| 1. |
- Magnusson, Louise, 1992-
(författare)
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Peripheral immunity in patients with autoimmune endocrine diseases and the influence of physiological adaptions during pregnancy
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes (T1D), Hashimoto’s thyroiditis (HT), Graves’ disease (GD), and autoimmune Addison’s disease (AD) appear to share immunogenetic mechanisms. This idea is not novel, as “autoimmune tautology” is an established concept. An issue with previous studies is that no or few simultaneous comparisons between these autoimmune endocrine diseases have been made. Due to methodological limitations, immune deviations associated with these diseases have also been examined for a limited number of immune cell lineages and analytes. High-dimensional single-cell mass cytometry was thus employed to phenotypically characterise all peripheral CD45+ cell lineages, whilst immune-related proteins in plasma and cell supernatants were analysed by proximity extension assay. Patients with new-onset T1D, HT, and AD had altered frequencies of distinct clusters within antigen-presenting and cytotoxic cell lineages. Importantly, previously unreported alterations of rare cell subsets from patients with HT and AD were identified. The systemic immunoprofile of patients with autoimmune endocrine diseases was in general similar. However, an increased abundance of CDCP1 and SLAMF1 in plasma from patients with T1D, HT, and GD might reflect a higher degree of inflammation and lymphocyte activation.Pregnancy in healthy women entails two important features: 1) an increase in fractional β-cell area and 2) peripheral immunomodulation. The effects of pregnancy on T1D remain nevertheless equivocal, as there are conflicting results on β-cell function and longitudinal analyses on peripheral immunity are lacking. β-cell function and the plasma proteome in pregnant women with long-standing T1D (L-T1D) were therefore examined during three occasions: 1) first trimester, 2) third trimester, and 3) two months postpartum. An oral glucose tolerance test was performed to measure both fasting and stimulated C-peptide concentrations in plasma. Plasma proteins related to cell regulatory and immunological processes were analysed by proximity extension assay. Glucose-induced insulin secretion was regained in pregnant women with L-T1D, which decreased slowly after parturition. The plasma proteome was dynamic during gestation, although few analytes were functionally linked. A recovered β-cell function might be related to elevated plasma levels of prolactin, prokineticin-1, or glucagon. Moreover, reduced plasma levels of proteins related to leukocyte migration, T cell activation, and antigen-presentation might have further protected an improved β-cell function.
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| 2. |
- Alvaeus, Julia, et al.
(författare)
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Fewer tumour draining sentinel nodes in patients with progressing muscle invasive bladder cancer, after neoadjuvant chemotherapy and radical cystectomy
- 2020
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Ingår i: World journal of urology. - : Springer. - 0724-4983 .- 1433-8726. ; 38, s. 2207-2213
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To examine the relationship between the number of tumour draining sentinel nodes (SNs) and pathoanatomical outcomes, in muscle-invasive bladder cancer (MIBC), in patients undergoing neoadjuvant chemotherapy (NAC) and radical cystectomy (RC).MATERIALS AND METHODS: In an ongoing prospective multicenter study, we included 230 patients with suspected urothelial MIBC from ten Swedish urological centers. All underwent TURb and clinical staging. From the cohort, 116 patients with urothelial MIBC; cT2-cT4aN0M0, underwent radical cystectomy (RC) and lymphadenectomy with SN-detection (SNd). 83 patients received cisplatin-based NAC and 33 were NAC-naïve. The number and locations of detected SNs and non-SNs were recorded for each patient. The NAC treated patients were categorized by pathoanatomical outcomes post-RC into three groups: complete responders (CR), stable disease (SD) and progressive disease (PD). Selected covariates with possible impact on SN-yield were tested in uni -and multivariate analyses for NAC-treated patients only.RESULTS: In NAC treated patients, the mean number of SNs was significantly higher in CR patients (3.3) and SD patients (3.6) compared with PD patients (1.4) (p = 0.034). In a linear multivariate regression model, the number of harvested nodes was the only independent variable that affected the number of SNs (p = 0.0004).CONCLUSIONS: The number of tumor-draining SNs in NAC-treated patients was significantly lower in patients with progressive disease.
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| 3. |
- Eldh, Maria, et al.
(författare)
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Proteomic Profiling of Tissue Exosomes Indicates Continuous Release of Malignant Exosomes in Urinary Bladder Cancer Patients, Even with Pathologically Undetectable Tumour
- 2021
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:13
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Urinary bladder cancer (UBC) has a high recurrence rate, and biomarkers for different treatment strategies are highly needed. This study investigated the release of nanovesicles called exosomes from urinary bladder tissue from tumour-proximal sites as well as tumour-distant sites in transurethrally resected (TUR-B) patients with or without preoperative neoadjuvant chemotherapy prior to ensuing radical cystectomy-all without remaining visible tumour after TUR-B. We show that cancer-promoting exosomes were detected from both sites, suggesting that the previous tumour has altered the whole bladder tissue into a cancer-supporting milieu. The exosomes may originate from remaining pathologically undetectable cancer cells or transformed epithelial cells, and the study supports the notion of exosomes as mediators of metastatic spread and as potential biomarkers. It also supports early and radical removal of the bladder in urinary bladder cancer patients. Invasive urothelial bladder cancer (UBC) has high recurrence rates even after radical cystectomy (RC). Exosomes are membrane-bound nanovesicles, which have been shown to contribute to carcinogenesis and metastasis. We previously showed that urinary exosomes display a malignant profile in UBC patients despite the absence of detectable tumour. Here, we investigated exosomes from sampling sites close to or distant from the former tumour, aiming to understand the effect of the tumour on the local milieu. Ten patients scheduled for cystectomy after transurethral bladder resection (TUR-B), without remaining detectable tumour, were included. Exosomes were isolated from tissue explants of both the previous tumour site and distant bladder tissue. Proteins were quantified by mass spectrometry in seven patients. Exosomes from the previous tumour site were enriched in inflammatory but not cancer-related pathways compared to distant tissue. However, the 69 most abundant proteins in tissue-derived exosomes regardless of site, 20 of which were also found in urinary exosomes from our previous study, were enriched for cancer-related metabolic pathways and associated with poor prognosis in an external mRNA dataset. The enrichment of cancer-related pathways in the most abundant proteins, regardless of sampling site, confirms our hypothesis that despite the absence of detectable tumour, the entire bladder releases exosomes that contribute to metastasis and highlights the need for early RC.
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| 4. |
- Hiltbrunner, Stefanie, et al.
(författare)
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Urinary Exosomes from Bladder Cancer Patients Show a Residual Cancer Phenotype despite Complete Pathological Downstaging
- 2020
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Invasive urinary bladder cancer shows high recurrence rates after cystectomy even with apparent complete downstaging at cystectomy. Exosomes are nano-sized vesicles important in cell-cell communication, which have been hypothesized to contribute to cancer dissemination and recurrence. The aim of this study was to investigate if pro-carcinogenic exosomes could be detected in urine from histologically downstaged bladder cancer patients. 13 Patients were included in this study. Paired ureter and urine samples from nine patients underwent mass spectrometry, while samples from the remaining patients were used for exosome characterization. At cystectomy, exosomes were isolated from bladder and ureter urine, whereafter quantitative proteome profiling was performed. Urinary exosomes clustered based on whether they came from the bladder, with tumour contact, or the ureters, without tumour contact, even though all came from completely downstaged patients. Proteins overexpressed in exosomes derived from bladder urine contained several oncogenes and were mainly associated with tumour metabolism pathways. Although patients were histologically tumour-free at cystectomy, the bladder urine contained exosomes with a carcinogenic metabolic profile. This suggests a continuous release of exosomes from the bladder, which may promote recurrence at distant sites through metabolic rewiring, even after apparent complete downstaging. These exosomes, coming from either undetected cancer cells or partly transformed cells, are likely to increase the risk of metastasis and encourages cystectomy even in completely downstaged patients.
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| 5. |
- Krantz, David, et al.
(författare)
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IL-16 processing in sentinel node regulatory T cells is a factor in bladder cancer immunity
- 2020
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Ingår i: Scandinavian Journal of Immunology. - : John Wiley & Sons. - 0300-9475 .- 1365-3083. ; 92:6
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Tidskriftsartikel (refereegranskat)abstract
- In the effort of developing new immunotherapies, the sentinel node (SN) has proven a promising source from which to harness an effective antitumour T cell response. However, tumour immune escape, a process in which regulatory T cells (Tregs) play a central role, remains a major limiting factor. Therefore, there is a clear need to increase the knowledge of Treg function and signalling in sentinel nodes. Here, we set out to explore whether the proteome in SN-resident T cells is altered by the tumour and to identify key proteins in SN T cell signalling, focusing on Tregs. Five patients with muscle-invasive urothelial bladder cancer were prospectively included. Mass spectrometry was performed on two patients, with validation and functional studies being performed on three additional patients and four healthy donors. At cystectomy, SN, non-SN lymph nodes and peripheral blood samples were collected from the patients and T cell subsets isolated through flow cytometry before downstream experiments. Proteomic analysis indicated that growth and immune signalling pathways are upregulated in SN-resident Tregs. Furthermore, centrality analysis identified the cytokine IL-16 to be central in the SN-Treg signalling network. We show that tumour-released factors, through activating caspase-3, increase Treg IL-16 processing into bioactive forms, reinforcing Treg suppressive capacity. In conclusion, we provide evidence that Tregs exposed to secreted factors from bladder tumours show increased immune and growth signalling and altered IL-16 processing which translates to enhanced Treg suppressive function, indicating altered IL-16 signalling as a novel tumour immune escape mechanism.
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| 6. |
- Krifors, Anders, et al.
(författare)
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Long-lasting T-cell response to SARS-CoV-2 antigens after vaccination-a prospective cohort study of HCWs working with COVID-19 patients
- 2023
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Ingår i: Infectious Diseases. - : Taylor & Francis. - 2374-4235 .- 2374-4243. ; 53:2, s. 142-148
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Vaccination against SARS-CoV-2 reduces the risk of hospitalisation and death, but vaccine-induced IgG antibodies against the spike protein (IgG S) decline over time. Less is known about the nature of the vaccine-induced T-cell response to SARS-CoV-2 antigens.METHODS: IgG antibodies against nucleocapsid protein (IgG N), IgG S, and T-cell response towards SARS-CoV-2 antigens were determined in samples taken between November 2020 and November 2021 from a cohort of healthcare workers at an Infectious Diseases Department. RT-PCR screening for SARS-CoV-2 was encouraged once every four weeks in addition to testing when symptomatic or identified through contact tracing. Vaccination data were collected at the end of the study.RESULTS: At inclusion, T-cell response to SARS-CoV-2 antigens was found in 10/15 (66.7%) of participants with a previous/current COVID-19 infection and in 9/54 (16.7%) of participants with no prior/current history of COVID-19 infection. All participants with complete follow-up (n = 59) received two doses of a SARS-CoV-2 vaccine during the study. All participants demonstrated detectable IgG (S) antibodies at the end of the study, in median 278 days (IQR 112) after the second vaccine dose. All but four participants displayed T-cell responses towards SARS-CoV-2 antigens. IgG S antibody levels correlated with time since the second vaccine dose. In addition, previous COVID-19 infection and the strength of the S1 T-cell response correlated with IgG S antibody levels. However, no correlation was demonstrated between the strength of the T-cell response and time since the second vaccine dose.CONCLUSION: COVID-19 vaccination induces robust T-cell responses that remain for at least nine months.
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| 7. |
- Melin, Jan, et al.
(författare)
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A third dose SARS-CoV-2 BNT162b2 mRNA vaccine results in improved immune response in hemodialysis patients
- 2022
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Ingår i: Upsala Journal of Medical Sciences. - : Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 127:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The hemodialysis (HD) population has been a vulnerable group during the coronavirus disease 2019 (COVID-19) pandemic. Advanced chronic kidney disease with uremia is associated with weaker immune response to infections and an attenuated response to vaccines. The aim of this study was to study the humoral and cellular response to the second and third doses of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) BNT162b2 mRNA vaccine in HD patients and to follow the response over time.Methods: The patients received their first two vaccine doses from 28 December 2020 within a 4-week interval and the third dose in September 2021 and were followed-up for humoral and cellular immune response at 1) 7-15 weeks and 2) 6-8 months after dose two (no t-cell reactivity measured), and 3) 3 weeks and 4) 3 months after dose three. Fifty patients were initially enrolled, and 40 patients were followed during the entire study. Levels of COVID-19 (SARS-CoV-2) IgG antibody against the Spike antigen (anti-S) and T-cell reactivity testing against the Spike protein using Enzyme-Linked ImmunoSpot (ELISPOT) technology were evaluated.Results: IgG antibodies to anti-S were detected in 35 (88%) of the 40 patients 7-15 weeks after vaccine dose two, 31 (78%) were positive, and 4 (10%) borderline. The median anti-S titer was 606 Abbott Units/milliliter (AU/mL) (interquartile range [IQR] 134-1,712). Three months after the third dose, anti-S was detected in 38 (95%) of 40 patients (P < 0.01 compared to after dose two), and the median anti-S titer was 9,910 AU/mL (IQR 2,325-26,975). Cellular reactivity was detected in 22 (55%), 34 (85%), and 28 (71%) of the 40 patients, and the median T-cell response was 9.5 (IQR 3.5-80), 51.5 (14.8-132), and 19.5 (8.8-54.2) units, respectively, for 6-8 months after dose two, 3 weeks, and 3 months after dose three.Conclusions: Our data show that a third dose of SARS-CoV-2 BNT162b2 mRNA vaccine gives a robust and improved immunological response in HD patients, but a few patients did not develop any anti-S response during the entire study, indicating the importance to monitor the vaccine response since those who do not respond could now be given monoclonal antibodies if they contract a COVID-19 infection or in the future antivirals.
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| 8. |
- Melin, Jan, et al.
(författare)
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Humoral and cellular response to SARS-CoV-2 BNT162b2 mRNA vaccine in hemodialysis patients
- 2021
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Ingår i: BMC Immunology. - : BioMed Central (BMC). - 1471-2172. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Hemodialysis (HD) patients have an increased risk of acquiring infections due to many health care contacts and may, in addition, have a suboptimal response to vaccination and a high mortality from Covid-19 infection. Methods In 50 HD patients (mean age 69.4 years, 62% men) administration of SARS-CoV-2BNT162b2 mRNA vaccine began in Dec 2020 and the immune response was evaluated 7-15 weeks after the last dose. Levels of Covid-19 (SARS-CoV-2) IgG antibody against the nucleocapsid antigen (anti-N) and the Spike antigen (anti-S) and T-cell reactivity testing against the Spike protein using ELISPOT technology were evaluated. Results Out of 50 patients, anti-S IgG antibodies indicating a vaccine effect or previous Covid-19 infection, were detected in 37 (74%), 5 (10%) had a borderline response and 8 (16%) were negative after two doses of vaccine. T-cell responses were detected in 29 (58%). Of the 37 patients with anti-S antibodies, 25 (68%) had a measurable T-cell response. 2 (40%) out of 5 patients with borderline anti-S and 2 (25%) without anti-S had a concomitant T-cell response. Twenty-seven (54%) had both an antibody and T-cell response. IgG antibodies to anti-N indicating a previous Covid-19 disease were detected in 7 (14%) patients. Conclusions Most HD patients develop a B- and/or T-cell response after vaccination against Covid-19 but approx. 20% had a limited immunological response. T-cell reactivity against Covid-19 was only present in a few of the anti-S antibody negative patients.
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| 9. |
- Rosenblatt, Robert, et al.
(författare)
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Blood transfusions during neoadjuvant chemotherapy for muscle-invasive urinary bladder cancer may have a negative impact on overall survival
- 2020
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Ingår i: Scandinavian journal of urology. - : Taylor & Francis. - 2168-1805 .- 2168-1813. ; 54:1, s. 46-51
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate the extent and plausible effects of blood transfusions given during cisplatin-based neoadjuvant chemotherapy (NAC) on overall survival in patients with muscle-invasive urothelial bladder cancer (MIBC) undergoing NAC and radical cystectomy (RC).Background: Several studies have demonstrated a decreased survival for MIBC patients receiving allogenic peri- and postoperative blood transfusions in conjunction with RC. No studies have previously investigated the effects of blood transfusions during NAC.Materials and methods: 120 patients with MIBC (cT2-T4aN0M0) undergoing NAC and RC between 2008 and 2014 at four Swedish cystectomy centers were retrospectively evaluated. Clinicopathological data were obtained, including data of allogenic blood administration. Survival data was analyzed by Kaplan–Meier plotting and Cox regression.Results: One third of the cohort received blood transfusions during the period of NAC. In univariate analysis, blood transfusions during NAC, nodal stage and advanced tumor stage (pT >2) were negative prognostic factors for survival. In multivariate analysis, only pNx and pT >2 remained significant negative prognostic factors. In a subgroup analysis consisting of patients with localized tumors without dissemination (n = 96), patients that received transfusions during NAC showed an 18.5% absolute risk increase of death at five years of observation, although without statistical significance (p = .197).Conclusions: This is the first time that the extent and plausible effects of allogenic blood transfusions during NAC is examined in MIBC. Data suggest that there may be an association between blood transfusion and poor pathological and oncological outcome. Firm conclusions are difficult to draw due to few study participants and the retrospective nature of the study.
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| 10. |
- Rosenblatt, Robert, 1982-
(författare)
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Neoadjuvant chemotherapy in muscle-invasive urinary bladder cancer : studies on treatment response, tumor draining lymph nodes and blood transfusion
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Muscle-invasive urinary bladder cancer is a deadly disease. Mortality rates remained unchanged for decades despite radical surgery.After several randomized trials, we today know that cisplatin based chemotherapy given prior to cystectomy, improves survival for every tenth patient. Markers that predict responsiveness to chemotherapy would spare unnecessary treatment to the majority of patients. In the search for signs of chemosensitivity, we performed a retrospective analysis of the Nordic cystectomy trials 1 & 2: Chemo treated patients had an almost doubled increase in tumor downstaging compared to the controls. More importantly, this group presented with a reduced absolute risk of death of more than 30% compared to the rest of the patients. These results were presented in paper I.Many cancers spread through the lymphatic system. Usually, there is at least one tumor draining lymph node, referred to as the sentinel node. If this node is free of metastases, there is no lymphatic spread of the disease, and consequently, no use of excavating all neighboring lymph nodes.Sentinel node detection, is an established method in breast cancer, penile cancer and malignant melanoma. Based on the same principles, members of our group developed a similar detection technique in bladder cancer. Unfortunately, sensitivity and specificity were too low to rely on this method as a diagnostic tool for lymphatic spread. Instead, it turned out in recent years that sentinel nodes in muscle invasive bladder cancer are valuable for translational research-lines - mainly in tumor immunology. As for example, sentinel nodes contain tumor specific T cells that are useful in adoptive immunotherapy.In paper II, we set out to test whether sentinel node detection was feasible after chemotherapy and/or tumor downstaging. In a prospective cohort of patients, we saw no difference in detection rates between the groups. Thus, we concluded, neither chemotherapy nor downstaging appeared to hamper the identification of sentinel nodes.The concept was expanded in paper III. After recruiting more patients to the cohort mentioned above, the average numbers of sentinel nodes in different categories of patients were compared. We saw a pattern of decreased number of sentinel nodes in those with locally advanced tumors. It seemed that the number of sentinel nodes had prognostic implications.In the last study, published in paper IV, we wanted to widen our knowledge on the clinical effects of blood transfusion. Mounting data suggests that perioperative blood products have a negative impact on long term survival after cancer surgery. How much allogenic blood was given during the chemotherapy prior to surgery ? It turned out that one third of the bladder cancer patients received blood, and these patients demonstrated a significantly worse overall survival.Neoadjuvant chemotherapy has added a new beneficial dimension to the treatment of muscle invasive bladder cancer. In these four studies, we addressed the effects of chemotherapy on pathoanatomical outcomes, on tumor lymphatics and further; we are suggesting consequences of neoadjuvant chemotherapy in conjunction with blood transfusion. It appears that the immune system is involved in all aspects investigated above. Most likely, an improved scientific understanding of the immune system will be crucial for future bladder cancer treatment options.
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| 11. |
- Saudi, Aws, et al.
(författare)
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Immune-activated B cells are dominant in prostate cancer
- 2023
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 15:3
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Tidskriftsartikel (refereegranskat)abstract
- B cells are multifaceted immune cells responding robustly during immune surveillance against tumor antigens by presentation to T cells and switched immunoglobulin production. However, B cells are unstudied in prostate cancer (PCa). We used flow cytometry to analyze B-cell subpopulations in peripheral blood and lymph nodes from intermediate-high risk PCa patients. B-cell subpopulations were related to clinicopathological factors. B-cell-receptor single-cell sequencing and VDJ analysis identified clonal B-cell expansion in blood and lymph nodes. Pathological staging was pT2 in 16%, pT3a in 48%, and pT3b in 36%. Lymph node metastases occurred in 5/25 patients (20%). Compared to healthy donors, the peripheral blood CD19+ B-cell compartment was significantly decreased in PCa patients and dominated by naïve B cells. The nodal B-cell compartment had significantly increased fractions of CD19+ B cells and switched memory B cells. Plasmablasts were observed in tumor-draining sentinel lymph nodes (SNs). VDJ analysis revealed clonal expansion in lymph nodes. Thus, activated B cells are increased in SNs from PCa patients. The increased fraction of switched memory cells and plasmablasts together with the presence of clonally expanded B cells indicate tumor-specific T-cell-dependent responses from B cells, supporting an important role for B cells in the protection against tumors.
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| 12. |
- Vollmer, Tino, et al.
(författare)
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The intratumoral CXCR3 chemokine system is predictive of chemotherapy response in human bladder cancer
- 2021
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 13:576
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Tidskriftsartikel (refereegranskat)abstract
- Chemotherapy has direct toxic effects on cancer cells; however, long-term cancer control and complete remission are likely to involve CD8+ T cell immune responses. To study the role of CD8+ T cell infiltration in the success of chemotherapy, we examined patients with muscle invasive bladder cancer (MIBC) who were categorized on the basis of the response to neoadjuvant chemotherapy (NAC). We identified the intratumoral CXCR3 chemokine system (ligands and receptor splice variants) as a critical component for tumor eradication upon NAC in MIBC. Through characterization of CD8+ T cells, we found that stem-like T cell subpopulations with abundant CXCR3alt, a variant form of the CXCL11 receptor, responded to CXCL11 in culture as demonstrated by migration and enhanced effector function. In tumor biopsies of patients with MIBC accessed before treatment, CXCL11 abundance correlated with high numbers of tumor-infiltrating T cells and response to NAC. The presence of CXCR3alt and CXCL11 was associated with improved overall survival in MIBC. Evaluation of both CXCR3alt and CXCL11 enabled discrimination between responder and nonresponder patients with MIBC before treatment. We validated the prognostic role of the CXCR3-CXCL11 chemokine system in an independent cohort of chemotherapy-treated and chemotherapy-naïve patients with MIBC from data in TCGA. In summary, our data revealed stimulatory activity of the CXCR3alt-CXCL11 chemokine system on CD8+ T cells that is predictive of chemotherapy responsiveness in MIBC. This may offer immunotherapeutic options for targeted activation of intratumoral stem-like T cells in solid tumors.
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| 13. |
- Wågström, Per, 1967-
(författare)
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Clinical and immunological aspects of IgG subclass deficiency : Predictors for the need of immunoglobulin replacement therapy
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Predominantly antibody deficiencies (PAD) are inborn errors of immunity, and associate with increased susceptibility to infections. Life-long immunoglobulin replacement therapy (IgRT) is introduced based on Ig-levels and the frequencies and severity of infections. The subgroup of PAD with immunoglobulin G subclass deficiency (IgGsd) is often less severe and the need of IgRT in these patients is unclear. Often many years pass before IgGsd is diagnosed, and repeated respiratory tract infections risk to confer lung tissue damage. The Swedish standard regimen in IgGsd is IgRT during 18 months followed by a period of discontinuation in order to evaluate the effect and restart it, if infections reoccur. It is a challenge to identify the subgroup of IgGsd-individuals in need of life-long treatment, and early reliable markers are warranted. Aim: The aim of this thesis was to identify clinical and laboratory factors predicting the need of long-term IgRT in IgGsd and evaluate its effects on immunological functions. Results: In paper I, the established clinical warning sign that is used to identify individuals with PAD in need of IgRT, was evaluated regarding the accuracy to identify IgGsd in a primary care register with data from 350,000 visits due to respiratory tract infections. The predictive value was low and according to medical records, a primary immunodeficiency was rarely suspected. In paper II, a lower frequency of homozygosity for the high affinity IgG receptor FcγRIIa H/H131 were found in IgGsd compared to controls. The finding supports the hypothesis that FcγR-polymorphisms may be of importance for susceptibility to infections in IgGsd and may have impact on the need of IgRT. In paper III, patient reported outcome showed that severe fatigue and low health related quality of life associated with the need of life-long IgRT. Systemic inflammation is known to associate with fatigue and in paper III and IV extensive immunophenotyping was performed when on and off IgRT. IgGsd patients were characterized by dysregulated plasma protein profiles enriched for factors associated with interleukin 10 signaling that were unaffected by IgRT. Among circulating immune cells, decreased proportions of activated B- and T cell subsets, as well as regulatory T cells, were found and partly restored during IgRT. Individuals needing life-long IgRT had a lower prevalence of protective pneumococcal specific IgG against 21 tested capsular serotypes. Co-morbidity with autoimmunity, atopy, lung disease and other factors such as higher age and occupation also associated to the need of IgRT. Conclusion: IgGsd patients were characterized by increased systemic inflammation, which was unaffected by IgRT. Decreased activation of lymphocyte subsets was partly restored during IgRT. Severe fatigue, protective IgG levels against a low number of pneumococcal serotypes, especially in conjunction with comorbidities were associated with the need for IgRT. Overall, no factor alone could predict the need of life-long IgRT.
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| 14. |
- Zhang, Lu, et al.
(författare)
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Immune responses against autologous tumor and human papilloma virus in lymph nodes from patients with penile cancer
- 2021
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Ingår i: Investigative and Clinical Urology. - : The Korean Urological Association. - 2466-0493 .- 2466-054X. ; 62
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Nearly half of penile cancers are related to human papillomavirus (HPV) infection. Investigations of tumor- and HPV-specific T cell reactivity in regional lymph nodes (LNs) from patients with penile cancer are warranted.MATERIALS AND METHODS: In this study, single-cell suspensions from LNs and peripheral blood from 11 patients with penile cancer were stained with antibodies for lymphocyte markers and analyzed by fluorescence-activated cell sorting (FACS). DNA was extracted from the tumor tissue and HPV status was investigated by PCR.RESULTS: T-cell reactivity against autologous tumor-extract and against the HPV-vaccine Gardasil® was tested by flow-cytometric assay of specific cell-mediated immune response in activated whole blood (FASCIA). CD4+/CD8+ ratios were significantly lower in HPV positive LNs (p<0.05). Immune responses to tumor extract assessed by blast transformation and expansion in vitro, of either CD4+ or CD8+ T-cells, were found in 9 of 13 LNs (69%). 5 of 6 tested patients demonstrated T cell recognition of tumor-associated antigen(s). In HPV-positive patients, dose-dependent T cell responses against L1 (late) HPV proteins (Gardasil vaccine) were demonstrated.CONCLUSIONS: LN-derived T cells from patients with penile cancer recognize tumor antigen(s) and in HPV-positive cases, there is a response against L1 (late) HPV proteins, being constituents of the Gardasil vaccine.
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| 15. |
- Zirakzadeh, A. Ali, et al.
(författare)
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Tumour-associated B cells in urothelial urinary bladder cancer
- 2020
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Ingår i: Scandinavian Journal of Immunology. - : Wiley-Blackwell. - 0300-9475 .- 1365-3083. ; 91:2
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Tidskriftsartikel (refereegranskat)abstract
- Tumour infiltrating B cells and CD38+ plasma cells have been correlated with survival in different malignancies but their role in urinary bladder cancer is unclear. IL-10 is a multifunctional cytokine with both anti-inflammatory and immunostimulatory properties, that can be released by regulatory B cells (Bregs). We have stained paraffin-embedded tumour sections from 31 patients with invasive urothelial urinary bladder cancer with respect to CD20+ B cells, CD38+ cells, IL-10-expressing cells, IgG, C1q and C3a and analysed the impact of these markers on survival. Interestingly, we observe tumour-associated CD20+ B cells forming follicle-like structures in tumours of some patients. We demonstrate that follicle-like structures, tumour-associated CD38+ cells, IL-10 produced by non-B cells, tumour infiltrating IgG and activation of the complement system, may associate to longer survival of urinary bladder cancer patients. IL-10 expression by tumour-associated Bregs may instead negatively affect prognosis. More research is needed to fully understand the role of B cells and IL-10 in urinary bladder cancer.
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