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Development and function of conventional and non-conventional lymphocytes
No full textThe three types of antigen receptors – B cell receptor (BCR), αβT cell receptor (TCR), and γδTCR – characterize the corresponding lymphocyte populations that form the adaptive immune system in jawed vertebrates. The random generation of antigen receptors inevitably results in the production of self-reactive receptors by a fraction of developing lymphocytes. Such cells have to be functionally or physically inactivated at the site of lymphocyte development (central tolerance) or in the secondary lymphoid organs (peripheral tolerance). In the case of T cell development in the thymus, some of autoreactive thymocytes are eliminated by negative selection, while others undergo agonist selection to innate-like lineages. This process is driven by the recognition of self-antigens and leads to the differentiation into specialized effector subsets, for example, invariant natural killer T (iNKT) cells, mucosal associated invariant T (MAIT) cells, intestinal intraepithelial lymphocytes (iIELs), as well as several γδT cell subsets1.Interestingly, recent studies demonstrated that many innate-like T cells, including both γδ and αβT cells, are thymus-resident2,3. The reason for the accumulation of effector T cells at the site of T cell development, where pathogen encounter is unlikely, remains enigmatic. These cells express a broad range of effector molecules that form a unique class of self-antigens, which are induced during infection alongside foreign antigens. How the immune system differentiates these self-antigens from molecules derived from pathogens remains poorly understood.All three classes of adaptive lymphocytes contain innate-like populations4,5, but γδT cells are particularly enriched for these cells6. Yet, while ligands for antigen receptors of both innate-like and conventional B cells and αβT cells are well characterized, the principles of antigen recognition by γδT cells, the nature of these antigens, and therefore the functions of γδT cells, remain largely elusive7,8.In this thesis, we first dissected the role of thymus-resident innate-like T cells in the induction of tolerance to inflammation-associated autoantigens. We found that minute number of these cells mediated efficient tolerance of CD8T cells to model inflammation-associated autoantigens. Furthermore, we found that expression of an endogenous T cell effector molecule, interferon γ (IFNγ), solely by hematopoietic cells (mainly T/NK/ILCs) was sufficient to mediate efficient tolerance of CD8+ T cells to this cytokine (Paper I).Secondly, we developed a pipeline for the assessment of the γδTCR specificities, demonstrated that a large fraction of γδT cells recognizes a diverse spectrum of unidentified molecules that do not belong to known classes of γδTCR ligands and identified one such novel ligand – interleukin IL17 receptor A (IL17RA). Further analysis suggested that IL17RA interacts with Vδ7-containing γδTCRs in a superantigen-like manner and is required for the functional maturation of a major subset of Vδ7 γδT cells (Paper II).Thirdly, in addition to these studies on the cell fate decisions involving innate-like T cells, we also investigated lineage choices made by conventional lymphocytes and elucidated how antigen availability influences the fate of activated B cells during the early immune response (Paper III).List of scientific papersI. Yuanyuan You*, Josefine Dunst*, Kewei Ye, Patrick A. Sandoz, Annika Reinhardt, Inga Sandrock, Natalia R. Comet, Rupak Dey Sarkar, Emily Yang, Estelle Duprez, Judith Agudo, Brian D. Brown, Paul J. Utz, Wolfgang Kastenmüller, Carmen Gerlach, Immo Prinz, Björn Önfelt & Taras Kreslavsky. Direct presentation of inflammation-associated self-antigens by thymic innate-like T cells induces elimination of autoreactive CD8+ thymocytes. Nature Immunology. 2024 Aug;25(8):1367-1382. https://doi.org/10.1038/s41590-024-01899-6II. Kewei Ye, Josefine Dunst, Stefanie Köhler, Anatoly Dubnovitsky, Yuanyuan You, Anja Kramer, Tommy Regen, Ari Waisman, Vivianne Malmström, Jan Kisielow, Thomas Winkler, Thomas Krey, and Taras Kreslavsky. Superantigen-like activation of V87 TCRs by the IL17 receptor A chain drives the differentiation of TH1-like y&T cells. [Manuscript]III. Vassilis Glaros*, René Rauschmeier*, Artem V Artemov*, Annika Reinhardt*, Sebastian Ols*, Aikaterini Emmanouilidi, Charlotte Gustafsson, Yuanyuan You, Claudio Mirabello, Asa K Björklund, Laurent Perez, Neil P King, Robert Månsson, Davide Angeletti, Karin Loré, Igor Adameyko, Meinrad Busslinger, Taras Kreslavsky. Limited access to antigen drives generation of early B cell memory while restraining the plasmablast response. Immunity. 2021 Sep 14;54(9):2005-2023.e10. https://doi.org/10.1016/j.immuni.2021.08.017* Equal contribution</p
Parental migration and risks of intellectual disability and autism
No full textBackground: Intellectual disability and autism are overlapping heterogeneous neurodevelopmental conditions with early onset. The prevalence of diagnosed autism has increased in recent decades. In addition, children with migrant parents have been shown to have a higher prevalence of autism with intellectual disability. However, there is limited evidence on time trends in the prevalence of intellectual disability and the association between parental migration and intellectual disability. The primary aim of this thesis was to describe the time trends and risks of intellectual disability, with and without autism, overall and in relation to parental migration.Methods: In study IV, we described the time trends in the prevalence of intellectual disability diagnosed by age 10, using a cohort that included 1,096,800 children born in Sweden from 2001 to 2011. The other three studies focused on intellectual disability, with and without autism. In study I, a systematic review, and study II, a cohort study including 670,098 children aged 0 to 17 who resided in Stockholm at any time from 2001 to 2011, we described the risks in relation to parental migration status and migration-related factors. Study III explored age at first recorded diagnosis by parental migration status, using a cohort including 1,769,499 children born in Sweden from 2001 to 2017.Results: The prevalence of mild, moderate, and other/unspecific intellectual disability diagnoses at age 10 increased in Sweden between 2011 and 2021, particularly in the later years, regardless of co-occurring autism. This trend remained unchanged after adjustment or stratification by birth weight, gestational age, or parental age, migration status, and education.Children with two migrant parents had higher risks of intellectual disability, both with and without autism, compared with children with two Swedish-born parents. The association was more pronounced if the parents had migrated from low- and middle-income countries and for reasons other than work or study. Additionally, among children with two migrant parents, being born either before or more than four years after maternal migration was associated with a lower risk of intellectual disability with autism, but not intellectual disability without autism. Furthermore, these children, particularly those with parents from low-income countries, were diagnosed with mild intellectual disability at younger ages compared with those with at least one Swedish-born parent, regardless of co- occurring autism.Conclusions: The recorded prevalence of mild and moderate intellectual disability has increased during the last decade in Sweden. This increase does not appear to be explained by concurrent changes in the distribution of sociodemographic or perinatal factors over time, such as an increase in the number of children born preterm, with low birth weight, to migrant parents, or to older mothers, nor by shifts in the levels of parental education. Instead, this increase may reflect changes in diagnostic practices over time.Children with migrant parents are more frequently diagnosed with intellectual disability, with and without autism, compared with their peers with Swedish-born parents. Our findings further indicate that the underlying factors linking parental migration to the risk of intellectual disability may vary depending on the co- occurrence of autism and the severity of the condition, at least in part. For intellectual disability overall, factors related to parental origin in low- and middle-income countries appear to play a role. In cases of intellectual disability with autism, environmental factors acting during pregnancy and associated with adverse migration-related circumstances may contribute. For mild intellectual disability, disparities in diagnostic practices between children with migrant parents from low-income countries and those with native-born parents may account for part of the observed associations.List of scientific papersI. Morinaga M, Rai D, Hollander AC, Petros N, Dalman C, Magnusson C. Migration or ethnic minority status and risk of autism spectrum disorders and intellectual disability: systematic review. Eur J Public Health. 2021;31(2):304-12. https://doi.org/10.1093/eurpub/ckaa108II. Morinaga M, Hollander AC, Heuvelman H, Lundberg M, Dalman C, Rai D, Magnusson C. Migration and risk of intellectual disability with and without autism: A population-based cohort study. Acta Psychiatr Scand. 2021;144(5):487-500. https://doi.org/10.1111/acps.13350III. Morinaga M, Magnusson C, Hollander AC, Ahlqvist VH, Lundberg M. Age at diagnosis of autism and intellectual disability in children with migrant parents: a nationwide population-based study. [Manuscript]IV. Morinaga M, Ahlqvist VH, Lundberg M, Hollander AC, Rai D, Magnusson C. Changes in the prevalence of intellectual disability among 10-year-old children in Sweden during 2011 through 2021: a total population study. J Neurodev Disord. 2024;16(1):58. https://doi.org/10.1186/s11689-024-09576-3</p
Hematopoietic stem and progenitor cell fate decisions during fetal development
No full textRare multipotent hematopoietic stem cells (HSCs) are responsible for the replenishment of blood cells throughout life. In the maturation process, from primitive HSCs to peripheral blood cells, the intermediate cells pass through multiple steps of increasingly lineage-restricted progenitors and cell fate decisions are made at each step. However, fetal hematopoiesis is more complex and less studied than adult hematopoiesis. The aim of this thesis was to further characterize and compare fetal, neonatal and adult mouse hematopoiesis including lineage-biased HSCs.Single HSC transplantation studies have previously demonstrated that adult mouse HSCs are heterogeneous in their ability to replenish different blood cell lineages upon transplantation. It remains unclear to what degree the adult patterns of lineage-bias and restriction exist during fetal development.In Study I, we investigated the potential lineage-bias of mouse HSCs from liver and bone marrow at the time of birth. Perinatal HSCs demonstrated less platelet (P)- and platelet-erythroid-myeloid (PEM)-bias/restriction and more consistent lymphoid reconstitution than adult HSCs. However, the development of P- and PEM-bias/restriction had already begun in perinatal HSCs in a distinct HSC subset expressing von Willebrand factor (Vwf-reporter+ HSCs). We compared the transcriptional landscapes of Vwf-reporter+ and Vwf-reporter liver perinatal HSCs through single-cell RNA sequencing and identified transcriptional lineage priming corresponding to their lineage bias upon transplantation. The study provides new insights into the blood reconstitution potential of HSCs at birth.Platelets are critical for hemostasis and play a role in both the innate and adaptive immune systems. Previous studies have implied the presence of an alternative, faster differentiation pathway for platelet production, however it has not been convincingly shown that such an alternative pathway can originate from true HSCs.In Study II, we demonstrated a non-hierarchical relationship between two different stem cell types in adult mouse bone marrow, Vwf-reporter multi-HSCs reconstituting all blood cell lineages and Vwf-reporter+ P-HSCs primarily reconstituting platelets. Single-cell RNA sequencing confirmed that platelet- restricted progenitors originating from Vwf-reporter+ P-HSCs are molecularly different from Vwf-reporter- multi-HSCs. Vwf-reporter- multi-HSCs use a slower multipotent differentiation pathway, whereas Vwf-reporter+ P-HSCs use an alternative and faster platelet-restricted pathway. After hematopoietic challenges by chemotherapy, the faster platelet-restricted pathway was activated for platelet replenishment. These discoveries could be of importance for the development of new treatments aimed at stimulating platelet recovery in clinical settings.B-cell development has been most extensively studied in mice, where the timing and anatomical location of the first embryonic hematopoietic cells with B- lymphocyte potential have been established. However, these cells represent multipotent stem or progenitor cells. In contrast, the timing, location, and properties of the first fetal B-cell restricted progenitors have yet to be determined.In Study III, we demonstrated that expression of Mb1 describes an earlier fetal stage of CD19- B-cell restricted progenitors than previously reported. These progenitors emerge at embryonic day 12.5 in the fetal liver and are molecularly distinct from subsequent stages of fetal B progenitor cells. Mini-bulk RNA sequencing revealed that the previously defined fetal liver and adult bone marrow PreProB cells can be subdivided by Mb1 expression. Progenitors expressing Mb1 have activated a transcriptional program compatible with B-cell specification which is not initiated in PreProB cells lacking Mb1 expression. These findings are relevant for understanding potential cellular targets and leukemia-initiating cells in the development of infant and childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL).List of scientific papersI. Platelet and myeloid lineage biases of transplanted single perinatal mouse hematopoietic stem cells. Karin Belander Strålin*, Joana Carrelha*, Axel Winroth, Christoph Ziegenhain, Michael Hagemann-Jensen, Laura M. Kettyle, Amy Hillen, Kari Högstrand, Ellen Markljung, Francesca Grasso, Masafumi Seki, Stefania Mazzi, Yiran Meng, Bishan Wu, Edwin Chari, Madeleine Lehander, Rickard Sandberg, Petter S. Woll, Sten Eirik W. Jacobsen. Cell Research 2023;33(11):883-886. https://doi.org/10.1038/s41422-023-00866-4II. Alternative platelet differentiation pathways initiated by nonhierarchically related hematopoietic stem cells. Joana Carrelha*, Stefania Mazzi*, Axel Winroth*, Michael Hagemann-Jensen, Christoph Ziegenhain, Kari Högstrand, Masafumi Seki, Margs S. Brennan, Madeleine Lehander, Bishan Wu, Yiran Meng, Ellen Markljung, Ruggiero Norfo, Hisashi Ishida, Karin Belander Strålin, Francesca Grasso, Christina Simoglou Karali, Affaf Aliouat, Amy Hillen, Edwin Chari, Kimberly Siletti, Supat Thongjuea, Adam J. Mead, Sten Linnarsson, Claus Nerlov, Rickard Sandberg, Tetsuichi Yoshizato, Petter S. Woll, Sten Eirik W. Jacobsen. Nature Immunology 2024;25(6):1007-1019. https://doi.org/10.1038/s41590-024-01845-6III. Identification of a B-cell restricted progenitor emerging early in fetal development. Karin Belander Strålin*, Masafumi Seki*, Joanna C. A. Green, Stephen Loughran, Kari Högstrand, Ellen Markljung, Axel Winroth Amy Hillen, Edwin Chari, Charlotta Boiers, Emanuele Azzoni, Joana Carrelha, Tetsuichi Yoshizato, Petter S. Woll, Sten Eirik W. Jacobsen. [Submitted]*Equal contribution</p
Neurodegenerative biomarkers outperform neuroinflammatory biomarkers in amyotrophic lateral sclerosis.
No full textOBJECTIVE: To describe the diagnostic and prognostic performance, and longitudinal trajectories, of potential biomarkers of neuroaxonal degeneration and neuroinflammation in amyotrophic lateral sclerosis (ALS). METHODS: This case-control study included 192 incident ALS patients, 42 ALS mimics, 114 neurological controls, and 117 healthy controls from Stockholm, Sweden. Forty-four ALS patients provided repeated measurements. We assessed biomarkers of (1)neuroaxonal degeneration: neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in cerebrospinal fluid (CSF) and NfL in serum, and (2)neuroinflammation: chitotriosidase-1 (CHIT1) and monocyte chemoattractant protein 1 (MCP-1) in CSF. To evaluate diagnostic performance, we calculated the area under the curve (AUC). To estimate prognostic performance, we applied quantile regression and Cox regression. We used linear regression models with robust standard errors to assess temporal changes over time. RESULTS: Neurofilaments performed better at differentiating ALS patients from mimics (AUC: pNfH 0.92, CSF NfL 0.86, serum NfL 0.91) than neuroinflammatory biomarkers (AUC: CHIT1 0.71, MCP-1 0.56). Combining biomarkers did not improve diagnostic performance. Similarly, neurofilaments performed better than neuroinflammatory biomarkers at predicting functional decline and survival. The stratified analysis revealed differences according to the site of onset: in bulbar patients, neurofilaments and CHIT1 performed worse at predicting survival and correlations were lower between biomarkers. Finally, in bulbar patients, neurofilaments and CHIT1 increased longitudinally but were stable in spinal patients. CONCLUSIONS: Biomarkers of neuroaxonal degeneration displayed better diagnostic and prognostic value compared with neuroinflammatory biomarkers. However, in contrast to spinal patients, in bulbar patients neurofilaments and CHIT1 performed worse at predicting survival and seemed to increase over time
Alterations of the immune response to influenza virus by immunotherapy and infection
No full textRespiratory tract infections and parasite infections are common and have a significant impact on global health and economy. Influenza virus is one of the most common causes of upper respiratory tract infection, infecting up to one billion people each year. Due to constant mutations in antigenic surface proteins, long- lasting protective immunity against subsequent infections is hard to achieve by natural infection and/or vaccination. Vaccines against seasonal influenza viruses are available but waning protection remains a challenge. Thus, other strategies to increase protection against influenza virus disease are needed. In addition, mammalian and avian influenza viruses can exchange genetic material within a host leading to generation of a new virus with potential to cause a pandemic. Twenty percent of the global population are infected with soil-transmitted helminths. The highest prevalences overlaps with the geographical areas where mortality due to respiratory tract infections, including influenza virus, is the highest. Experimentally it has been demonstrated that helminth infections can reduce the host immune response to vaccination and may ameliorate or aggravate disease induced by another pathogen. To date, little is known about the effects of a helminth infection on pre-existing immunity.The aim of this PhD project was to investigate how the development and maintenance of influenza virus immunity was affected by prophylactic immunotherapy with avian antibodies against influenza virus or intestinal helminth infection with Heligmosomoides polygyrus.To this end, mouse models were used to study the adaptive immune response against influenza virus. In Paper I, mice were infected with influenza virus and at different timepoints the mice were euthanised for analysis of the adaptive immune response in mediastinal lymph nodes (MLN), lungs, spleens, inguinal lymph nodes (ILN), and mesenteric lymph nodes (MesLN). In Paper II, mice were treated intranasally with influenza virus-specific IgY (IgY anti-H5N1) prior to and after influenza virus infection. Influenza virus-specific T cells were quantified in MLN, lungs, and spleens. To investigate the quality of the immunological memory, the mice received a second infection with homologous or heterologous influenza virus. In Paper III, the mice were infected with the intestinal nematode Heligmosomoides polygyrus (H. polygyrus) three weeks after influenza virus infection. At the end of the experiment, influenza virus-specific T cells were quantified by flow cytometry. In addition, gene expression and TCR repertoire analysis were performed on influenza virus-specific CD8+ T cells after trickle infection with H. polygyrus.In Paper I, the kinetics of the T cell response to influenza virus in mice, including CD4+ Trm and three subsets of CD8+ Trm were determined. The adaptive immune response was analysed in lungs and respiratory tract-draining MLN, as well as in spleen, ILN, and MesLN. Using CD69 as a marker of activation we observed a biphasic activation curve with local peaks at days three and 8 - 12 post infection among CD4+ T cells in all organs studied. CD8+ T cells in lungs and ILN displayed the same pattern whereas only a peak at three days post infection was observed in MLN, spleen, and MesLN. We hypothesized that the second peak observed in lungs was due to expansion of lung-resident T cells (Trm). During active infection and early after viral clearance, CD103-CD49a+ CD8+ Trm was the dominant Trm subset whereas CD103-CD49+ CD8+ Trm was the most abundant subset during the memory phase. To summarise, even though influenza virus is restricted to the respiratory tract, the infection elicits a systemic T cell response, albeit more pronounced in respiratory tract-associated tissues with local expansion of different Trm subsets at distinct stages after infection.In Paper II the impact on development of host immunity induced by influenza virus infection after passive immunization with influenza virus-specific avian IgY was investigated. The results demonstrated that protective homologous and heterologous immunity developed in influenza virus-infected mice receiving prophylactic IgY anti-H5N1. First, it was confirmed that prophylactic administration of influenza virus-specific IgY resulted in protection against disease symptoms and severe pneumonia after infection with influenza virus. Despite having a lower magnitude of the influenza virus-specific T cell response during acute infection, there was no significant difference after clearance of infection. Upon reinfection at 35 days post infection, mice previously treated with IgY anti-H5N1 were equally protected as mice not treated with IgY anti-H5N1 during primary infection. Nevertheless, challenge infection with heterologous influenza virus at 35 days post infection or homologous virus at three months post infection resulted in a minor and transient weight loss in the mice treated with IgY anti-H5N1. In addition, we demonstrated that repeated administration of IgY anti- H5N1 could prolong the survival in immunodeficient CB-17 SCID mice after influenza virus infection, indicating that passive immunization can be used to protect individuals with a severely impaired immune system. Taken together, prophylactic antibody therapy protects against disease while allowing for development of protective immunity against severe disease and death after re- exposure to homologous or heterologous influenza virus.The effects of infection with H. polygyrus on pre-existing cellular immunity against influenza virus was investigated in Paper III. It was found that mice infected with influenza virus and then with H. polygyrus ("co-infected") had a reduction in influenza virus-specific T cells at seven weeks post infection. Nevertheless, after exposure to a second infection with homologous influenza virus two months post primary infection, co-infected mice had the same level of protective immunity as mice previously infected with influenza virus only. In contrast, when challenged at four months post primary infection, co-infected mice presented with a transient, minor weight loss indicating a reduction in potency of immunity.To potentiate the effects worms and drive a strong immune response against another infection, repeated H. polygyrus infections were given. After trickle infection with H. polygyrus, genes associated with protein folding and immune function were differentially expressed in total and virus-specific CD8+ T cells of co-infected mice and mice infected with influenza virus only. Nevertheless, infection with H. polygyrus did not significantly affect the TCR repertoire of influenza virus-specific CD8+ T cells. The findings indicate that H. polygyrus causes a reduction and transcriptional changes in antigen-specific CD8+ T cells, which in turn may accelerate waning of the immunological memory against influenza virus.To summarize, influenza virus elicits a robust local immune response but also activates B cells and T cells in secondary lymphoid organs distant the site of infection. After resolution of infection, humoral and cellular immunity including CD103+CD49a+ CD8+ Trm is developed that confers protection against homologous and heterologous influenza viruses. Both prophylactic antibody therapy and intestinal helminth infections can modulate cellular immunity against influenza virus which manifests as waning immunity, which still protected the mice against severe disease. Nevertheless, treatment with IgY anti-H5N1 protected against influenza virus disease, reduced pulmonary inflammation, and allowed for generation of protective immunity. This makes prophylactic antibody therapy a suitable option and/or complement to influenza virus vaccination. In contrast, infection with H. polygyrus reduces the numbers of pre-existing antigen-specific T cells and can induce transcriptional alterations in influenza virus-specific CD8+ T cells. This can be taken into consideration when planning vaccination schedules in areas with high burden of helminth infections.List of scientific papersI. T cell kinetics reveal expansion of distinct lung T cell subsets in acute versus in resolved influenza virus infection. Eriksson, M., Nylén, S., Grönvik, K-O. Frontiers in Immunology. (2022) 13: 949299. https://doi.org/10.3389/fimmu.2022.949299II. Passive immunization of mice with IgY anti-H5N1 protects against experimental influenza virus infection and allows development of protective immunity. Eriksson, M., Nylén, S., Grönvik, K-O. Vaccine. (2024), 42, 25: 126133. https://doi.org/10.1016/j.vaccine.2024.07.034III. Impact of Heligmosomoides polygyrus on influenza virus- specific T cell immunity in mice Eriksson, M., Grönvik, K-O., Åbrink, M., Nylén, S. [Manuscript]</p
Neurocognitive deficits in substance use disorder and comorbid ADHD : predictors of pharmacological treatment response
No full textBackground: Attention deficit/hyperactivity disorder (ADHD) is common in patients with substance use disorder (SUD). Comorbid SUD+ADHD is associated with a range of severe complications, compared to having only one of these disorders. While it is well established that numerous neurocognitive impairments are associated with both amphetamine use disorder (ampUD) and ADHD individually, it is unknown how these impairments manifest in comorbid ampUD+ADHD. This is important since it may have clinical implications and provide insights into the mechanisms underpinning the observed challenges in treating this patient population.SUD+ADHD treatment guidelines recommend targeting both disorders. However, utilizing stimulant treatment, the first-choice pharmacotherapy for ADHD, in comorbid patients is not without controversy. Clinicians may be reluctant to prescribe stimulants due to concerns regarding diversion and misuse, which likely leads to practice variation.Stimulant treatment in patients with illicit stimulant use disorder (stimUD) and comorbid ADHD using robust doses is associated with a reduction in both substance use and ADHD symptoms. However, the effect of these higher than standard doses on objective measures of neurocognitive functions have not been investigated.Lastly, prospective real-world data on the clinical course of treatment seeking patients with SUD+ADHD is lacking, especially, regarding which factors contribute to treatment allocation and successful treatment outcomes.Aims:I: To explore the effect of robust doses of extended-release methylphenidate (MPH) on neurocognitive functioning in patients with amp-UD+ADHD.II: To investigate how different facets of impulsive behavior are expressed in patients with ampUD+ADHD.III: To describe treatments provided for comorbid SUD+ADHD in everyday clinical settings, and to explore factors that influence treatment allocation.IV: To investigate factors that contribute to successful ADHD and SUD treatment outcomes in a real-world clinical setting.Methods:Study I: Adult patients with comorbid ampUD+ADHD received single blinded doses of osmotic-controlled release oral delivery system (OROS) methylphenidate (MPH) with a target dose of 180 mg. Additionally, two other groups (ADHD only and healthy controls (HC)) were recruited. For the ADHD only group the target dose was 72 mg OROS-MPH and HCs did not receive any study medication. Participants were assessed repeatedly with a neurocognitive test battery.Study II: A cross-sectional study design was employed. Three groups (ampUD+ADHD, ADHD only and HC) were assessed on task-related impulsive choice and self-rated impulsive behavior.Study III and IV: An observational international prospective cohort design was employed. Treatment seeking patients with comorbid SUD+ADHD were recruited in nine countries at ten study sites. Data was collected through patient files, interviews with clinicians and patients at baseline, three months and nine months, respectively. Additionally, data from patient files on treatment allocation was collected at 4 weeks. Clinical and sociodemographic data was collected along with self-rating scales and structured interviews regarding substance use.ResultsStudy I: A total of nineteen participants in the ampUD+DHD group were included, out of which eleven completed the study and reached the target dose of 180 mg OROS-MPH. In the ADHD only group, sixteen participants were included and fifteen reached the target dose of 72 mg OROS-MPH and twenty-one HCs completed the study. On the third assessment (corresponding to a target dose of 180mg OROS-MPH), the ampUD+ADHD group presented with a significant improvement in response inhibition, working memory, sustained attention, self-rated ADHD symptoms and reduced craving, compared to baseline. The ampUD+ADHD group presented with more pronounced impairments in response inhibition, working memory and more self-rated ADHD symptoms, compared to ADHD only.Study II: Twenty-nine participants with ampUD+ADHD, 25 participants with ADHD only and 116 HC completed screening, including self-rating scales. Twenty, 16 and 114 participants completed computerized cognitive tasks in the ampUD+ADHD group, ADHD group and HC group, respectively. ampUD+ADHD reported significantly higher motor, attentional and non-planning impulsiveness, and presented with a significantly higher degree of impulsive choice, compared to both groups. There were no differences in task-related impulsiveness between ADHD only and HC.Study III: Five-hundred-seventy-eight treatment-seeking patients with SUD+ADHD were recruited. About two thirds received treatment for ADHD (62.8%), with 54.0% receiving pharmacological treatment, 34.0% receiving psychological treatment, and 25.1% receiving combined pharmacological and psychological treatment. Treatment strategies differed substantially across treatment sites. In addition, higher ADHD symptom severity and sobriety at intake were associated with receiving treatment for ADHD.Study IV: Stimulant treatment was significantly associated with better SUD treatment retention (OR: 2.4, 95% CI: 1.36-4.23), ≥30% reduction in ASRS total score (OR: 2.6, 95% CI: 1.22-6.12), and fewer heavy drinking days (IRR: 0.24, 95% CI: 0.13-0.42) at three months. Psychological ADHD treatment was significantly associated with fewer heavy drinking days at three months (IRR: 0.27, 95% CI: 0.14-0.51). Pharmacological treatments for SUD were not associated with treatment retention, ADHD nor SUD outcomes.Conclusions:I: Patients with ampUD+ADHD present with more severe neurocognitive deficits compared to patients with ADHD only. The effect of 180 mg OROS-MPH on cognition in patients with ADHD+AMPH was inconclusive. Future studies should consider recruitment issues and high drop-out rates in this study population.II: Patients with ampUD+ADHD have overall elevated levels of impulsivity compared to individuals with ADHD only. In addition, ampUD+ADHD is specifically associated with impairments in task-related impulsive choice, which was not found in ADHD only compared to HC. The neurocognitive profile in this specific patient group may represent a need for more systematic screening within healthcare settings to develop effective and targeted treatment for comorbid patients.III: SUD+ADHD treatment is suboptimal even in specialized health care centers and with substantial variation in clinical praxis. Further research is needed to better understand the barriers to implement treatment guidelines for ADHD+SUD.IV: The results from study IV suggests that ADHD treatment is associated with better SUD treatment retention, clinically relevant reductions in self-reported ADHD symptoms and significantly fewer heavy drinking days in patients with SUD+ADHD. This highlights the importance of providing ADHD treatment in this population. Future RCT's are warranted, especially on the effect of ADHD treatment in patients with alcohol use disorder (AUD)+ADHD. Such studies should preferably investigate combinations of ADHD treatments and SUD treatments using different doses of stimulants.List of scientific papersI. Brynte C, Konstenius M, Khemiri L, Bäcker A, Guterstam J, Levin FR, Jayaram-Lindström N, Franck J. The Effect of Methylphenidate on Cognition in Patients with Comorbid Attention Deficit/Hyperactivity Disorder and Amphetamine Use Disorder: An Exploratory Single-Blinded within-Subject Study. Eur Addict Res. 2024;30(1):1-13. Epub 2023 Nov 29. PMID: 38029734. https://doi.org/10.1159/000535016II. Brynte C, Khemiri L, Stenström H, Konstenius M, Lindström NJ, Franck J. Impulsive choice in individuals with comorbid amphetamine use disorder and attention deficit-hyperactivity disorder. BMC Psychiatry. 2023 Jul 24;23(1):537. PMID: 37488536; PMCID: PMC10367266. https://doi.org/10.1186/s12888-023-05034-xIII. Brynte C, Schellekens A, Csaba B, Begeman AHB, Crunelle CL, Daigre C, Demetrovics Z, Dom G, Grau-López L, Hernandez M, Icick R, Johnson B, Kapitány-Fövény M, van Kernebeek M, Konstenius M, Levin FR, Luderer M, Matthys F, Moggi F, Ramos-Quiroga JA, Schleussner L, Therribout N, Thomas A, Vorspan F, van den Brink W, Franck J. Treatments and treatment predictors in patients with substance use disorders (SUD) and comorbid attention deficit hyperactivity disorder (ADHD): First results from the International Naturalistic Cohort Study of ADHD and SUD (INCAS). [Manuscript]IV. Brynte C, Schellekens A, Csaba B, Begeman AHB, Crunelle CL, Daigre C, Demetrovics Z, Dom G, Grau-López L, Hernandez M, Icick R, Johnson B, Kapitány-Fövény M, van Kernebeek M, Konstenius M, Levin FR, Luderer M, Matthys F, Moggi F, Ramos-Quiroga JA, Schleussner L, Therribout N, Thomas A, Vorspan F, van den Brink W, Franck J. Predictors of treatment success in patients with substance use disorder (SUD) and co- morbid attention deficit/hyperactivity disorder (ADHD): Results from the International Naturalistic Cohort Study of ADHD and SUD (INCAS). [Manuscript]</p
Computerized, patient-entered medical histories to improve the management of patients with acute chest pain
No full textIntroduction: Chest pain is a common complaint in emergency departments (EDs), with causes ranging from benign to life-threatening conditions, such as an acute coronary syndrome (ACS). Self-reported computerized history taking (CHT) may provide automated collection of medical histories for calculating chest pain risk scores recommended for management. The overall aim of this thesis was to investigate the value of CHT in acute chest pain management.Methods: We examined the first 1,000 patients (mean age 55+17 years; 46% women), in the CLEOS-CPDS (Clinical Expert Operating System-Chest Pain Danderyd Study), a prospective cohort study of patients presenting to the ED at Danderyd University Hospital (Stockholm, Sweden) with acute chest pain in 2017-2019. Clinically stable adults (>18 years) with a non-diagnostic ECG and non-diagnostic serum biomarkers self-reported their medical histories using CHT software on a tablet. Studies conducted include: (I) a study protocol, (II) a utility study assessing CHT interview completion and duration, (III) an agreement study comparing CHT and electronic health record (EHR) data, and (IV-V) diagnostic accuracy studies, using CHT-derived risk scores, with and without the use of troponin testing, against 30-day major adverse cardiac event (MACE) and ACS outcomes.Results: Risk scores could be calculated in 74-83% of the participants by CHT and 10-31% by EHR data. The median time to collect the History, ECG, Age, Risk factors, Troponin (HEART) score was 23 (18-31) min. Agreement between CHT and EHR data was slight to moderate (kappa 0.19-0.70) for chest pain characteristics and moderate to almost perfect (kappa 0.55-0.91) for risk factors. A 30-day MACE occurred in 7.2% of participants. Using CHT-derived risk scores, the negative predictive value for a 30-day MACE was 0.98-0.99 (95% CI: 0.97-1.00), and a substantial fraction (up to 21%) of patients admitted with acute chest pain could be reclassified from "not low risk" to "low risk".Conclusions: CHT effectively collects comprehensive medical history data for risk stratification in acute chest pain patients, demonstrating high accuracy in ruling out 30-day MACE. This approach may improve individual patient management and reallocate resources to those in greatest need.List of scientific papersThis thesis is based on the following papers, which will be referenced by their corresponding Roman numerals:I. Brandberg H, Kahan T, Spaak J, Sundberg K, Koch S, Adeli A, Sundberg CJ, Zakim D. A prospective cohort study of self-reported computerised medical history taking for acute chest pain: protocol of the CLEOS-Chest Pain Danderyd Study (CLEOS-CPDS). BMJ Open. 2020 Jan 21;10(1):e031871. https://doi.org/10.1136/bmjopen-2019-031871II. Brandberg H, Sundberg CJ, Spaak J, Koch S, Zakim D, Kahan T. Use of self-reported computerized medical history taking for acute chest pain in the emergency department - the clinical expert operating system chest pain Danderyd study (CLEOS-CPDS): prospective cohort study. J Med Internet Res. 2021;23(4):e25493. https://doi.org/10.2196/25493III. Brandberg H, Sundberg CJ, Spaak J, Koch S, Kahan T. Are medical history data fit for risk stratification of patients with chest pain in emergency care? Comparing data collected from patients using computerized history taking with data documented by physicians in the electronic health record in the CLEOS-CPDS prospective cohort study. J Am Med Inform Assoc. 2024;31(7):1529-1539. https://doi.org/10.1093/jamia/ocae110IV. Brandberg H, Sundberg CJ, Spaak J, Koch S, Kahan T. Computerized self-reported medical history taking improves early rule-out of major adverse cardiac events in acute chest pain patients: the CLEOS-CPDS prospective cohort study. [Submitted]V. Brandberg H, Schierenbeck F, Sundberg CJ, Koch S, Spaak J, Kahan T. Performance of computerized self-reported medical history- taking and HEAR score for safe early rule-out of a major adverse cardiac event in acute chest pain patients: the CLEOS-CPDS prospective cohort study. [Submitted]</p
The role of liver X receptor (LXR) in intestinal inflammation and mucosal healing
No full textTissue repair following inflammatory damage is a critical process, essential for restoring tissue homeostasis. Nowhere is this more crucial than in the intestine, where the gut epithelium endures constant assaults from physical, chemical, and microbial threats. These challenges are ever-present, whether under normal conditions or during severe episodes of chronic intestinal diseases like inflammatory bowel disease (IBD). When an IBD flare-up occurs, the body is thrust into a dual struggle: it must urgently calm the overactive immune response while simultaneously mending the compromised epithelial barrier, a critical step toward achieving true mucosal healing.Current treatments aim to suppress inflammation by blocking inflammatory pathways, which, while necessary to quell the immediate immune response, may also promote the regenerative processes required for healing. Yet, the reality is stark: up to 50% of IBD patients either don't respond to these therapies or suffer relapses after an initial improvement. Despite the clear link between mucosal healing and long-term remission, no therapies currently exist that specifically promote epithelial regeneration to facilitate this healing process.We believe that the signals triggered by inflammation and tissue damage are intricately intertwined with the body's repair mechanisms. Effective communication between various cellular components-including but not limited to epithelial, immune, and stromal cells-is crucial for maintaining a healthy intestinal barrier under normal conditions and restoring it after injury and inflammation. In my thesis, I set out to unravel these complex interactions to deepen our understanding of the cellular and molecular mechanisms that drive intestinal inflammation damage and tissue repair.In Study I, we used spatial transcriptomics to reveal a transcriptomics profile in mouse colon at steady state and during mucosal healing with a previously unachieved spatial resolution. By integrating tissue bulk RNA sequencing and single cell RNA sequencing datasets from mouse and human, we identified distinct molecular regionalization and compartmentalized transcriptional programs with human relevance. This study provides a useful methodology and resource for the followings studies to understand mechanism involved in tissue regeneration.In Study II, B cell expansion was found to be a major event within the immune compartment during the tissue regeneration phase following withdrawal of Dextran Sulfate Sodium (DSS). Depletion of B cells from mice during recovery phase resulted in an improved outcome in experimental colitis. Mechanistic study using tissue and single cell RNA sequencing and immunostaining validation revealed that expanded B cells interfered with the interaction between stromal cells and epithelium by physically reducing their proximity. The findings emphasize the impact of cellular interactions and the local microenvironment on tissue regeneration. They suggest that targeting B cells during the regenerative phase may be a promising approach to improve the management of colitis and related intestinal disorders.In Study III, Liver X receptor (LXR) was identified as a common pathway induced by tissue damage in the intestine. Activation of LXR by feeding a synthetic LXR ligand GW3965 in diet resulted in enhanced crypt cell proliferation in vivo with an improved histological outcome in DSS and irradiation induced damage. Mechanistically, the pro-regenerative effect of LXR is achieved by inducing amphiregulin expression in epithelial cells and regulated by the upstream endogenous ligands producing enzyme Cyp27a1. Surprisingly, the elevated regenerative capacity did not result in increased tumor burden, in contrast, activating LXR modulates the anti-tumor immunity and suppressed tumorigenesis in both AOM-DSS induced and ApcMin/+ tumor models. This study unveiled the bi- directional modulation of LXR in enhancing regeneration while controlling tumorigenesis.In Study IV, we observed that LXR activation dampened tuft cell and Type 2 innate lymphoid cells (ILC2) abundance in the small intestine of wild type C57BL/6 mice during homeostasis. The decreased tuft cell and ILC2 number failed to be rescued by an inducer of tuft cell expansion, i.e. succinate but was rescued by rIL-25 in vitro and in vivo and. This negative regulation resulted in impaired anti-helminth response in the mouse infected by Nippostrongylus brasiliensis and Heligmosomoides polygyrus, as well as impaired mast cell activation, indicating a role of LXR in suppressing type 2 immunity. Similarly, LXR activation in BALB/c mice was found to inhibit mast cells and showed a protective role by preventing weight loss in an OVA-induced food allergy model. This study underscores the function of LXR in controlling innate type 2 immunity during mucosal homeostasis and in limiting type 2 inflammation upon challenges.Collectively, this thesis contributes to spatially resolved transcriptomic profile of murine intestine in naïve and challenged conditions, underscoring the novel finding of LXR modulation in intestinal inflammation and mucosal healing. The findings in thesis further our understanding of restoring balance, enhancing tissue resilience, and paving the way for novel treatments that could transform the management of inflammatory diseases in the intestine, such as IBD.List of scientific papersI. Sara M. Parigi#, Ludvig Larsson#, Srustidhar Das#, Ricardo O. Ramirez Flores, Annika Frede, Kumar P. Tripathi, Oscar E. Diaz, Katja Selin, Rodrigo A. Morales, Xinxin Luo, Gustavo Monasterio, Camilla Engblom, Nicola Gagliani, Julio Saez-Rodriguez, Joakim Lundeberg & Eduardo J. Villablanca*The spatial transcriptomic landscape of the healing mouse intestine following damage Nature Communication. 13, 828 (2022). https://doi.org/10.1038/s41467-022-28497-0II. Annika Frede#, Paulo Czarnewski#, Gustavo Monasterio#, Kumar P Tripathi, David A Bejarano, Ricardo O Ramirez Flores, Chiara Sorini, Ludvig Larsson, Xinxin Luo, Laura Geerlings, Claudio Novella-Rausell, Chiara Zagami, Raoul Kuiper, Rodrigo A Morales, Francisca Castillo, Matthew Hunt, Livia Lacerda Mariano, Yue O O Hu, Camilla Engblom, Ana-Maria Lennon- Duménil, Romy Mittenzwei, Astrid M Westendorf, Nadine Hövelmeyer, Joakim Lundeberg, Julio Saez-Rodriguez, Andreas Schlitzer, Srustidhar Das, Eduardo J Villablanca*B cell expansion hinders the stroma-epithelium regenerative cross talk during mucosal healing Immunity. 2022 Dec 13;55(12):2336-2351.e12. https://doi.org/10.1016/j.immuni.2022.11.002III. Srustidhar Das*#, S. Martina. Parigi#, Xinxin Luo#, Jennifer Fransson, Bianca Carola Kern, Ali Okhovat, Oscar E. Diaz, Chiara Sorini, Paulo Czarnewski, Anna T. Webb, Rodrigo A. Morales, Sacha Lebon, Gustavo Monasterio, Francisca Castillo, Kumar P. Tripathi, Ning He, Penelope Pelczar, Nicola Schaltenberg, Marjorie De la Fuente, Francisco López-Köstner, Susanne Nylén, Hjalte List Larsen, Raoul Kuiper, Per Antonson, Marcela A. Hermoso, Samuel Huber, Moshe Biton, Sandra Scharaw, Jan-Åke Gustafsson, Pekka Katajisto, Eduardo J. Villablanca*Liver X receptor unlinks intestinal regeneration and tumorigenesis. Nature. [Accepted]IV. Xinxin Luo, Qilin Zhu, Jennifer Fransson, Tilde Andersson, Ning He, Marta Campillo Poveda, Claire Ciancia, Ricardo O. Ramírez Flores, Ludvig Larsson, Sara Martina Parigi, Rodrigo A. Morales Castro, Bianca C. Kern, Francisca Castillo, Joakim Lundeberg, Julio Saez-Rodriguez, Srustidhar Das, Rick M. Maizels, Christoph Schneider, and Eduardo J. Villablanca*Liver X Receptor modulates type 2 immune responses in parasitic infection and food allergy. [Manuscript]# Equal contribution* Corresponding author</p
Psychological treatment and facial affect recognition in individuals with psychosis
No full textAlthough Facial affect recognition (FAR), is associated with a lower level of functioning in individuals with Schizophrenia (SZ), it is unclear if the deficit is present in individuals with first episode psychosis (FEP) and if FAR is associated with symptoms of psychosis. Study I was a cross-sectional study, aiming to investigate 1) the presence of FAR in FEP and 2) if FAR was associated with symptoms of psychosis. A total of n=67 participants with FEP and n=51 controls were included. Results showed that participants with FEP had significantly more impaired general (pPsychotherapy is a recommended adjunctive treatment to antipsychotic medication and a psychotherapeutic method, Acceptance and commitment therapy for psychosis (ACTp), has shown promising results, but more research is needed, both in the group- and inpatient setting.Study II was a feasibility pilot randomized controlled trial aiming to develop and evaluate group-ACTp (G-ACTp) for outpatients. Participants attending clinics for individuals with FEP were allocated to G-ACTp (=8) or individual CBTp (n=6). A total of 18 sessions were given in both treatments. Session attendance varied and the patients comprehended G-ACTp well but performed behavior change to a lesser degree. Participants struggled to fill out selfassessment questionnaires and recruitment was challenging. An exploratory analysis compared G-ACTp to CBTp and indicated that participants in CBTp may have performed significantly more homework. There was also an indication that participants in both groups might have significantly decreased their impairment and that the CBTp group also might have improved significantly in valued living. However, the limitations in this study are large and the results can only be seen as a hypothesis that needs to be further investigated in larger future RCTs. To conclude, participants needed support to attend treatment, perform behavior change, and fill out self-assessment forms. Recruitment was challenging and the results from the comparison,s between G-ACTp and CBTp as well as within both treatments should be interpreted with caution because of the small sample size.Study III was a single case study developing and evaluating ACTp in the inpatient setting. A total of n=12 inpatients with symptoms of psychosis were included and given up to 10 daily sessions of ACTp. Daily measures during baseline and treatment, as well as pre-post treatment, were calculated. Recruiting and conducting ACTp in inpatient wards was feasible and the treated individuals found the therapy quite acceptable. Yet, a majority of the participants were unable to complete all ACTp sessions because of discharge. However, depression, health-related quality of life, and anxiety significantly improved in around 6/12 participants. To conclude, it was feasible to give ACTp in the inpatient setting, and participants improved during treatment. However, a shorter treatment manual could have been more feasible in the inpatient setting. Moreover, since no control-group was used it is uncertain if improvements were due to ACTp or standard treatment. Therefore, the results are preliminary and need to be further investigated in future RCTs.To broaden the limited access to psychotherapy, frontline staff treating individuals with psychosis could be trained to give brief psychotherapeutic techniques. However, it is unclear how inpatient staff perceive the training and application of ACTp. Study IV was a qualitative study aiming to explore how frontline inpatient staff experience conversations with psychotic inpatients as well as training and applying the ACTp in these conversations. A total of n=16/31 frontline staff members were interviewed after having received up to 9 hours of training and subsequent supervision in ACTp. The semi-structured interviews (30-50 min) were analyzed according to Thematic analysis. Results showed that participants used several skills to build relationships with patients. Participants also valued the ACTp training and learned new skills. However, they struggled to learn the techniques and perceived a lack of fit between ACTp, the patients, and the inpatient setting. Finally, patient-related factors also affected motivation to train and use ACTp. To conclude, it was feasible to train the inpatient staff. Although there was some benefit of the training, the staff learned only parts of the ACT techniques and found it challenging to use them with inpatients.List of scientific papersI. Larsson, C*., Lee, M*., Lundgren, T., Erhardt, S., Sellgren, C. M., Cervenka, S., Borg, J., Bölte, S., & Fatouros-Bergman, H. (2022). Facial affect recognition in first-episode psychosis is impaired but not associated with psychotic symptoms. Heliyon, 8(9), e10424–e10424. *Authors contributed equallyhttps://doi.org/10.1016/j.heliyon.2022.e10424II. Larsson, C., Parling, T., Sahin, K., Jacobsson, A., Scott, M., Kaldo, V., Lundgren, T., Fatouros-Bergman, H. Feasibility of Group Acceptance and Commitment Therapy for Psychosis -a Pilot Study. [Manuscript]III. Larsson, C., Fatouros-Bergman, H., Isaksson, A., Johansson, M., Kaldo, V., Parling, T., & Lundgren, T. (2022). Acceptance and Commitment Therapy for inpatients with psychosis –an acceptability and feasibility single case AB designed study. Journal of Contextual Behavioral Science, 25, 44–60.https://doi.org/10.1016/j.jcbs.2022.05.008IV. Larsson, C., Parling, T., Reinebo, G., Sjödin, M., Hedström, R., Kaldo, V., Lundgren, T., Fatouros-Bergman, H. Implementing ACTp Techniques for Inpatients with Psychosis -A Qualitative Study of the Experiences of Frontline Staff. [Submitted]</p
Deciphering oligodendrocyte lineage heterogeneity in development and disease
No full textOligodendrocytes are the myelinating glia of the central nervous system (CNS). By forming lipid-rich myelin membranes that spirally enwrap axonal segments, oligodendrocytes ensure rapid saltatory impulse propagation, structural integrity, and metabolic and trophic support to the nerves. Oligodendrocyte lineage (OLG)(1) arises from oligodendrocyte precursor cells (OPCs), which emerge from radial glia during early embryonic development in an intricate, spatiotemporally defined fashion. As highly migratory, OPCs rapidly populate the brain and the spinal cord and begin transitioning to differentiation-committed oligodendrocyte precursors (COPs). Shortly after birth, myelin synthesis occurs with the newly-formed and myelin-forming oligodendrocytes (NFOLs and MFOLs), which finally differentiate into mature oligodendrocytes (MOLs), completing the lineage trajectory. These populations possess unique transcriptional signatures reflecting their lineage differentiation state. Moreover, MOLs, in particular, comprise several transcriptionally distinct cell clusters, the functional significance of which remains unclear.In multiple sclerosis (MS), myelinating oligodendrocytes become the primary targets of chronic CNS inflammation. Consequently, the accumulating myelin damage materializes in the form of multifocal lesions, the pathological hallmarks of MS. In parallel, OLG respond to pathological environments by promoting myelin repair but also by expressing genes involved in complement formation, interferon response, and major histocompatibility complex (MHC) I and II, among others. Thus, their transcriptional heterogeneity(2) expands, and the emergence of the disease-associated (DA) states suggests that OLG might not be just passive targets of the immune system but potentially active players in immunomodulation. Nevertheless, when and where the DA states emerge, how they affect the remyelination, and whether they carry protective or detrimental functions in the context of MS remains to be determined.This thesis aimed to bridge the gap between the transcriptional diversity of OLG and its significance in health and disease. The work can be divided into three central topics: 1) Deciphering OLG heterogeneity in development and health (Papers I-II, i, iii); 2) Adaptations of spatial transcriptomics tools to investigate physiological and pathological phenomena (Papers II-IV, ii-iv); and 3) Elucidating the dynamics and potential roles of OLG heterogeneity in pathologies (Papers I, IV, and v).(1) Oligodendrocyte lineage cells, i.e., oligodendroglia (OLG).(2) The terms heterogeneity and diversity are used interchangeably in this thesis.List of scientific papersI. Distinct oligodendrocyte populations have spatial preference and different responses to spinal cord injury. Elisa M. Floriddia#, T‰nia LourenŤo, Shupei Zhang, David van Bruggen, Markus M. Hilscher, Petra Kukanja, Jo‹o P. GonŤalves dos Santos, Mźge Altőnkšk, Chika Yokota, Enric Llorens-Bobadilla, Sara B. Mulinyawe, M‡rio Gr‹os, Lu O. Sun, Jonas FrisŽn, Mats Nilsson, GonŤalo Castelo-Branco#. Nature Communications. 2020;11(1):5860. #Correspondence. https://doi.org/10.1038/s41467-020-19453-x II. Spatial and temporal heterogeneity in the lineage progression of fine oligodendrocyte subtypes. Markus M. Hilscher#, Christoffer Mattsson Langseth, Petra Kukanja, Chika Yokota, Mats Nilsson* and GonŤalo Castelo-Branco*#. BMC Biology. 2022;20(1):122. *Equal contribution. #Correspondence. https://doi.org/10.1186/s12915-022-01325-z III. Spatial epigenomeĐtranscriptome co-profiling of mammalian tissues. Di Zhang*, Yanxiang Deng*#, Petra Kukanja, Eneritz Agirre, Marek Bartosovic, Mingze Dong, Cong Ma, Sai Ma, Graham Su, Shuozhen Bao, Yang Liu, Yang Xiao, Gorazd B. Rosoklija, Andrew J. Dwork, J. John Mann, Kam W. Leong, Maura Boldrini, Liya Wang, Maximilian Haeussler, Benjamin J. Raphael, Yuval Kluger, GonŤalo Castelo-Branco# and Rong Fan#. Nature. 2023;616(7955):113-122. #Correspondence. https://doi.org/10.1038/s41586-023-05795-1 IV. Cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology. Petra Kukanja*#, Christoffer Mattsson Langseth*#, Leslie A. Rubio Rodr’guez-Kirby, Eneritz Agirre, Chao Zheng, Amitha Raman, Chika Yokota, Christophe Avenel, Katarina Tiklov‡, AndrŽ O. Guerreiro-Cacais, Tomas Olsson, Markus M. Hilscher, Mats Nilsson# and GonŤalo Castelo-Branco#. Cell. 2024;187(8):1990-2009.e19. *Equal contribution. #Correspondence. https://doi.org/10.1016/j.cell.2024.02.030 </p