TNF-α -238, -308, -863 polymorphisms,and brucellosis infection

BackgroundBrucella abortus is an intracellular bacterium that affects humans and domestic animals. Tumor necrosis factor-alpha (TNF-α) has been shown as a key player in the induction of cell-mediated resistance against Brucella infection. We aimed to evaluate the possible influence of the TNF-α promoter polymorphisms (-308 G/A, -238 G/A, and -863 C/A) on the susceptibility of human brucellosis.MethodologyA total of 153 patients with active brucellosis and 128 healthy individuals were recruited. All subjects were genotyped for the polymorphisms in the TNF-α gene by Allele-Specific polymerase chain reaction analysis.ResultsOur results showed that the TNF-α -308 GG genotype was significantly more frequently present in controls than in brucellosis patients (91% vs. 75%), thus was a protective factor against developing brucellosis (OR = 0.313, p = 0.001). In contrast, the -308 GA genotype (OR = 3.026, p = 0.002) and minor allele (A) (OR = 3.058, p = 0.001) as well as AAG haplotype (OR = 4.014, p = 0.001) conferred an increased risk of brucellosis. However, the -238 G/A and -863 C/A polymorphisms were not associated with the risk of brucellosis at both allelic and genotypic levels (p > 0.05).ConclusionOur study revealed that the TNF-α -308 A allele or GA heterozygosity or AAG haplotype were associated with an increased risk of brucellosis in our population.     

TNFA -308G>A and -238G>A polymorphisms and risk to systemic sclerosis: impact on TNF-α serum levels,TNFA mRNA expression,and autoantibodies

Clinical and Experimental Medicine - Systemic sclerosis (SSc) is a rare autoimmune disease with high mortality, characterized by chronic inflammation and fibrosis, which are processes associated...     

Matrix metalloproteinase-2, -9, -12, and tissue inhibitor of metalloproteinase 2 gene polymorphisms and cutaneous expressions in patients with Behçet's disease

Matrix metalloproteinases (MMPs) induce leukocyte migration into inflammation sites that lead to either promotion or repression of inflammation by activating or inactivating cytokines. An increased level of MMP-9 and a decreased level of MMP-2 have been observed in Beh?et's disease (BD). This study was performed to analyze the relationship between MMP-2, -9, -12 and the tissue inhibitor of metalloproteinase-2 (TIMP-2) promoter polymorphisms in developing BD. The expression of MMP-2 and -9 was also evaluated in the skin of BD. The MMPs and TIMP-2 polymorphisms were confirmed by using polymerase chain reaction-restriction fragment length polymorphism in 251 BD and 312 controls. Cutaneous expression of MMP-2 and -9 in 17 BD patients with erythema nodosum (EN) or EN-like lesion was compared with 14 patients with idiopathic EN by immunohistochemical stains. The frequency of MMP-2-1575*G/*G and MMP-2-735*C/*C genotypes was shown to be lower in BD, whereas MMP-9-1562*C/*C was significantly higher in BD compared with the controls. The frequency of common haplotype MMP-2-1575*G -735*C was significantly lower in BD patients than in controls (P = 0.0046, permutation P = 0.009). No significant differences were observed between BD and controls in the allele and genotype frequencies of MMP-12-82A>G or TIMP-2-418G>C polymorphisms. The tissue expression of MMP-2, shown by immunohistochemistry, was significantly lower in BD compared with the controls. However, the expression of MMP-9 was significantly higher in BD. These results suggest that MMP-2 and -9 could each modulate the development of BD in opposite directions. Major genotypes of the MMP-2-1575*G/*G and MMP-2-735*C/*C and the common MMP-2-1575*G -735*C haplotype may provide some protection against development of BD, while MMP-9-1562*C/*C may promote the disease. The reciprocal expression of MMP-2 and -9 in the skin tissue of BD was also confirmed.     

Expression of GFRα-1, GFRα-2, and c-Ret mRNAs in rat adrenal gland

Glial cell line-derived neurotrophic factor (GDNF), an important factor for developing and lesioned pre- and postganglionic sympathetic neurons, and its congeners signal through a receptor complex consisting of the tyrosine kinase c-Ret and a lipid-anchored receptor (GFR-1-4). Using in situ hybridization we show now that the mRNA for GFR-2 is abundant in the adult rat adrenal medulla and its chromaffin cells. Coexpression of c-Ret and GFR-1 mRNA's is restricted to a scarce subpopulation of medullary sympathetic neurons. Both GFR-1 and GFR-2 mRNA's are associated with preganglionic nerve trunks in the adrenal cortex. It is conceivable therefore that GDNF and related factors may activate chromaffin and preganglionic Schwann cells through a GFR- receptor in absence of c-Ret.     

Comparison of interferon-γ-, interleukin (IL)-17- and IL-22-expressing CD4 T cells, IL-22-expressing granulocytes and proinflammatory cytokines during latent and active tuberculosis infection

In this study, we investigated the role and expression of T helper type 17 (Th17) cells and Th17 cytokines in human tuberculosis. We show that the basal proportion of interferon (IFN)-γ-, interleukin (IL)-17- and IL-22-expressing CD4(+) T cells and IL-22-expressing granulocytes in peripheral blood were significantly lower in latently infected healthy individuals and active tuberculosis patients compared to healthy controls. In contrast, CD4(+) T cells expressing IL-17, IL-22 and IFN-γ were increased significantly following mycobacterial antigens stimulation in both latent and actively infected patients. Interestingly, proinflammatory IFN-γ and tumour necrosis factor (TNF)-α were increased following antigen stimulation in latent infection. Similarly, IL-1β, IL-4, IL-8, IL-22 and TNF-α were increased in the serum of latently infected individuals, whereas IL-6 and TNF-α were increased significantly in actively infected patients. Overall, we observed differential induction of IL-17-, IL-22- and IFN-γ-expressing CD4(+) T cells, IL-22-expressing granulocytes and proinflammatory cytokines in circulation and following antigenic stimulation in latent and active tuberculosis.     

Effect of histamine on the production of matrix metalloproteinases-1, -3, -8 and -13, and TNFα and PGE<Subscript>2</Subscript> by human articular chondrocytes and synovial fibroblasts in vitro: a comparative study

Histamine has many regulatory activities and is well recognised for its importance in allergic and inflammatory disorders. Recently, histamine has been implicated in the pathophysiological processes of both rheumatoid and osteoarthritis, where human articular chondrocytes (HACs) and rheumatoid synovial fibroblasts (RSFs) are reported to express histamine receptors. This study has demonstrated H₁ and H₂ histamine receptors using immunohistochemistry on HACs and RSFs in vitro and has compared the effects of histamine (20 M) on both cell types with regard to the production of matrix metalloproteinases (MMPs-1, -3, -8 and -13), the proinflammatory cytokine tumour necrosis factor (TNF) and prostaglandin E₂ (PGE₂). On incubation with histamine, HACs showed increased production of MMP-3, MMP-13, TNF and PGE₂ (statistical significance P=0.02, 0.005, 0.008 and 0.03, respectively, students t-test), but MMP-1 expression was unaffected. In contrast, the RSF showed a histamine-induced increase in MMP-1 (P=0.028) and an approximate 10-fold level of MMP-3 and PGE₂ release over that of HACs, each being stimulated by histamine (P=0.02 and 0.032, respectively, students t-test). However, MMP-8, MMP-13 and TNF were not detected for RSF cultures. Our results show that histamine modifies the behaviour of both HACs and RSFs in vitro, but different effects were observed for the production of specific MMPs and TNF by the two cell types.     

Clinical, morphologic, immunophenotypic, and molecular cytogenetic assessment of CD4-/CD8-γδ T-cell large granular lymphocytic leukemia

γδ T-cell large granular lymphocytic (T-LGL) leukemia of the CD4-/CD8- subtype is rare, and data are limited in the literature. This study evaluated the clinical, morphologic, immunophenotypic, and molecular cytogenetic features of 7 cases of CD4-/CD8- γδ T-LGL leukemia. Although this variant shares several clinical and morphologic features with the more common T-LGL leukemias, the incidences of autoimmune hemolytic anemia and pure red cell aplasia are higher. Another striking feature observed in our study was the lack of increased large granular lymphocytes in the peripheral blood in the majority of cases despite prominent bone marrow or splenic involvement. CD4-/CD8- γδ T-LGL leukemia also displays an immunophenotype and pattern of splenic involvement overlapping with hepatosplenic T-cell lymphoma. Clinically, this variant of T-LGL leukemia shows an overall indolent course, but treatment is often required in the initial stages of the disease. Awareness of these features is important for early recognition and accurate diagnosis of patients with CD4-/CD8- γδ T-LGL leukemia.     

Biological continuum of benign, atypical, and malignant mesenchymal neoplasms - does it exist?

The characterization of specific cytogenetic and molecular abnormalities in benign and malignant soft tissue tumours has increased our understanding and knowledge of the biology of these rare neoplasms in recent years and has led to the modification of a number of traditional classification schemes. Contrary to popular belief, it is reasonable to propose that there exists a molecular, genetic, and morphological continuum of benign, atypical, and malignant mesenchymal neoplasms. The identification of characteristic molecular changes in benign lipomas, lipomas with minimal atypia, and atypical lipomatous tumours, well-differentiated liposarcomas supports the hypothesis of a stepwise process in the pathogenesis of these neoplasms. Not only are these findings important for our understanding of the biology of soft tissue tumours, but they also may increase diagnostic and prognostic accuracy.     

Mechanical properties,electronic structure and bonding of α- and β-tricalcium phosphates with surface characterization

The mechanical properties and electronic structure of α- and β-tricalcium phosphate (TCP) crystals are studied by using two ab initio density functional methods, the Vienna Ab initio Simulation Package (VASP) and the orthogonalized linear combination of atomic orbitals method. Based on the VASP optimized crystal structures, the elastic constants of α- and β-TCP are obtained using an effective stress–strain computational scheme. From the calculated elastic constants, the bulk modulus, shear modulus, Young’s modulus and Poisson’s ratios are obtained. The results show that the mechanical properties of the two crystals are comparable and that α-TCP is somewhat softer than β-TCP. Comparison with experimental extrapolations of the elastic constants shows significant differences, which attest to the difficulty of obtaining single crystal samples. The calculated electronic structure results show that both crystals are large gap insulators with a direct band gap of 4.89 eV for α-TCP and 5.25 eV for β-TCP. Effective charge calculations show that, on average, β-TCP has slightly less charge transfer per Ca than α-TCP. The (0 1 0) ((0 0 1)) surface model for α-TCP (β-TCP) is studied using a supercell slab geometry and fully relaxed to obtain the optimized structures. The estimated surface formation energies are 0.777 and 0.842 J m^?2 for α-TCP and β-TCP, respectively. The electronic structures of the two surface models are compared with the bulk models. Charge density analysis shows that the surfaces of both TCP crystals are positively charged overall owing to the presence of Ca ions near the surfaces.     

Chicken SLAMF4 (CD244, 2B4), a receptor expressed on thrombocytes,monocytes, NK cells,and subsets of αβ-, γδ- T cells and B cells binds to SLAMF2

The SLAM family of membrane receptors is involved in the regulation of immune responses by controlling cytokines production, cytotoxicity as well as cell development, differentiation and proliferation, but has only been described in chickens, recently. The aim of this study was to characterize the avian homologue to mammalian SLAMF4 (CD244, 2B4), a cell surface molecule which belongs to the SLAM family of membrane receptors. We generated a SLAMF4 specific monoclonal antibody (mab) designated 8C7 and analyzed the SLAMF4 expression on cells isolated from various lymphoid organs. Subsets of αβ and γδ T cells found in peripheral blood lymphocytes (PBL) and spleen coexpressed SLAMF4. The expression was restricted to CD8α⁺ T cells, whereas CD4⁺ T cells and all thymocytes showed little or no reactivity upon staining with the 8C7 mab. Blood and splenic γδ T cells could be further differentiated according to their expression levels of SLAMF4 into two and three subsets, respectively. SLAMF4 was absent from bursal and splenic B cells, however, it was expressed by a distinct fraction of circulating B cells that were characterized by high level expression of Bu1, Ig, and CD40. SLAMF4 was also present on NK cells isolated from intestine of adult chickens or embryonic splenocytes identified by their coexpression of the 28-4 NK cell marker. Moreover, SLAMF4 expression was found on thrombocytes and monocytes. The interaction of SLAMF4 with SLAMF2 was proven by a reporter assay and could be blocked with the 8C7 mab. In conclusion, the avian SLAMF4 expression markedly differs from mammals; it binds to SLAMF2 and will be an important tool to discriminate several γδ T cell subsets.     

Knowledge,motivations, expectations,and traits of an African,African-American,and Afro-Caribbean sequencing cohort and comparisons to the original ClinSeq® cohort

PurposeRacial minority populations are underrepresented in genomics research. This study enrolled African-descended individuals in a sequencing study and reported their characteristics.MethodsWe purposively recruited 467 individuals self-identified as African, African American, or Afro-Caribbean to the ClinSeq® study and surveyed them about knowledge, motivations, expectations, and traits. Summary statistics were calculated and compared with data from the study’s original cohort, which was primarily White and self-referred.ResultsRecruitment took five years and 83% of enrollees completed the survey. Participants had modest knowledge about benefits and limitations of sequencing (x̅s = 5.1, ranges: 0–10), and less than the original cohort (x̅= 7.5 and 7.7, respectively). Common motivations to enroll were learning information relevant to personal health (49%) or family members’ health (33%), and most had realistic expectations of sequencing. Like the original cohort, they had high levels of optimism, openness, and resilience.ConclusionEarly adopters may have relatively consistent personality traits irrespective of majority/minority status and recruitment methods, but high levels of genomics knowledge are not universal. Research should determine whether recruitment and consent procedures provide adequate education to promote informed choices and realistic expectations, which are vital to ethical research and increasing genomics research participation in underrepresented communities.