Serotonin and its 5-HT1 receptor in human mastocytosis.

Context: Human mastocytosis is a rare disease, in which the serotonergic system may be involved.

Objective: The objective of the present study was to examine the possible presence of serotonin (5-HT) and its 5-HT1A receptor (R) in the skin of patients with mastocytosis. In addition, the effect of the 5-HT1AR was tested on human mastocytosis cells, cultured in vitro.

Two SNPs in the promoter region of the CTLA-4 gene affect binding of transcription factors and are associated with human myasthenia gravis.

Objectives: The molecular mechanisms underlying the regulation of the CD152 (CTLA-4) gene are largely unknown. Two single nucleotide polymorphisms (SNPs) located in the promoter region are suspected to contribute to the pathogenesis of myasthenia gravis (MG) through regulation of gene expression. SETTING, SUBJECTS AND DESIGN: One hundred and sixty-five unrelated Swedish-Caucasian patients with MG (103 females and 62 males, age 17 to 92 years) and 148 ethnically matched healthy individuals were studied.

Human Soluble CD80 is generated by alternative splicing, and recombinant soluble CD80 binds to CD28 and CD152 influencing T-cell activation.

CD80 is a costimulatory factor mainly expressed on the surface of activated monocytes, B cells and dendritic cells. In this study, we demonstrate that 24% of healthy individuals have soluble forms of CD80, sCD80, in their serum. The concentration of sCD80 ranged from 0 to 1 mg/l.

Characterization of the expanded T-cell populations in patients with Wegener's granulomatosis.

Objectives: Wegener's granulomatosis (WG) is a chronic inflammatory disease characterized by granulomatosis inflammation, systemic vasculitis and glomerulonephritis. In patients, the peripheral T cells are characterized by mono/oligoclonal CD4+/CD8+ T-cell AV/BV receptor expansions, with aberrant expression of activation markers. This study was designed to characterize the phenotypic differences between the expanded and nonexpanded T-cell populations.

B7-H3 and B7-H4 expression in non-small-cell lung cancer.

Inhibitory regulatory functions of B7-H3 and B7-H4 regarding T-cell activation have been reported recently. Little is known about the significance of human B7-H3 and B7-H4 expression in non-small-cell lung cancer (NSCLC), and we conducted the present study to address this issue in cell lines and tumor tissue from 70 patients. B7-H3 is over-expressed by all six NSCLC cell lines on both mRNA and protein level.

Circulating CD4+CD25+ and CD4+CD25+ T cells in myasthenia gravis and in relation to thymectomy.

Studies in experimental animal models of human autoimmune diseases have revealed that CD4(+)CD25(+) T regulatory (Tr) cells are of thymic origin and have potentials in preventing auto-aggressive immunity. Myasthenia gravis (MG) is the best-characterized autoimmune disease. Changes in the thymus are found in a majority of patients with MG.

The autoimmune T and B cell repertoires in monozygotic twins discordant for myasthenia gravis.

Two pairs of monozygotic twins, discordant for myasthenia gravis (MG) for more than 30 years, were studied regarding T cell and antibody reactivity against disease related autoantigens, the acetylcholine receptor, one idiotypic and one anti-idiotypic human monoclonal antibody. The healthy and myasthenic twins had very similar autoantibody repertoires. IgG fractions from both healthy and myasthenic twins had the same capacity to decrease the free acetylcholine receptor content in mice after passive transfer.

Abnormal expression of CTLA-4 by T cells from patients with myasthenia gravis: effect of an AT-rich gene sequence.

Cytolytic T lymphocyte-associated antigen-4 (CTLA-4) plays a critical role in the down-regulation of antigen-activated immune responses. The aberrant CTLA-4 expression is characterized by low surface and intracellular levels of CTLA-4 protein, impaired up-regulation of CTLA-4 in T cells in response to ConA stimulation and high levels of soluble CTLA-4 (sCTLA-4) in serum. The serum levels of sCTLA-4 are positively correlated with the serum concentration of antibodies against the acetylcholine receptor.

A CTLA-4 gene polymorphism at position -318 in the promoter region affects the expression of protein.

CTLA-4 is an important negative regulator of the immune system. The regulation of the CTLA-4 gene (Ctla-4) transcription is poorly understood. A single nucleotide polymorphism (SNP) at -318 in the Ctla-4 promoter region is associated with certain autoimmune diseases.

CDS1 and promoter single nucleotide polymorphisms of the CTLA-4 gene in human myasthenia gravis.

The cytotoxic T lymphocyte associated protein 4 (CTLA-4) gene (Ctla-4) is a candidate gene for autoimmune disease. We here report results of two single nucleotide polymorphisms (SNPs) in the Ctla-4, a +49 A/G SNP in CDS1 and a C/T promoter SNP at position -318. There were no differences in these two SNPs between patients and healthy individuals.

Expression of CTLA-4 by human monocytes.

Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a receptor present on T cells that plays a critical role in the downregulation of antigen-activated immune responses. CTLA-4 interacts with the ligands CD80 and CD86 on antigen-presenting cells (APC), and also directs the assembly of inhibitory signalling complexes that lead to quiescence or anergy. In this study, we show that human monocytes constitutively express CTLA-4.

Novel genetic association of Wegener's granulomatosis with the interleukin 10 gene.

Objective: Wegener's granulomatosis (WG) is a necrotizing vasculitis characterized by clonal expansions of T cells and production of antibodies against proteinase 3. The disease is associated with expanded dinucleotide repeats in the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene, suggesting that genetic variation(s) in T cell related gene(s) could contribute to the T cell hyperactivity in WG. We investigated the polymorphisms in the genes of 2 cytokines, interleukin 4 (IL-4) and IL-10, which are essential for the polarization of T cells towards Th2 development and for the Ig production by B cells.

Regulation of surface and intracellular expression of CTLA-4 on human peripheral T cells.

Cytotoxic T-lymphocyte-associated antigen (CTLA-4) is an important downregulator of T-cell activation. In order to analyze the expression and regulation of CTLA-4 on human peripheral T cells, CTLA-4 mRNA and protein expression were determined using analysis by reverse transcription-polymerase chain reaction (RT-PCR) and FACs, respectively. Intracellular CTLA-4 was constitutively expressed in unstimulated CD4+ and CD8+ T cells.

Disruption of the IL-1beta gene diminishes acetylcholine receptor-induced immune responses in a murine model of myasthenia gravis.

Human autoimmune myasthenia gravis (MG) is associated with the IL-1beta TaqI RFLP allele 2. Individuals positive for this allele have high levels of inducible IL-1beta in their peripheral blood. Here, we have characterized MG induction and the immune response elicited by Torpedo acetylcholine receptor (AChR) immunization in wild-type and IL-1beta deficient (-/-) mice.

Dinucleotide repeat expansion in the CTLA-4 gene leads to T cell hyper-reactivity via the CD28 pathway in myasthenia gravis.

CD28 is required to promote T cell proliferation and cytokine production, while the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) functions as a negative modulator for T cell activation. We previously reported that alleles with longer PCR products (designated as allele xx) in an (AT)n polymorphism in Ctla-4 are associated with myasthenia gravis with thymoma, while the shortest allele, 86, is negatively associated with the disease. Here, we demonstrate that serum IL-2 sRalpha increases parallel to the length of (AT)n in Ctla-4.

Polymorphisms in CTLA-4 but not tumor necrosis factor-alpha or interleukin 1beta genes are associated with Wegener's granulomatosis.

Objective: The genetic factors predisposing to Wegener's granulomatosis (WG) are largely unknown. T cells are clearly involved in the disease, as are the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta). The cytotoxic T lymphocyte associated antigen-4 (CTLA-4) suppresses antigen-specific immune responses by opposing the CD28 pathway, and is crucial for a balanced T cell activation.

Polymorphisms at - 174 and in the 3' flanking region of interleukin-6 (IL-6) gene in patients with myasthenia gravis.

We examined the bi-allelic polymorphism at - 174 in the promoter region and the polymorphism in the 3' flanking AT rich region of the interleukin-6 (IL-6) gene in Swedish patients with myasthenia gravis (MG) and ethnically matched healthy individuals. There was no association between the polymorphisms and the disease. There was no relation of the polymorphisms to the clinical variables, the thymic histopathologies, the level of serum acetylcholine receptor antibodies or the concentrations of IgG and its subclasses.

Expanded T cell populations in patients with Wegener's granulomatosis: characteristics and correlates with disease activity.

Patients with Wegener's granulomatosis have a high prevalence of expanded populations of CD4+ and CD8+ T cells bearing different alpha/beta T cell receptors. To elucidate the role of these populations, we studied the phenotypic and functional characteristics of 13 expanded T cell populations in four patients for a period of 35-51 months. The expanded populations generally showed a persistently high expression of the activation markers HLA-DR and CD25.

T-cell expansions with conserved T-cell receptor beta chain motifs in the peripheral blood of HLA-DRB1*0401 positive patients with necrotizing vasculitis.

T lymphocytes are implicated in the pathogenesis of systemic vasculitis such as Wegener's granulomatosis (WG) and polyarteritis nodosa (PAN). In the present study, we have characterized in detail the T-cell receptor (TCR) of peripheral blood T cells from eight vasculitis patients of known HLA class II genotypes. We used flow cytometry to outline the exact TCR V gene expression, complementarity determining region 3 (CDR3) fragment analysis to estimate the degree of clonality and cDNA sequencing to define the exact TCR or beta chain sequences.

Abnormal T cell receptor V gene usage in myasthenia gravis: prevalence and characterization of expanded T cell populations.

The usage of T cell receptor (TCR) Valpha/Vbeta chains on cells from 38 patients with myasthenia gravis (MG) was determined by flow cytometry. There was a decreased number of cells expressing Vbeta2 in CD8+ and Vbeta3 in CD4+ cells in patients compared with healthy individuals. Abnormal expansions of T cells using particular TCR Valpha/Vbeta gene products were found in 18/38 patients.

Polymorphism in tumor necrosis factor genes associated with myasthenia gravis.

The aim of this study was to analyze associations between myasthenia gravis (MG) and polymorphisms in the tumor necrosis factor (TNF) region in 79 Swedish patients and 155 unrelated controls. The frequency of the TNFa2 allele of a microsatellite located 3.5 kb upstream of the lymphotoxin alpha (LT-alpha) gene in the TNF region was found to be increased in overall MG patients compared to controls.