Publications

BackgroundParaneoplastic autoimmunity develops as consequences of immune reactions to cancer and exhibits a wide range of clinical manifestations. The autoimmune signs are often visible before the underlying malignancy is diagnosed, and a prompt diagnosis of paraneoplasia is crucial to enable early tumor detection. We characterized the immune responses underlying the severe mucocutaneous blistering disease paraneoplastic pemphigus.MethodsWe used a two-step approach to proteome-wide autoantibody repertoire analysis and independent validation in patients with paraneoplastic pemphigus (n = 84) and non-paraneoplastic autoimmune blistering diseases (n = 103).ResultsOur findings reveal that paraneoplastic pemphigus features a broad repertoire of disease-specific autoantibodies that mainly target tissue-specific proteins in the skin and mucous membranes. Importantly, we identify SERPINB3 as a major autoantibody target with an expression pattern and clinical association suggesting a role in bronchiolitis obliterans. Autoantibody profiles are similar across neoplasias, except in thymoma patients, who additionally express multiple cytokine autoantibodies.ConclusionsOur findings reveal a disease-defining autoantibody repertoire in paraneoplastic pemphigus that corresponds with clinical manifestations and holds high potential for early cancer detection in patients with blistering disease.

Why cancer arises, progresses, or proves fatal in some people but not others remains largely unresolved. Antibody repertoires, including autoantibodies targeting immune pathways, may shape cancer immunosurveillance. Mapping antibody landscapes across cancer-free, at-risk, and cancer-affected individuals could clarify their roles in cancer susceptibility and disease outcome.

Background: Increased stromal Platelet-derived growth factor receptor beta (PDGFRβ) expression is a hallmark of the desmoplastic tissue reaction in cancer and marks subsets of cancer-associated fibroblasts, pericytes, and smooth muscle cells. However, its functional status in situ has been anticipated from static expression measures, which cannot determine whether high receptor abundance reflects active signaling.Methods: We established two second-generation proximity ligation assays (PLAs) to quantify PDGFRβ activation in the in situ environment of human lung cancer by detecting either phosphorylated PDGFRβ or its interaction with the adaptor protein Grb2. The immunofluorescence-based assays were applied to tissue-microarrays including diagnostic samples from over 600 non-small cell lung cancer (NSCLC) patients.Results: In lung cancer tissue, activation scores correlated with PDGFRβ expression but revealed a more nuanced receptor status, indicating variable activation despite similar expression levels. Higher PDGFRβ activation was associated with increased recurrence risk exclusively in squamous cell carcinoma, a finding not captured by conventional immunohistochemistry. This activation was accompanied by a specific stromal profile enriched for LRRC15- and FAP-positive cells, a pattern absent in adenocarcinomas.Conclusion: PDGFRβ activation status provides functional information beyond receptor expression, uncovering clinically relevant, otherwise overlooked, stromal phenotypes. The approach illustrates the diagnostic potential of functional protein assays in the era of precision medicine.

The E3 ubiquitin ligase Casitas B-lineage lymphoma (CBL) promotes positive selection and antigen responses in mouse T lymphocytes by ubiquitinating ZAP70. Conversely, mouse CBL and CBL-B mutually redundantly regulate SYK ubiquitination and B cell receptor signaling. Here we studied individuals with somatically homozygous CBL loss-of-function variants in leukocytes. Human CBL is largely redundant for the development and function of human T cells. Conversely, B cell development is altered at the immature stage, with a tenfold increase in transitional cells, enhanced survival of autoreactive clones and impaired tolerance manifested by autoantibody production. B cell maturation is intrinsically impaired by reduced apoptosis and dysregulated B cell receptor signaling. CBL deficiency impairs humoral immunity by limiting memory B cell formation and reducing class switching and somatic hypermutation. Consequently, antigen-specific B cell generation and adaptive immune memory are disrupted, predisposing individuals to infection. Human CBL is critical for B cell development and function but redundant for T cell biology.

BackgroundPilonidal sinus disease (PSD) is common in young adults, yet real-world data integrating quality of life (QoL) with surgical outcomes are limited. We aimed to describe national surgical practice for PSD in Turkey and to compare complications, recurrence, and QoL between excision-based and non-excisional (minimally invasive) procedures.MethodsThis was a retrospective analysis of a prospectively maintained nationwide database including adults undergoing first surgery for PSD in 41 centers between January 2019 and January 2020. Sociodemographic and clinical data, perioperative variables, complications, and recurrence were recorded. QoL was assessed using the EQ-5D-5L (including EQ-VAS) and pain using a 10-point visual analog scale (VAS) at baseline and at postoperative day 1, day 7, 6 months, and 12 months. Patients were grouped according to surgical approach: simple excision, excision + flap and non-excisional procedures.ResultsData from 1369 patients were analyzed (simple excision, n = 194; excision + flap, n = 983; non-excisional, n = 192). Overall, postoperative bleeding occurred in 12.3%, wound infection in 9.2%, and wound separation in 10.2% of patients, with wound separation being more frequent after excision + flap than non-excisional procedures. Recurrence at 12 months was observed in 51 patients (3.7% overall), with rates of 3.1% in the simple excision group, 4.1% in the excision + flap group, and 2.6% in the non-excisional group (p = 0.545). Median pain VAS decreased from 4 (IQR 2–6) at baseline to 0 (0–0) at 12 months in all groups (p < 0.001 within groups). EQ-VAS improved by a median of 18 (IQR 8–40) points in the simple excision group, 15 (6–30) in the excision + flap group, and 29 (15–40) in the non-excisional group (p < 0.001 between groups).ConclusionsIn this nationwide real-world cohort, non-excisional procedures were associated with shorter operative time, shorter hospital stay, fewer wound-related complications, and greater early improvements in QoL and patient satisfaction compared with excision-based procedures, without an apparent increase in 12-month recurrence. Given the retrospective design, baseline imbalances between groups, and limited follow-up, these findings should be confirmed in prospective comparative studies with longer follow-up.

Background: Interferons play a central role in antiviral defense, but their dysregulation contributes to inflammation and immune dysfunction in respiratory viral infections, including COVID-19. While interferon-stimulated genes (ISGs) are essential effectors of this response, their expression patterns in patients are heterogeneous and not always predictive of disease severity. The immunometabolic consequences of this heterogeneity remain poorly understood.Methods: We analyzed hospitalized COVID-19 patients (n = 37) and uninfected controls (n = 31) using whole-blood transcriptomics, immune cell deconvolution, plasma proteomics, and standardized plasma metabolomics from a previously generated dataset within this cohort. Patients were stratified into low (LIS), moderate (MIS), and high (HIS) ISG score clusters. Plasma innate immune activation markers were measured by ELISA. Interferon-directed antibody reactivity was analyzed by multiplex bead-based assays measuring antigen reactivity. Functional immune responses were assessed via ex vivo stimulation of healthy donor immune cells with patient plasma, and correlations were performed between metabolites and immune activation markers.Results: HIS patients exhibited increased inflammatory mediators and innate immune cell expansion compared with LIS and MIS groups. However, within the HIS group, severe cases displayed distinct metabolic and immune dysregulation. Specifically, severe HIS cases showed reductions in phospholipids, sphingolipids, and tricarboxylic acid cycle intermediates, suggestive of disrupted mitochondrial and lipid metabolism. Plasma from severe HIS patients tended to impair neutrophil and monocyte activation, indicating functional attenuation of innate immune activation within a shared high-ISG background. Correlation analysis revealed that branched-chain lipids, tryptophan-derived metabolites, and a branched-chain dicarboxylic acid were positively associated with immune activation markers. Although type-I interferon neutralization was detected in a subset of patients with IFN antigen reactivity, these samples did not fully account for the observed ISG heterogeneity or disease severity.Conclusions: High ISG expression in COVID-19 defines a transcriptional endotype associated with systemic inflammation and innate immune activation. However, severe cases within this group exhibit metabolic constraints and reduced innate immune responsiveness, supporting an immune-metabolic axis in which inflammatory mediators and altered lipid/energy metabolism intersect with innate immune function. These findings motivate future studies to determine whether interferon-associated immune-metabolic states during acute infection relate to persistent inflammation or post-acute sequelae in selected patient subsets.

Fulminant viral hepatitis (FVH) is a devastating condition caused by hepatotropic viruses such as hepatitis A virus (HAV), hepatitis B virus (HBV), and HSV-1/2. We studied 149 FVH patients (73 males and 76 females, aged 1-76) for blood autoantibodies (auto-Abs) neutralizing type I interferons (IFNs; IFN-alpha 2, -beta, -omega). Six of 16 (37.5%) HSV-triggered FVH patients carried such auto-Abs on admission, including three with a previously known autoimmune disease. These patients contrasted with 133 HAV- (n = 46) or HBV-triggered (n = 87) patients, none of whom had such detectable auto-Abs. Odds ratios for HSV-triggered FVH in individuals with auto-Abs ranged from 35.3 (95% CI: 13.0-96.2; P < 10-7) for those neutralizing only 100 pg/ml IFN-alpha/omega to 1,895 (CI: 448.5-8,002; P < 10-12) for those neutralizing both IFN-alpha and IFN-omega at 10 ng/ml. Over one third of HSV-triggered FVH cases in this international cohort were due to preexisting auto-Abs. This finding highlights auto-Abs against type I IFNs as a major determinant of HSV-FVH and paves the way for targeted preventive or therapeutic interventions.

This genome-wide association study (GWAS) explores the genetic components of severe adverse events following COVID-19 vaccination, with focus on myocarditis and pericarditis. Three SNPs (rs536572545, rs146289966 and rs142297026) near the SCAF11 gene were linked to pericarditis, while rs570375365 in the LRRC4C gene was associated with myocarditis. These findings suggest that genetic variants may influence inflammation pathways, providing a basis for further investigation into the immunological responses triggered by vaccines.

CD4+ T cells are indispensable for optimal immunity to Mycobacterium tuberculosis (M.tb), a pathogen that triggers tuberculosis (TB) in humans. M.tb-specific human CD4+ T cells are known to polarize toward an interferon-gamma (IFN-gamma)-producing, CCR4-CCR6+CXCR3+T-bet+ROR gamma T+ T helper 1* cell (TH1*cell) memory phenotype. We report that autosomal recessive deficiency of the human lymphocytic surface receptor LY9 (SLAMF3 and CD229), which is found in less than 10-5 individuals in the general population, underlies TB in three unrelated patients due to selective impairment in IFN-gamma production by TH1* cells. TH1* cells express higher levels of LY9 than other CD4+ T cells. Mechanistically, LY9 polarizes na & iuml;ve CD4+ T cells toward memory TH1* cells by inducing T-bet via signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) and ROR gamma T (thymus-specific retinoid-related orphan receptor gamma) without SAP. LY9 costimulation enhances TCR-driven IFN-gamma production of memory TH1*, but not TH1, cells in a T cell-intrinsic manner via NFAT1 (nuclear factor of activated T cells 1) and ROR gamma T. LY9 is likely to govern an optimal TH1* cell- and IFN-gamma-dependent protective immunity to M.tb in humans.

Objective To determine whether autoantibodies against interferons are present and play a role in disease modulation in idiopathic inflammatory myopathies (IIMs).Methods We screened for autoantibodies against a large number of interferons (IFNs) and other cytokines in a cross-sectional observational cohort of Swedish patients with anti-synthetase syndrome (n=51) and dermatomyositis (n=48), matched together with blood donors (n=100) from general population, using both planar and suspension-based multiplex assays. A single patient with autoimmune polyendocrine syndrome, type-1 (APS-1), known to harbour autoantibodies that neutralise type-I interferons, was included as a reference biological positive. The functional ability of autoantibodies to neutralise type-I interferons was tested in vitro, using an IFN-α/β responsive cell reporter assay.Result The initial screening of plasma samples indicated a repertoire of autoantibodies in IIM patients against a number of common myositis-specific and myositis-associated antigens. On screening for autoantibodies against type-I, II or III interferons, we did not find any evidence of anti-IFN autoantibodies being present in any of the IIM patient subgroups or the blood donors from general population. Additionally, none of the tested plasma samples, except the APS-1, exhibited neutralisation of physiological concentration IFN-α2, further confirming a complete lack of functional autoantibodies against IFN-α subtypes in this cohort.Conclusions We did not detect neutralising autoantibodies against IFN-α and autoantibodies against other types of IFNs in a Swedish cohort of IIM patients. These findings contrast with the presence of autoantibodies against type-I IFNs in other systemic autoimmune diseases, such as systemic lupus erythematosus, characterised by type-I IFN overactivation.

Biological sex is closely associated with the properties and extent of the immune response, with males and females showing different susceptibilities to diseases and variations in immunity. Androgens, predominantly in males, generally suppress immune responses, while estrogens, more abundant in females, tend to enhance immunity. It is also established that sex hormones at least partially explain sex biases in different diseases, particularly autoimmune diseases in females. These differences are influenced by hormonal, genetic, and environmental factors, and vary throughout life stages. The advent of gender-affirming hormone therapy offers a novel opportunity to study the immunological effects of sex hormones. Despite the limited studies on this topic, available research has revealed that testosterone therapy in transgender men may suppress certain immune functions, such as type I interferon responses, while increasing inflammation markers like TNF-alpha. Transgender women on estrogen therapy also experience alterations in coagulation-related and inflammatory characteristics. Furthermore, other possible alterations in immune regulation can be inferred from the assessment of inflammatory and autoimmune markers in transgender individuals receiving hormone therapy. Understanding the complex interactions between sex hormones and the immune system, particularly through the unique perspective offered by gender-affirming hormone therapies, may facilitate the development of targeted therapies for infections and autoimmune diseases while also improving healthcare outcomes for transgender individuals. Here we review immune dynamics throughout life in both sexes and provide a summary of novel findings drawn from studies exploring gender-affirming hormone therapy.

Severe COVID-19 is characterized by immune-coagulation dysregulation, yet the contribution of related autoantibodies remains poorly understood. We investigated relationships between plasma autoantibody reactivities, whole-blood transcriptomics, plasma proteomics, and clinical laboratory parameters in a cohort of hospitalized COVID-19 patients. Transcriptomic analysis revealed that 42 curated coagulation and complement cascade genes were upregulated in severe cases compared to healthy controls, with 15 genes, including CR1L, ELANE, ITGA2B, ITGB3, VWF, TFPI, PROS1, MMRN1, and SELP (> 1.2 log2 fold-change), also significantly different from mild cases. Autoantibody profiling against eight coagulation-related proteins (ADAMTS13, Factor V, Protein S, SERPINC1, Apo-H, PROC1, Prothrombin, and PF4) showed reactivities below positivity thresholds across all groups. Using an exploratory approach, in severe cases, subthreshold autoantibody candidates (FDR < 0.25) showed negative correlation trends with select gene expressions and inflammatory markers (Factor V with IL-6 and CXCL10), suggesting potential disease-specific immunomodulatory associations. In contrast, while mild cases exhibited stronger gene-protein correlations, they showed limited associations with antigen reactivities or clinical laboratory parameters. Additionally, no correlations were observed between autoantibodies and platelet-counts or Fibrin-D-dimer levels. Age-associated increases in antigen reactivities were noted in severe disease, implying a role for immunosenescence. These findings support further investigation into the role of subthreshold autoantibody candidates in thromboinflammatory COVID-19 pathogenesis.

Purpose: The purpose of this study is to investigate the recurrence rates for the treatment of pilonidal sinus disease (PSD) in Turkey and the factors associated with recurrence of PSD after surgery on a nationwide scale.Methods: This national, multicenter, database review was conducted in Turkey by the PISI TURKEY Research Group, and included recipients of PSD surgery in 41 select hospitals in Turkey, between January 2019 and January 2020. Data were collected by completion of standardized data forms. Sociodemographic and anthropometric data, comorbidities, PSD type, previous PSD interventions, index PSD intervention, recurrence, and complications were collected from baseline to postoperative 12 months.Results: The data of 1662 patients from 41 centers were analyzed. The median age was 25 (21-32) years, and 80.26% of the cases were male. The recurrence rate following index operations was 6.26% in the 12-month period. Age (p = 0.594) and sex distribution (p = 0.441) were similar in patients with and without recurrence. The recurrent group had significantly higher frequencies of type V PSD (p < 0.001), wound site infection (p < 0.001), and wound separation (p < 0.001), whereas the non-recurrent group had a significantly higher frequency of type III PSD (p < 0.001). Multivariable logistic regression revealed that prior recurrence, postoperative wound site infection, and postoperative wound separation were independently associated with recurrence.Conclusions: The recurrence rate after PSD surgery in Turkey was close to the lower ranges reported in prior literature. Turkish patients with a history of prior recurrence, postoperative wound site infection, or postoperative wound separation should be considered to have higher risks for recurrence.

Paraneoplastic syndromes represent a clinically heterogeneous group of disorders that arise in cancer patients. Although their underlying mechanisms are only partly understood, immune or endocrine mechanisms are believed to play key roles. Autoimmune-mediated paraneoplastic syndromes (AMPS) are typically characterized by the presence of autoantibodies, making their identification important for both AMPS diagnosis and early cancer detection. This review synthesizes emerging insights into the pathogenesis of AMPS, with a particular focus on how genomic instability in cancer cells promotes immune recognition of altered self-proteins. Mechanisms such as ectopic expression, protein modifications (such as isoaspartylation), and gene amplifications can disrupt immune tolerance, leading to autoimmunity. Additionally, chronic inflammation and the formation of tertiary lymphoid structures within the tumor microenvironment contribute to both antitumor immunity and autoimmunity. Immune checkpoint inhibitors (ICIs), have revolutionized cancer treatment by enhancing antitumor immunity, but they can also induce immune-related adverse events (irAEs), some of which mimic AMPS. These irAEs highlight the critical roles of both humoral and cellular immunity in AMPS development. By exploring the relationships between ICI treatment, immune tolerance, and tumor-specific antigens, this review aims to clarify the mechanisms driving AMPS and their dual role in cancer control and immune-mediated disease. Bridging these knowledge gaps may inform the development of novel therapeutic strategies for managing AMPS and in optimizing the use of ICIs in cancer care.

Using labels, placards, or external texts a museum can deepen the visitors’ understanding of displayed objects. But the question arises, how can a museum work with the mythology surrounding the objects? This thesis looks closely at two museums in Sweden, the Gotland Museum in Visby and the Swedish history museum in Stockholm. It takes a closer look at if and how the museums’ texts have changed over time – specifically between 1872 and 2024 – when dealing with ancient Nordic mythology. The thesis also aims to find and suggest possible correlations between textual changes and social changes, for example the Second World War and its repercussions. To explore these correlations, two theories are applied, the critical discourse analysis and a narrative theory. To be able to witness a possible linguistic change over time, museum exhibitions and publications are analysed using specific discourses such as myth, magic, religion, cult, and paganism.With the help of theoretical works, changes in the two museums’ informative texts are observed, such as how their earlier output explained Thor’s hammer Mjölnir as a “hammer-like decoration” or only gave a few letters-worth of connections to the mythological background in brackets in the late 19th century. Later they explained these myths as paganism and fantasy during the 1940s, 50s and 60s. Today’s exhibitions show a linguistic change as to how the museums explained connections to the myths with words such as “could perhaps” or “might be”. These changes over time are suggested to be linked to social change such as the union and dismantling of the union between Norway and Sweden, the Second World War, and the use of motifs by later xenophobic groups, and finally, more recent Neo-Paganism in Sweden and around the world.This is a two years’ master´s thesis in Museum and Cultural Heritage studies.

While Coronavirus disease 2019 (COVID-19) vaccines have proven to be both effective and generally safe, rare but severe adverse events following immunization (AEFIs) are described. Autoantibodies to platelet factor-4 are associated with catastrophic thrombotic AEFIs, but comprehensive investigations of other autoantibodies are lacking. We aimed to detect and describe autoantibodies targeting coagulation-related proteins in a population-wide cohort (SWEDEGENE) including AEFIs attributed to COVID-19 vaccines in Sweden. Subjects were recruited from December 2020 to October 2022 and were stratified based on diagnosis and COVID-19 exposure. Screening was carried out in two phases, with a multiplex bead-based assay in the first subset (until September 2021) and with targeted assays for the second (until October 2022). Positivity was defined based on absolute, relative, and biological/technical thresholds. Patients with coagulation-related AEFIs were older and the Vaxzevria vaccine was overrepresented in this group. Two cases had antiphospholipid antibodies but none had PF4 antibodies. We identified six positives for protein S autoantibodies. Protein S concentrations were negatively correlated with autoantibody response in patients with immunoreactivity and functional analysis revealed low protein S activity in three subjects. Our population-wide analysis reveals cases with autoantibodies against protein S which possibly underlie coagulopathic AEFIs.

Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.