo-Wang; Holmøy, Trygve; Høglund, Rune Alexander & Vartdal, Frode [Show all 9 contributors for this article] (2022). Stereotyped B-cell responses are linked to IgG constant region polymorphisms in multiple sclerosis. European Journal of Immunology. ISSN 0014-2980. 52(4), p. 550–565. doi: 10.1002/eji.202149576. Full text in Research Archive Show summary

  Clonally related B cells infiltrate the brain, meninges, and cerebrospinal fluid of MS patients, but the mechanisms driving the B-cell response and shaping the immunoglobulin repertoires remain unclear. Here, we used single-cell full-length RNA-seq and BCR reconstruction to simultaneously assess the phenotypes, isotypes, constant region polymorphisms, and the paired heavy- and light-chain repertoires in intrathecal B cells. We detected extensive clonal connections between the memory B cell and antibody-secreting cell (ASC) compartments and observed clonally related cells of different isotypes including IgM/IgG1, IgG1/IgA1, IgG1/IgG2, and IgM/IgA1. There was a strong dominance of the G1m1 allotype constant region polymorphisms in ASCs, but not in memory B cells. Tightly linked to the G1m1 allotype, we found a preferential pairing of the immunoglobulin heavy-chain variable (IGHV)4 gene family with the κ variable (IGKV)1 gene family. The IGHV4-39 gene was most used and showed the highest frequency of pairing with IGKV1-5 and IGKV1(D)-33. These results link IgG constant region polymorphisms to stereotyped B-cell responses in MS and indicate that the intrathecal B-cell response in these patients could be directed against structurally similar epitopes

• Sollid, Ludvig Magne; Lundin, Knut Erik Aslaksen; Leivestad, Torbjørn; Spurkland, Anne & Vartdal, Frode (2021). Erik Thorsby (1938-2021). Immunogenetics. ISSN 0093-7711. 73(3), p. 203–205. doi: 10.1007/s00251-021-01218-5. Full text in Research Archive
• Tomescu-Baciu, Alina; Johansen, Jorunn; Holmøy, Trygve; Greiff, Victor; Stensland, Maria & Souza, Gustavo Antonio De [Show all 8 contributors for this article] (2019). Persistence of intrathecal oligoclonal B cells and IgG in multiple sclerosis. Journal of Neuroimmunology. ISSN 0165-5728. 333:576966, p. 1–7. doi: 10.1016/j.jneuroim.2019.576966. Full text in Research Archive Show summary

  In multiple sclerosis (MS), B cells are trafficking across the blood-brain barrier, but it is not known how this relates to the synthesis of oligoclonal IgG. We used quantitative mass spectrometry of oligoclonal bands and high-throughput sequencing of immunoglobulin heavy-chain variable transcripts to study the longitudinal B cell response in the cerebrospinal fluid (CSF) and blood of two MS patients. Twenty of 22 (91%) and 25 of 28 (89%) of oligoclonal band peptides persisted in samples collected 18 months apart, in spite of a dynamic exchange across the blood-CSF barrier of B lineage cells connecting to oligoclonal IgG.

• Høglund, Rune Alexander; Polak, Justyna; Vartdal, Frode; Holmøy, Trygve & Lossius, Peter Andreas Vold (2018). B-cell composition in the blood and cerebrospinal fluid of multiple sclerosis patients treated with dimethyl fumarate. Multiple Sclerosis and Related Disorders. ISSN 2211-0348. 26, p. 90–95. doi: 10.1016/j.msard.2018.08.032. Full text in Research Archive Show summary

  Background:B cells may contribute to the immunopathogenesis of multiple sclerosis (MS). Dimethyl fumarate(DMF) has recently been shown to reduce the frequency of memory B cells in blood, but it is not known whetherthe drug influences the cellular composition in the cerebrospinalfluid (CSF).Methods:A cross-sectional study examining the cellular composition in blood and cerebrospinalfluid (CSF) from10 patients treated with DMF and 18 patients receiving other disease modifying drugs or no treatment.Results:Patients treated with DMF had reduced proportions of memory B cells in blood compared to other MSpatients (p=0.0007), and the reduction correlated with treatment duration (rs=−0.75,p=0.021). In theCSF, the absolute number of mononuclear cells were significantly lower in DMF-treated patients compared to theother patients (p= 0.023), and there was a disproportionate decrease of plasmablasts (p=0.031).Conclusion:The results of this exploratory study support a B-cell mediated mechanism of action for DMF in bothblood and CSF.

• Tomescu-Baciu, Alina; Vartdal, Frode; Holmøy, Trygve; Vedeler, Christian A. & Lossius, Peter Andreas Vold (2018). G1m1 predominance of intrathecal virus-specific antibodies in multiple sclerosis. Annals of clinical and translational neurology. 5(10), p. 1303–1309. doi: 10.1002/acn3.642. Full text in Research Archive Show summary

  We have previously shown that plasmablasts of the G1m1 allotype of IgG1 are selectively enriched in the cerebrospinal fluid of G1m1/G1m3 heterozygous patients with multiple sclerosis, whereas both allotypes are equally used in neuroborreliosis. Here, we demonstrate a strong preference for the G1m1 allotype in the intrathecal humoral immune responses against measles, rubella, and varicella zoster virus in G1m1/G1m3 heterozygous multiple sclerosis patients. Conversely, intrathecally synthesized varicella zoster virus‐specific IgG1 in varicella zoster virus meningoencephalitis comprised both allotypes. This implies that G1m1 B cells are selected to the central nervous system of multiple sclerosis patients regardless of specificity and suggests that an antigen‐independent mechanism could drive the intrathecal humoral immune response.

• Lossius, Peter Andreas Vold; Tomescu-Baciu, Alina; Holmøy, Trygve; Vedeler, Christian A.; Røsjø, Egil Rørvik & Lorentzen, Åslaug Rudjord [Show all 8 contributors for this article] (2017). Selective intrathecal enrichment of G1m1-positive B cells in multiple sclerosis. Annals of clinical and translational neurology. 4(10), p. 756–761. doi: 10.1002/acn3.451. Full text in Research Archive Show summary

  Immunoglobulin gamma (IgG) heavy chain genes are associated with susceptibility to multiple sclerosis (MS) and IgG levels in the cerebrospinal fluid (CSF). However, how these variants are implicated in disease mechanisms remains unknown. Here, we show that proliferating plasmablasts expressing the G1m1 allotype of IgG1 are selectively enriched in CSF of G1m1/G1m3 heterozygous MS patients, whereas plasmablasts expressing either G1m1 or G1m3 are evenly distributed in blood. Moreover, there was a preferential intrathecal synthesis of oligoclonal IgG1 of the G1m1 allotype in heterozygous patients, whereas controls with Lyme neuroborreliosis displayed oligoclonal IgG1 of both allotypes. This points to a disease‐specific mechanism involved in B‐cell establishment within the central nervous system in MS.

• Lossius, Peter Andreas Vold; Johansen, Jorunn; Vartdal, Frode & Holmøy, Trygve (2016). High-throughput sequencing of immune repertoires in multiple sclerosis. Annals of clinical and translational neurology. 3(4), p. 295–306. doi: 10.1002/acn3.295. Full text in Research Archive Show summary

  T cells and B cells are crucial in the initiation and maintenance of multiple sclerosis (MS), and the activation of these cells is believed to be mediated through specific recognition of antigens by the T- and B-cell receptors. The antigen receptors are highly polymorphic due to recombination (T- and B-cell receptors) and mutation (B-cell receptors) of the encoding genes, which can therefore be used as fingerprints to track individual T- and B-cell clones. Such studies can shed light on mechanisms driving the immune responses and provide new insights into the pathogenesis. Here, we summarize studies that have explored the T- and B-cell receptor repertoires using earlier methodological approaches, and we focus on how high-throughput sequencing has provided new knowledge by surveying the immune repertoires in MS in even greater detail and with unprecedented depth.

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• Vartdal, Frode (2018). Gratulerer med studievalget! 138(12). Full text in Research Archive
• Gornitzka, Mari Bergstøl; Lossius, Andreas; Røsjø, Egil Rørvik & Vartdal, Frode (2026). Resolving the Immunoglobulin Heavy Chain Locus Methodological advances, genetic diversity, and constant region bias in multiple sclerosis. Universitetet i Oslo. ISSN 9788234808791. Full text in Research Archive Show summary

  Antibodies and B-cell receptors are central components of the human adaptive immune system. These molecules, collectively termed immunoglobulins, can bind a wide range of pathogens with remarkable specificity. This breadth of recognition is achieved through somatic recombination and hypermutation of the loci that encode immunoglobulins. The immunoglobulin heavy chain (IGH) locus encodes the largest subunit of this molecule, which forms the central scaffold, contributes to antigen binding, and mediates effector functions. The IGH locus is genetically complex due to extensive repetitive sequences, segmental duplications, and structural variation, which has limited comprehensive characterization; to date, the locus has been fully resolved only twice. The IGH locus displays considerable genetic variation between individuals, yet much of this diversity is still unmapped. Because germline IGH variation shapes the expressed antibody repertoire and influences immune responses to infection and vaccination, gaps in our understanding of IGH diversity impede efforts to study these germline effects. Closing this gap is therefore essential for advancing immunogenetics. A novel method for characterizing the IGH locus is presented in this thesis. We demonstrate that this method generates single-contig complete haplotypes with very few errors and employ it to 16 donors, completely resolving 31 new IGH haplotypes. Across these assemblies, we identify novel alleles, copy number variations and structural variants, which are likely to have biologically meaningful effects. The motivation for IGH locus characterization was to investigate haplotypes carrying different IGH constant gene polymorphisms. In particular, the G1m1 allotype of IgG1, which has a heavily biased expression pattern in multiple sclerosis. Using our method on a cohort of Norwegian patients, we mapped the genetic architecture of their IGH to reveal differences between G1m1 and non-G1m1-containing haplotypes. In the second part of this thesis, the emphasis turns from IGH germline genetics to expression of IGH transcripts. Immunoglobulin repertoires are frequently analyzed in the context of vaccination, infection, and autoimmunity, where selective usage of specific variable genes can shape functional outcomes. However, analyses of IGH constant-gene usage typically stop at the isotype level, overlooking the potential relevance of allelic variation in constant regions. To address this gap, we developed a tool for reconstructing and analyzing immunoglobulin sequences from single-cell RNA-seq data. This enables robust recovery of full-length paired heavy and light chains, even from cells with low transcript abundance. Overall, this thesis broadens our understanding of IGH genetic diversity and introduces two methodological approaches that make it possible to study immunogenetic variation with far greater resolution. These tools lay the groundwork for future efforts to link germline architecture with the behavior of expressed antibody repertoires.

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