Association between serum markers of the humoral immune system and inflammation in the Swedish AMORIS study.

BACKGROUND: Although the onset of inflammatory cascades may profoundly influence the nature of antibody responses, the interplay between inflammatory and humoral (antibody) immune markers remains unclear. Thus, we explored the reciprocity between the humoral immune system and inflammation and assessed how external socio-demographic factors may influence these interactions. From the AMORIS cohort, 5513 individuals were identified with baseline measurements of serum humoral immune [immunoglobulin G, A & M (IgG, IgA, IgM)] and inflammation (C-reactive protein (CRP), albumin, haptoglobin, white blood cells (WBC), iron and total iron-binding capacity) markers measured on the same day. Correlation analysis, principal component analysis and hierarchical clustering were used to evaluate biomarkers correlation, variation and associations. Multivariate analysis of variance was used to assess associations between biomarkers and educational level, socio-economic status, sex and age. RESULTS: Frequently used serum markers for inflammation, CRP, haptoglobin and white blood cells, correlated together. Hierarchical clustering and principal component analysis confirmed the interaction between these main biological responses, showing an acute response component (CRP, Haptoglobin, WBC, IgM) and adaptive response component (Albumin, Iron, TIBC, IgA, IgG). A socioeconomic gradient associated with worse health outcomes was observed, specifically low educational level, older age and male sex were associated with serum levels that indicated infection and inflammation. CONCLUSIONS: These findings indicate that serum markers of the humoral immune system and inflammation closely interact in response to infection or inflammation. Clustering analysis presented two main immune response components: an acute and an adaptive response, comprising markers of both biological pathways. Future studies should shift from single internal marker assessment to multiple humoral and inflammation serum markers combined, when assessing risk of clinical outcomes such as cancer.

Serum Immunoglobulin G Is Associated With Decreased Risk of Pancreatic Cancer in the Swedish AMORIS Study.

Background: Emerging evidence points to potential roles of the humoral immune responses in the development of pancreatic cancer. Epidemiological studies have suggested involvement of viral and bacterial infections in pancreatic carcinogenesis. Experimental studies have reported high expression levels of antigens in pancreatic cancer cells. Therefore, we aimed to investigate the role of different components of humoral immunity in the context of pancreatic cancer. We evaluated associations between pre-diagnostic serum markers of the overall humoral immune system [immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM)], and the risk of pancreatic cancer in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) study. Methods: We selected all participants (≥20 years old) with baseline measurements of IgA, IgG or IgM (n = 41,900, 136,221, and 29,919, respectively). Participants were excluded if they had a history of chronic pancreatitis and individuals were free from pancreatic cancer at baseline. Multivariate Cox proportional hazards regression was used to estimate risk of pancreatic cancer for medical cut-offs of IgA, IgG, and IgM. Results: Compared to the reference level of 6.10-14.99 g/L, risk of pancreatic cancer was elevated among those with IgG levels <6.10 g/L [HR: 1.69 (95% CI 0.99-2.87)], and an inverse association was observed among those with IgG levels ≥15.00 g/L [0.82 (95% CI 0.64-1.05); Ptrend = 0.027]. The association appeared to be stronger for women than men [HR: 0.64 (95% CI 0.43-0.97) and 0.95 (95% CI 0.69-1.29), respectively]. No associations were observed with IgA or IgM. Conclusion: An inverse association was observed between pre-diagnostic serum levels of IgG and risk of pancreatic cancer. Our findings highlight the need to further investigate the role of immune response in pancreatic cancer etiology.

Association of Serum Immunoglobulin Levels with Solid Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: The nature of humoral immunity in carcinogenesis remains poorly understood. In this systematic review and meta-analysis, we aimed to evaluate the association of serum immunoglobulin classes with solid cancer and test our hypothesis that the immune escape of tumors is accompanied by dysregulated systemic immunoglobulin class-switching. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched the Cochrane Library, Embase, and MEDLINE/PubMed databases for observational studies investigating the association between serum immunoglobulins (IgA, IgG, and IgM) and histologically confirmed diagnosis of solid cancer in adults. We selected case-control studies, including more than 20 cases, and those explicitly stating that no form of anticancer treatment was administered prior to immunoglobulin measurement. No eligible cohort studies were identified. The primary summary measure was the standardized mean difference (SMD) with 95% confidence intervals (CI) calculated using a random effects model. RESULTS: Pooling 11 eligible studies comparing serum IgA levels in 1,351 patients and 560 control subjects revealed a statistically significant SMD (1.50; 95% CI, 0.96-2.04). Nonsignificant SMDs were observed for the 14 selected studies investigating serum IgG [SMD, -0.02 (95% CI, -0.22 to 0.18)] and for the 10 studies reporting serum IgM [SMD, 0.11 (95% CI, -0.10 to 0.32)]. Substantial heterogeneity between studies was observed despite sensitivity analysis by immunoglobulin measurement method, control matching, type of cancer, stage of disease, and sequential study exclusion. CONCLUSIONS: Serum immunoglobulin levels in patients diagnosed with solid cancer might be skewed toward class-switching to IgA, possibly reflecting Th2-polarized immunity. IMPACT: Further combinatorial analyses of serum immunoglobulin isotypes alongside other immune parameters in databases and observational studies are warranted.

Serum IgG Is Associated With Risk of Melanoma in the Swedish AMORIS Study.

Background: Relatively little is known about the role of the humoral immune system in melanoma. Tumor infiltrating B cells in melanoma patients have been associated with increased T cell activation in tumors as well as improved patient survival. Immunoglobulins may play an important part in the anti-tumor immune response. We hypothesized that increased levels of pre-diagnostic serum Ig may be protective against melanoma development. Hence, we evaluated associations between pre-diagnostic serum markers of the immunoglobulin A (IgA), IgG and IgM, and risk of developing melanoma in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) study. Methods: Study participants aged ≥20 years with baseline measurements of IgG, IgA and IgM taken between 1985 and 1996 were selected (n = 29,876). All individuals were free from melanoma at baseline and 162 study participants developed melanoma during follow up. Cox proportional hazards regression was carried out for medical cut-offs of IgA, IgG, and IgM. Results: Compared to the reference level of 6.10-14.99 g/l, we observed a positive but not significant association with risk of melanoma for those with IgG levels <6.10 g/L [HR: 1.05 (95% CI 0.39-2.86)] and an inverse association for those with IgG levels ≥15.00 g/L [HR: 0.60 (95% CI 0.34-1.05); P trend = 0.08]. No associations with serum IgA or IgM were identified. Conclusions: The humoral response might provide a protective role against the development of melanoma, mediated through IgG. Further research is needed to characterize this response which may be exploitable for development of future therapies.

Chronic inflammation markers are associated with risk of pancreatic cancer in the Swedish AMORIS cohort study.

BACKGROUND: Nested case-control studies examining the association between serum markers of chronic inflammation, focused on three specific biomarkers (CRP, IL-8 and TNF-α), and risk of pancreatic cancer have reported no associations. In this study, we evaluated associations between standard pre-diagnostic serum markers of chronic inflammation (CRP, albumin, haptoglobin and leukocytes) and pancreatic cancer risk in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) prospective cohort study. METHODS: We selected all participants (≥20 years old) with baseline measurements of CRP, albumin, haptoglobin and leukocytes between 1985 and 1996 (n = 61,597). Participants were excluded if they had a history of chronic pancreatitis and all individuals were free from pancreatic cancer at baseline. Cox proportional multivariable hazards regression analysis was carried out for medical cut-offs of CRP, albumin, haptoglobin and leukocytes. RESULTS: We observed an increased risk of pancreatic cancer for those individuals with higher levels of serum haptoglobin (≥1.4 g/L), CRP (≥10 mg/L) and leukocytes (≥10 × 109 cells/L) compared to those with haptoglobin levels < 1.4 g/L, CRP levels < 10 mg/L and Leukocyte levels < 10 × 109 cells/L [haptoglobin HR: 2.23 (95% CI 1.72-2.88), CRP HR: 1.32 (95% CI 1.00-1.74), leukocytes HR: 2.20 (95% CI 1.52-3.18)]. No associations were noted for serum albumin. CONCLUSIONS: We found an increased risk of pancreatic cancer associated with pre-diagnostic serum levels of haptoglobin, CRP and leukocytes. Our finding suggests a possible role of chronic inflammation in the aetiology of pancreatic cancer and highlight the need to further investigate this association.

Serum immunoglobulin levels and the risk of bladder cancer in the AMORIS Cohort.

BACKGROUND: The anti-tumour T-cell response in bladder cancer has been shown to correlate with response to treatment and prognosis. However, little is known about the role of humoral immunity in this highly immunogenic human cancer, which is characterised by a high mutation-associated neoantigen load and a strong response to immunotherapy. In the present study, we interrogated the Swedish Apolipoprotein Mortality Risk Study (AMORIS) to explore the relationship between pre-diagnostic serum immunoglobulin levels and the risk of developing bladder cancer. METHODS: Our analysis included all AMORIS participants aged 20 years or older, who had all three major serum immunoglobulins (IgA, IgM, IgG) recorded at the same baseline measurement (n = 29,876). All participants were free from bladder cancer at the time of measurement. Samples were obtained between 1985-1996, with follow-up information until 2011. Multivariate Cox proportional hazards regression was used to investigate the association between bladder cancer risk and different levels of pre-diagnostic serum immunoglobulins. RESULTS: During a mean follow-up period of 15.31 years, 163 (0.5%) individuals were diagnosed with bladder cancer. Multivariate Cox regression showed an inverse association between pre-diagnostic serum IgM levels ≥ 1.4 g/L and bladder cancer risk compared to serum IgM levels < 1.4 g/L [HR: 0.68 (95% CI 0.45-1.03)]. Corresponding associations could not be established for serum IgA or IgG. CONCLUSION: Our findings implicate serum IgM in the pathogenesis of bladder cancer and suggest that the concept of humoral immune surveillance against cancer warrants further mechanistic investigation.

The global prevalence of erectile dysfunction: a review.

OBJECTIVE: To evaluate the global prevalence of erectile dysfunction (ED); as well as its association with physiological and pathological ageing by examining the relationship between ED and cardiovascular disease (CVD), benign prostatic hyperplasia (BPH), and dementia. We also aimed to characterise discrepancies caused by the use of different ED screening tools. METHODS: The Excerpta Medica dataBASE (EMBASE) and Medical Literature Analysis and Retrieval System Online (MEDLINE) were searched to find population-based studies investigating the prevalence of ED and the association between ED and CVD, BPH, and dementia in the general population. RESULTS: The global prevalence of ED was 3-76.5%. ED was associated with increasing age. Use of the International Index of Erectile Function (IIEF) and Massachusetts Male Aging Study (MMAS)-derived questionnaire identified a high prevalence of ED in young men. ED was positively associated with CVD. Men with ED have an increased risk of all-cause mortality odds ratio (OR) 1.26 (95% confidence interval [CI] 1.01-1.57), as well as CVD mortality OR 1.43 (95% CI 1.00-2.05). Men with ED are 1.33-6.24-times more likely to have BPH then men without ED, and 1.68-times more likely to develop dementia than men without ED. CONCLUSION: ED screening tools in population-based studies are a major source of discrepancy. Non-validated questionnaires may be less sensitive than the IIEF and MMAS-derived questionnaire. ED constitutes a large burden on society given its high prevalence and impact on quality of life, and is also a risk factor for CVD, dementia, and all-cause mortality.

Immune mediator expression signatures are associated with improved outcome in ovarian carcinoma.

Immune and inflammatory cascades may play multiple roles in ovarian cancer. We aimed to identify relationships between expression of immune and inflammatory mediators and patient outcomes. We interrogated differential gene expression of 44 markers and marker combinations (n = 1,978) in 1,656 ovarian carcinoma patient tumors, alongside matched 5-year overall survival (OS) data in silico. Using machine learning methods, we investigated whether genomic expression of these 44 mediators can discriminate between malignant and non-malignant tissues in 839 ovarian cancer and 115 non-malignant ovary samples. We furthermore assessed inflammation markers in 289 ovarian cancer patients' sera in the Swedish Apolipoprotein MOrtality-related RISk (AMORIS) cohort. Expression of the 44 mediators could discriminate between malignant and non-malignant tissues with at least 96% accuracy. Higher expression of classical Th1, Th2, Th17, anti-parasitic/infection and M1 macrophage mediator signatures were associated with better OS. Contrastingly, inflammatory and angiogenic mediators, CXCL-12, C-reactive protein (CRP) and platelet-derived growth factor subunit A (PDGFA) were negatively associated with OS. Of the serum inflammatory markers in the AMORIS cohort, women with ovarian cancer who had elevated levels of haptoglobin (≥1.4 g/L) had a higher risk of dying from ovarian cancer compared to those with haptoglobin levels <1.4 g/L (HR = 2.09, 95% CI:1.38-3.16). Our findings indicate that elevated "classical" immune mediators, associated with response to pathogen antigen challenge, may confer immunological advantage in ovarian cancer, while inflammatory markers appear to have negative prognostic value. These highlight associations between immune protection, inflammation and clinical outcomes, and offer opportunities for patient stratification based on secretome markers.

Selenium and Sex Steroid Hormones in a U.S. Nationally Representative Sample of Men: A Role for the Link between Selenium and Estradiol in Prostate Carcinogenesis?

BACKGROUND: Given the recent findings from pooled studies about a potential inverse association between selenium levels and prostate cancer risk, this cross-sectional study aimed to investigate the association between serum selenium and serum concentrations of sex steroid hormones including estradiol in a nationally representative sample of U.S. men to investigate one mechanism by which selenium may influence prostate cancer risk. METHODS: The study included 1,420 men ages 20 years or older who participated in the Third National Health and Nutrition Examination Survey between 1988 and 1994. We calculated age/race-ethnicity-adjusted and multivariable-adjusted geometric mean serum concentrations of total and estimated free testosterone and estradiol, androstanediol glucuronide, and sex hormone binding globulin, and compared them across quartiles of serum selenium. RESULTS: Adjusting for age, race/ethnicity, smoking status, serum cotinine, household income, physical activity, alcohol consumption, and percent body fat, mean total estradiol [e.g., Q1, 38.00 pg/mL (95% confidence interval (CI), 36.03-40.08) vs. Q4, 35.29 pg/mL (95% CI, 33.53-37.14); P trend = 0.050] and free estradiol [e.g., Q1, 0.96 pg/mL (95% CI, 0.92-1.01) vs. Q4, 0.90 (95% CI, 0.85-0.95); P trend = 0.065] concentrations decreased over quartiles of selenium. Stratification by smoking and alcohol consumption, showed that the latter observation was stronger for never smokers (P interaction = 0.073) and those with limited alcohol intake (P interaction = 0.017). No associations were observed for the other sex steroid hormones studied. CONCLUSIONS: Our findings suggests that a possible mechanism by which selenium may be protective for prostate cancer is related to estrogen. IMPACT: Further studies of longitudinal measurements of serum and toenail selenium in relation to serum measurements of sex steroid hormones are needed.