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Objectives: To explore the human leucocyte antigen (HLA)-DRB1 allele frequency in Dupuytren's disease (DD). Method: HLA-DRB1 genotypes were analysed by sequence-specific primers (SSPs) in samples collected from 172 men participating in a nested case-control study on the clinical manifestations and progression of DD. Of those, 121 had signs of DD while 51 did not. Of the 121 men with DD, 49 had contracted fingers or had been operated on, while 72 had nodules or fibrous cords in the palms. Odds ratios (ORs) and 95% confidence interval (CIs) were used to evaluate the results. Results: The HLA-DRB1*01 allele was observed in 26 of the 121 affected men (23.7%) but in only four of the controls (7.8%) (OR 3.22, 95% CI 1.06-9.75). The HLA-DRB1*01 allele frequency in those affected was 11%, while in the control group it was 4% (OR 3.07, 95% CI 1.05-9.03). Conclusions: This observation indicates a possible association of HLA-DRB1*01 with DD, but further studies are needed for confirmation. [ABSTRACT FROM AUTHOR]

Untreated earlobe capillary blood samples from 5958 girls were screened for rubella antibodies by placing them directly onto haemolysis-in-gel (HIG) test plates. The method is in our experience quick, reliable and also acceptable to young girls. The method is convenient for testing for natural immunity before vaccination and in most but not all cases satisfactory as a test for seroconversion after vaccination. A comparison was made between naturally infected girls and a group of vaccinated girls. Vaccinated girls had lower values and most of the low or doubtful positives were in this group. Serum samples from 51 low positive girls were tested by the haemagglutination inhibition (HI) test and the serum HIG test and their results compared with their respective direct HIG values. [ABSTRACT FROM PUBLISHER]

CD8 + cytotoxic T lymphocytes (CTLs) are critical mediators of anti-tumor immunity, and controlling the mechanisms that govern CTL functions could be crucial for enhancing patient outcome. Previously, we reported that hepatocyte growth factor (HGF) limits effective murine CTL responses via antigen-presenting cells. Here, we show that a fraction of murine effector CTLs expresses the HGF receptor c-Met (c-Met + CTLs). Phenotypic and functional analysis of c-Met + CTLs reveals that they display enhanced cytolytic capacities compared to their c-Met - CTL counterparts. Furthermore, HGF directly restrains the cytolytic function of c-Met + CTLs in cell-mediated cytotoxicity reactions in vitro and in vivo and abrogates T-cell responses against metastatic melanoma in vivo Finally, we establish in three murine tumor settings and in human melanoma tissues that c-Met + CTLs are a naturally occurring CD8 + T-cell population. Together, our findings suggest that the HGF/c-Met pathway could be exploited to control CD8 + T-cell-mediated anti-tumor immunity., (© 2017 The Authors.)

Background: Accumulating evidence indicate that B cells can exhibit pro- or anti-inflammatory activities. Similar to interleukin (IL)-10-competent B cells, we recently showed that transforming growth factor (TGF)-β1-producing regulatory B cells limit the induction of autoimmune neuroinflammation in mice, making them potentially important in maintaining peripheral immune tolerance in central nervous system inflammatory demyelinating disorders such as multiple sclerosis., Methods: In this study, we compared B cell production of TGF-β1 and IL-10, the two most studied regulatory cytokines, and the pro-inflammatory B cell-derived IL-6 and tumor necrosis factor cytokines under basal conditions and following polyclonal stimulation with dual B cell receptor (BCR) cross-linking and Toll-like receptor (TLR)9 engagement., Results: We showed that resting TGF-β1-producing B cells fall within both the naïve (CD27 - ) and memory (CD27 + ) B cell compartments. We found no spontaneous B cell-derived IL-10, IL-6 or tumor necrosis factor (TNF) production. Human B cell activation with anti-Ig antibodies plus CPG-B leads to only modest IL-10 production by memory CD19 + CD27 + B cells while expression levels of IL-6 and TNF by both naive and memory B cells were strongly induced. Remarkably, stimulated B cells showed significantly reduced capacity to produce TGF-β1., Conclusions: These findings indicate that B cell activation may facilitate the development of excessive immune responses and autoimmunity by restricting B cell-derived TGF-β1 production by resting B cells and favoring in turns the proinflammatory actions of activated cytokine-producing B cells.

Studies in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), have shown that regulatory B cells modulate the course of the disease via the production of suppressive cytokines. While data indicate a role for transforming growth factor (TGF)-β1 expression in regulatory B cell functions, this mechanism has not yet been tested in autoimmune neuroinflammation. Transgenic mice deficient for TGF-β1 expression in B cells (B-TGF-β1 -/- ) were tested in EAE induced by recombinant mouse myelin oligodendrocyte glycoprotein (rmMOG). In this model, B-TGF-β1 -/- mice showed an earlier onset of neurologic impairment compared to their littermate controls. Exacerbated EAE susceptibility in B-TGF-β1 -/- mice was associated with augmented CNS T helper (Th)1/17 responses. Moreover, selective B cell TGF-β1-deficiency increased the frequencies and activation of myeloid dendritic cells, potent professional antigen-presenting cells (APCs), suggesting that B cell-derived TGF-β1 can constrain Th1/17 responses through inhibition of APC activity. Collectively our data suggest that B cells can down-regulate the function of APCs, and in turn encephalitogenic Th1/17 responses, via TGF-β1, findings that may be relevant to B cell-targeted therapies.

Hepatocyte growth factor (HGF) limits mouse autoimmune neuroinflammation by promoting the development of tolerogenic dendritic cells (DCs). Given the role played by DCs in the establishment of immunological tolerance, agents that coerce DCs to adopt a protolerogenic function are currently under investigation for multiple sclerosis (MS) therapy. Here, we studied the immunomodulatory effects of HGF on DCs derived from human monocytes. DCs differentiated in the presence of HGF adopt a protolerogenic phenotype with increased ability to generate regulatory T cells, a property that might be exploited therapeutically in T cell-mediated immune disorders such as MS., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Interferon-β is a first-line therapy used to prevent relapses in relapsing-remitting multiple sclerosis. The clinical benefit of interferon-β in relapsing-remitting multiple sclerosis is attributed to its immunomodulatory effects on inflammatory mediators and T cell reactivity. Here, we evaluated the production of hepatocyte growth factor, a neuroprotective and neuroinflammation-suppressive mediator, by peripheral blood mononuclear cells collected from interferon-β--treated relapsing-remitting multiple sclerosis patients, relapsing remitting multiple sclerosis patients not treated with interferon-β, and healthy volunteers. Using intracellular flow cytometry analysis, increased production of hepatocyte growth factor was observed in circulating CD14(+) monocytes from patients undergoing long-term treatment with interferon-β versus untreated patients. Complementary in vitro studies confirmed that treatment with interferon-β induced rapid and transient transcription of the hepatocyte growth factor gene in CD14(+) monocytes and that intracellular and secreted monocytic hepatocyte growth factor protein levels were markedly stimulated by interferon-β treatment. Additional exploration revealed that "pro-inflammatory" (CD14(+)CD16(+)) monocytes produced similar levels of hepatocyte growth factor in response to interferon-β as "classical" (CD14(+)CD16(-)) monocytes, and that CD14(+) monocytes but not CD4(+) T cells express the hepatocyte growth factor receptor c-Met. Our findings suggest that interferon-β may mediate some of its therapeutic effects in relapsing-remitting multiple sclerosis through the induction of hepatocyte growth factor by blood monocytes by coupling immune regulation and neuroprotection.

Background and Objectives: The occurrence of two or more cases of multiple myeloma (MM) in the same family has been reported from time to time. The current study is the first population- and cancer-registry-based survey to investigate familiality of premalignant or malignant B-cell proliferation., Design and Methods: A family registry of 218 multiple myeloma cases was compared with the records of the Icelandic Cancer Registry in order to analyze the pedigrees for the occurrence of families with multiple cases of paraproteinemia and hematologic malignancies., Results: The relative risk of developing monoclonal gammopathies of unknown significance (MGUS) was not increased among first-degree relatives of MM patients, but there was a significantly increased risk of developing MM for females separately (RR = 3.23, CI 1.17-7.01) and for males and females combined (RR = 2.33, CI 1.12-4.26). Analysis for all hematologic malignancies showed an increased risk for female relatives of MM patients (RR = 1.95, CI 1.10-3.20). Eight families were identified in which the propositus with MM had > 1 relatives with MGUS and > 1 with another hematologic malignancy, including 4 families with another relative with MM. In three families both myeloid and lymphoid malignancies occurred., Interpretation and Conclusions: Although inheritance does not appear to be a major risk factor for the development of paraproteinemias a significant risk of developing MM was found for female relatives. The occurrence of multiple cases of benign and malignant paraproteinemias in a few families does suggest a hereditary contribution. Further studies of such families might reveal clues on pathogenesis.

The term monoclonal gammopathy (MG) signifies the benign or malignant clonal growth of B lymphocytes. In the present study, monoclonal gammopathy of unknown significance (MGUS) was defined as those patients with no identified haematological malignancy. A database was constructed of all 713 MG patients in Iceland between 1976 and 1997 and compared with the Icelandic Cancer Registry. The age-standardized incidence per 100 000 of MG was 10.3 for males and 8.6 for females, calculated for the whole period, rising steadily from 5.8 (men) and 4.9 (women) during the 5-year period 1976-80 to 14.7 (men) and 12.5 (women) during the last 5 year period. Age-standardized incidence rates were very low for subjects under 50 years of age, then increased with age from 11 and 17 per 100 000 at 50-54, to 169 and 119 per 100 000 at age 80-84, for men and women respectively. No association was detected between MG and non-haematological malignancies, neither retrospectively nor prospectively. Haematological malignancy was diagnosed in 209 (29.3%) cases before the recorded finding of MG or within the same calendar year, leaving 504 (70.7%) patients diagnosed with MGUS. Of these, 51 (10%) progressed to multiple myeloma or Waldenström's macroglobulinaemia after a mean interval of 3.8 years; mean follow-up was 7.4 years, median 6 years. The most common immunoglobulin (Ig) class was IgG (55%), followed by IgM (32%) and IgA (13%). MGUS was a highly significant risk factor for developing haematological malignancies and the risk was significantly greater for MG of the IgA class compared with either IgG or IgM.

Objective: To study MHC haplotypes and C4AQ0 in Caucasian multicase systemic lupus erythematosus (SLE) families from Iceland., Methods: Eight families with 26 SLE patients, 98 non-SLE first-degree relatives, and a control group were studied. For statistical analysis one SLE patient and one first-degree relative were randomly chosen from each family. C4 allotyping was performed by protein electrophoresis, HLA typing of class I by the lymphocytotoxicity test, and typing of class II alleles with polymerase chain reaction with sequence specific primers., Results: Six of the 8 families showed a high background of C4A protein deficiency (C4AQ0) and a significant increase was seen in C4AQ0 in the randomly chosen group of patients. A similar tendency that was statistically nonsignificant was seen in first-degree relatives. In the SLE patients C4AQ0 was found on several MHC haplotypes. Half the patients with C4A protein deficiency carry C4AQ0 on the classical C4A deletion haplotype B8-C4AQ0-C4B1-DR3 or variants of it, and the remaining C4A deficient patients on other non-DR3 carrying haplotypes. The transmission of C4AQ0 from parents to patients was in most cases through the family line, although in some instances it originates from outside the multicase SLE family through spouses married into the family., Conclusion: In these Caucasian multicase SLE families from Iceland, C4AQ0 shows weaker linkage disequilibrium with DR3 than reported in studies on other white populations, emphasizing the role of ethnicity. The common factor in the MHC haplotypes studied is C4AQ0, supporting a hypothesis that C4AQ0 may be an independent risk factor for SLE.

Objective: Approximately 5% of cancer patients are diagnosed with tumour of unknown origin (3-4% in Iceland). Of those 10-30% have liver metastases. Liver metastases of unknown origin is thus not an uncommon problem. In the present study information about the origin and histology of liver metastases of unknown origin was compiled., Material and Methods: Records of all biopsies from liver metastases performed in the years 1987-1996 were retrieved from the medical database of the Department of Pathology at the University of Iceland. The biopsies came from a group of 176 patients. Ninety-two cases, in which the origin of the primary tumour was suspected or known, were excluded from the study, leaving 84 cases where the primary was completely unknown. The database of the Icelandic Cancer Society was used to gather data about the final tissue diagnosis and the location of the primary tumour when known., Results: The Cancer Society data revealed the location of the primary tumour in 55 of the 84 cases of liver metastases of unknown origin. The most prevalent (75%) primary tumours were cancers of the pancreas (15), lung (13) and colon/rectum (12). The tissue diagnosis was adenocarcinoma in 33 of the 55 cases. In the male patients 83% of the adenocarcinoma metastases came from the colon/rectum or pancreas. The corresponding figure for the female patients was 67%, while 20% of the tumours in females originated in the gallbladder and biliary tree., Conclusions: In two thirds of the cases of liver metastases of unknown origin the primary tumour was later discovered. The most prevalent tumours were cancers in the pancreas, lung and colon/rectum. Adenocarcinoma was the tissue diagnosis in 60% of cases.

The records of a cohort of 11,580 females and 11,366 males participating in an Icelandic cardiovascular risk factor study were linked with the Icelandic Cancer Registry, identifying 1,785 males and 1,490 females who had been registered with neoplastic diseases from 1968 to 1995. The interval between the time of measurement of the variables and the diagnosis of the malignancy ranged from 4 to 27 years. The variables consisted of answers from a questionnaire on smoking and the use of hypertensive drugs and anthropometric and biochemical measurements. Cox's regression was applied to analyze the predictive power of the variables on the risk of cancer after the first examination at the Heart Preventive Clinic, Reykjavík. Univariate analyses, adjusted for age, were performed for each variable and each major site. Within each major site, multivariate regression analysis was applied for variables that were found significantly (10% level in univariate analysis) positive or negative as risk factors. The results show that smoking is the most important risk factor, negative only for endometrium. For lung cancer, the risk is twice as strong for females as it is for males, whereas for pancreas, males have a relative risk ratio of 4.5, compared with 2.4 for females. Height is a risk factor for all sites for each sex, for breast in females, and for kidney in males. Several anthropometric risk factors were studied. Some of these can describe positive or negative relative risk ratios for cancer, and their use may shed light on cancer pathogenesis. Serum cholesterol is a negative risk factor for breast cancer in females, but triglycerides are a positive risk factor for cervix cancer in females and for colon or rectum and thyroid cancer in males. Serum glucose is a positive risk factor for prostate cancer and a negative risk factor for lymphomas and leukemias.