Sahlgrenska Academy / Sahlgrenska akademinhttps://hdl.handle.net/2077/172024-03-19T06:18:06Z2024-03-19T06:18:06ZHumoral lmmune Response with Focus of lgG Glycosylation -In murine modelsGupta, Pritihttps://hdl.handle.net/2077/796982024-03-14T21:00:26Z2024-03-14T00:00:00ZHumoral lmmune Response with Focus of lgG Glycosylation -In murine models
Gupta, Priti
The humoral immune system orchestrates a vital defense mechanism through the secretion of antibodies, especially Immunoglobulin G (IgG), which actively targets and neutralizes foreign particles and pathogens. Glycosylation is a post-translational modification of proteins that affects their size, shape, and folding. IgG glycosylation, plays a pivotal role in mediating both pro- and anti-inflammatory effects in diseases, thereby regulating pathogenicity through alterations in interaction with fragment crystallizable gamma receptors (FcγRs). Despite the recognized importance of IgG glycosylation, the influence of various factors such as estrogen, inflammation, and aging on the humoral immune response remains unexplored in functional models. Therefore, the primary objective of this Ph.D. thesis is to unravel the impact of these factors, with a particular focus on IgG glycosylation, in murine models. First, we investigated whether Bazedoxifene, a 3rd generation selective estrogen receptor modulator (SERM) exhibits estrogen-ic characteristics in IgG glycosylation under immune-induced postmenopausal conditions. Results demonstrated that Bazedoxifene did not mimic estrogenic effects on IgG glycosylation during pathogenic immune responses. Second, we investigated es-trogen's effects on IgG glycosylation in healthy postmenopausal mice. The findings revealed that estrogen treatment in healthy postmenopausal states increased IgG glycosylation, thereby mitigating IgG pathogenicity. Finally, we investigated the impact of aging and toll-like receptor 2 (TLR2) on the humoral immune response to bacteremia. Utilizing young and old wild-type (WT) and TLR2-/- mice under both healthy and bacteremia conditions, the study showed that TLR2 and aging significantly altered immunoglobulin levels. Additionally, bacteremia induced a limited response in aged mice, with increased IgG glycosylation observed in healthy and infected conditions in wild-type old mice. In summary, this thesis demonstrated the regulation of humoral immune response and the factors including age, sex hormones, and the presence of TLR2, can markedly influence the humoral immune response and IgG glycosylation, leading to a shift from pro- to anti-inflammatory states or vice versa beyond diseased environments.
2024-03-14T00:00:00ZNK cell recognition of malignant cells - a CRISPR approach to define novel mediatorsLinnea, Kristensonhttps://hdl.handle.net/2077/796992024-03-14T21:04:33Z2024-03-14T00:00:00ZNK cell recognition of malignant cells - a CRISPR approach to define novel mediators
Linnea, Kristenson
Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system, capable of eliminating malignant cells. Their activity is intricately regulated through a balanced interplay between activating and inhibitory receptors that interact with molecules on their prospective target cells. This thesis employed genome editing to delve deeper into genes and molecules that influence these dynamic interactions. A loss-of-function genome-wide CRISPR screen using the leukemic cell line K562 with NK cell cytotoxicity as the selective pressure, unveiled genes impacting target cell susceptibility. TMEM30A depletion (paper I) rendered target cells partially resistant to NK-cell-induced lysis. Subsequent investigations elucidated its role in phospholipid transport within the plasma membrane. Loss-of-function mutations in TMEM30A, observed in certain cancers, upregulated phosphatidylserine on the cell surface enabling interaction with inhibitory NK cell receptor TIM-3, providing protection from NK cells. BAP1, another gene identified in the CRISPR screen (paper II) was found to support MHC class I expression through involvement in interferon-γ signalling. Depletion of BAP1 increased target cell sensitivity to NK cells by eliminating the inhibitory signal. The CRISPR/Cas9 technique was further employed to suppress the expression of crucial ligands for activating NK cell receptors. This manipulation allowed the investigation of alternative receptor-ligand interactions and provided a model to decipher the impact of a single nucleotide polymorphism (SNP) in the receptor NKG2D gene on NK cell function (paper III). Notably, the identified SNP in the linked gene for NKG2A emerged as the key driver of NK cell function and additionally influenced the clinical outcome of immunotherapy in acute myeloid leukemia. Leveraging this established model cell line, dominantly killed via NKp46, a subsequent genome-wide CRISPR/Cas9 screen was conducted to identify potential ligand candidates for the NKp46 receptor (paper IV). In conclusion, CRISPR/Cas9 technology proved to be instrumental in uncovering molecular mechanisms that regulate the interaction between NK cells and their target cells, which may pave the way for therapeutic interventions in cancer.
2024-03-14T00:00:00ZQuality of life and long-term side effects after anal cancer treatmentAxelsson, Annahttps://hdl.handle.net/2077/793332024-02-28T21:00:35Z2024-02-28T00:00:00ZQuality of life and long-term side effects after anal cancer treatment
Axelsson, Anna
Anal cancer is a rare type of cancer with approximately two hundred new cases in Sweden per year. Treatment usually consists of a combination of radiotherapy and chemotherapy. Overall prognosis is good but about 10% of patients require pelvic surgery to be cured. This is referred to as “salvage surgery”. In this thesis we wanted to investigate patient reported quality of life (QoL) and long-term side effects after anal cancer treatment. Two hundred and five patients with anal cancer, diagnosed between 2011 and 2013 in Sweden, answered a comprehensive questionnaire at three and six years after diagnosis. One hundred and ninety-five patients returned the questionnaire at three years and one hundred and fifty-five patients at six years.
We found QoL to be good in 40% of the patients and low in 60% at both three and six years. Patients with bother from one or more functions had a higher risk of impaired QoL. Major bother was more prevalent in patients that reported low QoL. Impaired bowel function was common and remained stable between three and six years. The combination of chemotherapy and radiotherapy was associated with a higher risk of bowel side effects than radiotherapy alone. Both urinary and sexual function deteriorated between three and six years. Chemotherapy was not associated with a higher risk of urinary incontinence.
With a qualitative approach we explored patients’ experiences of bodily functions and QoL after salvage surgery. Eighteen in-depth interviews were performed. Inductive content analysis resulted in 8 categories and 1 theme describing the acceptance and reorientation to a new life despite several long-term bodily changes and functional side-effects.
There are significant long-term side effects after treatment for anal cancer, and there is a clear relationship between symptom burden, bother and QoL. Although bodily functions deteriorate over time QoL does not, indicating an adaptation process between three and six years.
2024-02-28T00:00:00ZHealth conditions, functioning and social outcomes in adults with cerebral palsyJonsson, Ulricahttps://hdl.handle.net/2077/793352024-02-27T12:37:18Z2024-02-21T00:00:00ZHealth conditions, functioning and social outcomes in adults with cerebral palsy
Jonsson, Ulrica
Background: A majority of individuals with cerebral palsy (CP) are adults,
and yet healthcare and research are focused on children. In comparison to the
consequences in childhood, little is known about the long-term consequences
of CP.
Aims: To explore the health, functioning, and social outcomes in a populationbased
cohort of middle-aged adults with CP in western Sweden.
Methods: The total cohort of individuals with CP born between 1959-1978 in
the CP Register of western Sweden formed the basis for this thesis. Childhood
data from the CP Register was used to compare survivors from the total cohort
with the total cohort. Register data on the survivors’ social outcomes and of
sex and age matched controls in the general population were gathered from
Statistics Sweden and compared. All survivors still residing in the region were
invited to a follow-up assessment of impairments and health conditions. The
presence of impairments at the follow-up assessment in adulthood were
compared to childhood data from the CP Register.
Results: The survivors differed from children with CP in the distribution of
CP subtypes and had less severe associated impairments. Among the survivors,
there was a decline in walking ability from childhood to adulthood and an
increase in individuals with intellectual disability and epilepsy. In adulthood,
pain and gastrointestinal, respiratory, and psychiatric disorders were common,
and social outcomes, such as education, living arrangements, employment, and
income differed greatly from the general population.
Conclusions: CP has serious long-term consequences for health and social
outcomes. From childhood to adulthood, the presence and severity of CPrelated
impairments may change, and other health conditions may develop. In
order to improve health and functioning and provide equal opportunities for
adults with CP so that they can fully participate in society, it is recommended
that specialized services and follow-up be extended into adulthood.
2024-02-21T00:00:00Z