bluuebunny/crossref_metadata_2025 huggingface dataset:
Cellular mechanisms of insulin resistance, lipodystrophy and atherosclerosis induced by HIV protease inhibitors
Authors: Rudich A. , Ben‐Romano R. , Etzion S. , Bashan N.
Published: January 2005

Accumulating clinical evidence now links HIV protease inhibitors (HPIs) to the pathogenesis of insulin resistance, dyslipidaemia, lipodystrophy and atherosclerosis associated with highly active anti‐retroviral therapy. Here we briefly describe the evidence for a distinct causative role for HPIs, and explore the cellular mechanisms proposed to underlie these side‐effects. Acute inhibition of GLUT4‐mediated glucose transport, and defective insulin signalling induced by chronic exposure to nelfinavir, are described as cellular mechanisms of insulin resistance. Interference with adipogenesis and adipocyte apoptosis and nelfinavir‐induced activation of lipolysis are discussed as potential mechanisms of HPI‐induced lipodystrophy. HPI‐induced free radical production, apoptosis and increased glucose utilization in vascular smooth muscle cells are presented as possible novel mechanisms for atherosclerosis. Common pathways and cause–effect relationships between the various cellular mechanisms presented are then discussed, with emphasis on the role of insulin resistance, free radical production and enhanced lipolysis. Understanding the cellular mechanisms of HPI‐induced side‐effects will enhance the search for improved anti‐retroviral therapy, and may also shed light on the pathogenesis of common forms of insulin resistance, dyslipidaemia and atherosclerosis.
The brown adipose cell: a model for understanding the molecular mechanisms of insulin resistance
Authors: Valverde A. M. , Benito M. , Lorenzo M.
Published: January 2005

Type 2 diabetes mellitus is a complex metabolic disease that occurs when insulin secretion can no longer compensate insulin resistance in peripheral tissues. At the molecular level, insulin resistance correlates with impaired insulin signalling. This review provides new insights into the molecular mechanisms of insulin action and resistance in brown adipose tissue and pinpoints the role of this tissue in the control of glucose homeostasis. Brown adipocytes are target cells for insulin and IGF‐I action, especially during late foetal development when insulin supports survival and promotes both adipogenic and thermogenic differentiation. The main pathway involved in insulin induction of adipogenic differentiation, monitored by fatty acid synthase expression, is the cascade insulin receptor substrate (IRS)‐1/phosphatidylinositol 3‐kinase (PI3K)/Akt. Glucose transport in these cells is maintained mainly by the activity of GLUT4. Acute insulin treatment stimulates glucose transport largely by mediating translocation of GLUT4 to the plasma membrane, involving the activation of IRS‐2/PI3K, and the downstream targets Akt and protein kinase C ζ. Tumour necrosis factor (TNF‐α) caused insulin resistance on glucose uptake by impairing insulin signalling at the level of IRS‐2. Activation of stress kinases and phosphatases by this cytokine contribute to insulin resistance. Furthermore, brown adipocytes are also target cells for rosiglitazone action since they show a high expression of peroxisome proliferator activated receptor γ, and rosiglitazone increased the expression of the thermogenic uncoupling protein 1. Rosiglitazone ameliorates insulin resistance provoked by TNF‐α, completely restoring insulin‐stimulated glucose uptake in parallel to the insulin signalling cascade. Accordingly, foetal brown adipocytes represent a model for investigating insulin action, as well as for the mechanism by which rosiglitazone increase insulin sensitivity under situations that mimic insulin resistance.
Regional differences of insulin action in adipose tissue: insights from in vivo and in vitro studies
Authors: Giorgino F. , Laviola L. , Eriksson J. W.
Published: January 2005

Adipose tissue is now recognized to have a multitude of functions that are of importance in the regulation of energy balance and substrate metabolism. Different hormones, in particular insulin and catecholamines, govern the storage and utilization of energy in the triglyceride depots. In addition, adipocytes produce several different substances with endocrine or paracrine functions, which regulate the overall energetic homeostasis. With excess energy storage, obesity develops, leading to increased risk for type 2 diabetes and cardiovascular disease. The distribution of body fat appears to be even more important than the total amount of fat. Abdominal and, in particular, visceral adiposity is strongly linked to insulin resistance, type 2 diabetes, hypertension and dyslipidaemia, leading to increased risk of cardiovascular disease. The adverse metabolic impact of visceral fat has been attributed to distinct biological properties of adipocytes in this depot compared with other adipose tissue depots. Indeed, regional variations in the metabolic activity of fat cells have been observed. Furthermore, expression studies aiming at defining the unique biological properties of adipose tissues from distinct anatomical sites have identified depot‐related differences in the protein content of fat‐produced molecules. In this review we wish to summarize important results from the literature and also some recent data from our own work. The main scope is to describe the biological functions of adipose tissue, and to focus on metabolic, hormonal, and signalling differences between fat depots.
Production of interleukin (IL)-10 and IL-12 by murine colonic dendritic cells in response to microbial stimuli
Authors: Rigby R J , Knight S C , Kamm M A , Stagg A J
Published: January 2005

Intestinal dendritic cells (DC) are likely to regulate immunity to gut microflora, but little is known about their responses to bacterial antigens. Therefore, DC from normal murine colon were characterized and their cytokine responses to components of Gram-negative and/or Gram-positive bacteria assessed. Cells were obtained by digestion of colonic tissue and contained DC that were identified by flow cytometry as CD11c+ major histocompatibility complex (MHC) class II+ cells. Purified DC were obtained by immunomagnetic separation plus cell sorting. DC had the morphology of immature myeloid cells, were endocytically active, expressed low levels of co-stimulatory molecules and stimulated a weak allogeneic mixed leucocyte reaction. Analysis of flow cytometry data by a sensitive subtraction method allowed measurement of production of interleukin (IL)-12 and IL-10 by small numbers of gut DC by intracellular staining. Fewer than 5% of unstimulated DC produced either IL-10 or IL-12. IL-10 production was significantly up-regulated following stimulation with Bifidobacteria longum, but not after exposure to lipopolysaccharide (LPS) or Streptococcus faecium. In contrast, colonic DC produced IL-12 in response to both LPS and B.longum. Thus, colonic DC can produce both IL-12 and IL-10 following bacterial stimulation. Cell wall components from different bacteria stimulate distinct responses and may direct immune responses differentially in the gut.
Dietary n-3 polyunsaturated fatty acids suppress splenic CD4+ T cell function in interleukin (IL)-10–/– mice
Authors: Ly L H , Smith R , Chapkin R S , McMurray D N
Published: January 2005

Our laboratory has demonstrated that down-regulation of proliferation and cytokine synthesis by CD4+ T cells in mice fed diets rich in n-3 polyunsaturated fatty acids (PUFA) is highly dependent on the involvement of the co-stimulatory molecule, CD28. It has been reported that the inhibitory cytokine interleukin (IL)-10 acts directly on T cells which up-regulate IL-10 receptor (IL-10R) expression following stimulation via CD28 by efficiently blocking proliferation and cytokine production. Thus, it was hypothesized that dietary n-3 PUFA would suppress T cell function through the effects of IL-10. The proliferation of purified splenic CD4+ T cells activated in vitro with anti-CD3 and anti-CD28 (αCD3/CD28) from conventional mice (C57BL/6) fed either a control corn oil (CO)-enriched diet devoid of n-3 PUFA, docosahexaenoic acid (DHA; 22 : 6) or eicosapentaenoic acid (EPA; 20 : 5) for 14 days was suppressed by dietary DHA and EPA. Surprisingly, a similar trend was seen in IL-10 gene knock-out (IL-10–/–) mice fed dietary n-3 PUFA. IL-10R cell surface expression was also significantly down-regulated on CD4+ T cells from both the C57BL/6 and IL-10–/– mice fed dietary n-3 PUFA after 72 h of in vitro stimulation with αCD3/CD28. Enzyme-linked immunosorbent assay (ELISA) measurements revealed that C57BL/6 mice fed DHA had significantly reduced interferon (IFN)-γ and IL-10 levels 48 h post-activation. However, CD4+ T cells from IL-10–/– mice fed dietary n-3 PUFA produced significantly greater levels of IFN-γ than the CO-fed group. Our data suggest that in the absence of IL-10, CD4+ T cells from n-3 PUFA-fed mice may up-regulate IFN-γ. Suppressed CD4+ T cells from n-3 PUFA-fed C57BL/6 mice may use mechanisms other than IL-10 to down-regulate T cell function.
Effects of prolactin and cortisol on natural killer (NK) cell surface expression and function of human natural cytotoxicity receptors (NKp46, NKp44 and NKp30)
Authors: Mavoungou E , Bouyou-Akotet M K , Kremsner P G
Published: January 2005

The surface density of the triggering receptors (e.g. NKp46 and NKp30) responsible for natural killer (NK) cell-mediated cytotoxicity determines the ability of NK cells to kill susceptible target cells. In this study, we show that prolactin up-regulates and cortisol down-regulates the surface expression of NKp46 and NKp30. The prolactin-mediated activation and the cortisol-mediated inhibition of natural cytotoxicity receptor (NCR) surface expression reflects gene regulation at the transcriptional level. NKp46 and NKp30 are the major receptors involved in the NK-mediated killing of K562, a human chronic myelogenous leukaemia cell line. Accordingly, the prolactin dramatically increased the NK-mediated killing of the K562 cell line, whereas cortisol abolished this activity. Our data suggest a mechanism by which prolactin activates the lytic function of NK cells, and cortisol inhibits the NK-mediated attack.
Analysis of the susceptibility of CD57+ T cells to CD3-mediated apoptosis
Authors: Shinomiya N , Koike Y , Koyama H , Takayama E , Habu Y , Fukasawa M , Tanuma S , Seki S
Published: January 2005

After stimulation with anti-CD3 antibody in vitro, CD57+ T cells showed a greater susceptibility to apoptosis than CD57–αβT cell receptor (TCR)+ T cells (regular αβ T cells). The apoptotic fraction of CD57+ T cells showed an increased production of active caspase-3. An increase in both Fas expression and Fas-ligand (FasL) production was also observed in CD57+ T cells, whereas the expression of survivin was suppressed in CD57+ T cells compared to that of regular αβ T cells. CD57+ T cells display a biased expansion of a few Vβ T cell fractions in individuals, but such Vβ T cells were not specifically susceptible to CD3-mediated apoptosis. The TCR expression level of CD57+ T cells was much lower than that of regular T cells and anti-TCR antibody stimulation induced a smaller apoptotic proportion of CD57+ T cells than did anti-CD3 antibody. Although the CD3ɛ expression levels were similar in both T cell subsets, the CD3ζ level of CD57+ T cells was significantly higher than that of regular T cells. These results suggest that several apoptotic and anti-apoptotic molecules are involved in the CD3-induced apoptosis of CD57+ T cells and raise the possibility that the imbalance in expression of the CD3ɛ and CD3ζ chains may also contribute to the susceptibility of CD57+ T cells to undergo apoptosis.
Excessive expression of Txk, a member of the Tec family of tyrosine kinases, contributes to excessive Th1 cytokine production by T lymphocytes in patients with Behcet's disease
Authors: Nagafuchi H , Takeno M , Yoshikawa H , Kurokawa M S , Nara K , Takada E , Masuda C , Mizoguchi M , Suzuki N
Published: January 2005

Excessive Th1 cell function is importantly involved in the pathogenesis of Behcet's disease (BD). We previously found that Txk, a member of the Tec family of tyrosine kinases, acts as a Th1 cell specific transcription factor. To investigate immune aberration in the pathogenesis of BD, we studied the expression of Txk and Th1 cytokines in peripheral blood lymphocytes (PBL) and skin lesions in patients with BD. Cytokine production by the lymphocytes was assessed using ELISA. PBL produced excessive Th1 associated cytokines including IFN-γ and IL-12 spontaneously and in response to exogenous HSP60-derived peptide stimulation, which was shown to induce proliferation of PBL, in patients with BD. Circulating CD4+ T cells expressed excessive Txk protein. A majority of cells infiltrating into skin lesions expressed IFN-γ in the BD specimens. IL-12 and IL-18 were also expressed in the mononuclear cell aggregates. Lymphocytes accumulating in the skin lesion expressed higher levels of Txk as compared with atopic dermatitis lesions, a typical Th2 disease. IFN-γ, IL-18 and Il-12 were detected in the BD skin lesions, which may induce preferential development of Th1 cells in patients with BD. The mononuclear cell aggregates contained Txk expressing cells in such skin lesions. Collectively, Txk expressing Th1 cells and the Th1 associated cytokines may play a critical role in the development of skin lesions in BD.
Interactions between the mannose receptor and thyroid autoantigens
Authors: Chazenbalk G D , Pichurin P N , Guo J , Rapoport B , McLachlan S M
Published: January 2005

Thyroid autoantigens require internalization and processing by antigen-presenting cells to induce immune responses. Besides pinocytosis, antigen uptake can be receptor-mediated. The mannose receptor (ManR) has a cysteine rich domain (CR) and eight carbohydrate recognition domains (CRD) that bind glycosylated proteins. The TSH receptor (TSHR), thyroid peroxidase (TPO) and thyroglobulin (Tg) are glycoproteins. To investigate a role for the ManR in thyroid autoimmunity, we tested the interaction between these autoantigens and chimeric ManRs. Plasmids encoding the CR-domain linked to IgG-Fc (CR-Fc) and CDR domains 4–7 linked to IgG-Fc (CDR4-7-Fc) were expressed and purified with Protein A. Enzyme-linked immunosorbent assay (ELISA) plates were coated with human thyroid autoantigens and CR-Fc or CRD4-7-Fc binding detected with peroxidase-conjugated anti-IgG-Fc. CRD4-7-Fc binding was highest for the TSHR, followed by Tg and was minimal for TPO. CR-Fc bound to Tg but not to TSHR or TPO. The interaction between the TSHR and CRD-Fc was calcium-dependent; it was inhibited by mannose (not galactose), and required a glycosylated TSHR A-subunit. Moreover, precomplexing the TSHR A-subunit with CRD-Fc (but not CR-Fc), or adding mannose (but not galactose), decreased in vitro responses of splenocytes from TSHR-immunized mice. Our data indicate that the ManR may participate in autoimmune responses to Tg and the TSHR but not to TPO. Most important, ManR binding of heavily glycosylated TSHR A-subunits suggests a mechanism by which the minute amounts of A-subunit protein shed from the thyroid may be captured by antigen-presenting cells located in the gland or in draining lymph nodes.
Deficiency of the mannan-binding lectin pathway of complement and poor outcome in cystic fibrosis: bacterial colonization may be decisive for a relationship
Authors: Carlsson M , Sjöholm A G , Eriksson L , Thiel S , Jensenius J C , Segelmark M , Truedsson L
Published: January 2005

In cystic fibrosis (CF) prognosis concerning lung damage development is highly variable and difficult to predict. Mannan-binding lectin (MBL) deficiency has been reported to be associated with poor outcome in CF lung disease. MBL is a recognition molecule of the MBL pathway of the complement system and is encoded by a gene characterized by a high degree of polymorphism. Some genotypes result in low serum concentrations of MBL. MBL-associated serine protease 2 (MASP-2) is another protein belonging to the MBL pathway. A mutation resulting in low levels of MASP-2 in serum has been described recently. In the present study, 112 CF patients aged 4–54 years were investigated for MBL and MASP-2 genotypes, serum levels of MBL and MASP-2 and the MBL pathway function in serum. No correlation to reduced lung function or need for lung transplantation was seen, either for MBL deficiency, MASP-2 gene mutation or reduced MBL pathway function. However, in the 27 patients colonized with Staphylococcus aureus, MBL-deficient genotypes were associated with decreased lung function. As expected, MBL pathway function in serum was reduced both in MBL-deficient patients and in patients carrying a mutant MASP-2 allele. An unexpected finding was that CF patients had higher serum levels of MBL than healthy controls when corrected for MBL genotype. In conclusion, MBL pathway function was affected both by MBL and by MASP-2 genotypes. However, MBL or MASP-2 levels in serum did not affect the clinical outcome in the cohort of CF patients studied.
Correlation of disease evolution with progressive inflammatory cell activation and migration in the IL-4 transgenic mouse model of atopic dermatitis
Authors: Chen Lin , Martinez O , Venkataramani P , Lin S-X , Prabhakar B S , Chan L S
Published: January 2005

Atopic dermatitis is a chronic inflammatory skin disease characterized by inflammatory cell infiltration in the skin. In order to assess the roles of inflammatory cells in this disease, we analysed the activation status and surface markers of various leucocytes in the IL-4 transgenic mouse model of atopic dermatitis, by flow cytometry, immuofluorescence microscopy, and T cell proliferation assays. The studies were performed with a nontransgenic mouse control and transgenic mice at three disease stages: before disease onset, early skin disease, and late skin disease, so that we can delineate the immunological sequence of events. As the skin disease evolves, the skin draining lymph node cells from IL-4-Tg mice show a spontaneous proliferation and a progressively enhanced proliferative response to stimulants including anti-CD3, Con A, PHA, and Staphylococcus enterotoxins A and B. As the disease evolves, the percent of lymphoid organ T cells expressing activation molecules (CD44 and CD69) and costimulatory molecules (ICOS and PD-1) are progressively increased; the percent and total number of T cells are reduced in an incremental manner in the secondary lymphoid organs while the number of T cells infiltrating the skin increases in an incremental fashion; the total number of dendritic antigen presenting cells, macrophages, and NK cells gradually increases in the lymphoid organs. Collectively, our results suggest that there is a continued and progressive migration of activated inflammatory cells from the secondary lymphoid organs into the skin where they participate in immune responses resulting in the pathology associated with inflammation.
Alteration of newly induced endochondral bone formation in adult mice without tumour necrosis factor receptor 1
Authors: Lukić I K , Grčević D , Kovačić N , Katavić V , Ivčević S , Kalajzić I , Marušić A
Published: January 2005

Tumour necrosis factor (TNF)-α, a major proinflammatory cytokine, exerts its role on bone cells through two receptors (TNFR1 and TNFR2). TNFR1, but not TNFR2, is expressed by osteoblasts and its function in bone formation in vivo is not fully understood. We compared in vivo new bone formation in TNFR1-deficient (TNFR1–/–) mice and wild-type mice, using two models of bone formation: intramembranous ossification following tibial marrow ablation and endochondral ossification induced by bone morphogenetic protein (BMP)-2. Intramembranous osteogenesis in TNFR1–/– mice did not differ from the wild-type mice either in histomorphometric parameters or mRNA expression of bone-related markers and inflammatory cytokines. During endochondral osteogenesis, TNFR1–/– mice formed more cartilage (at post-implantation day 9), followed by more bone and bone marrow (at day 12). mRNAs for BMP-2, -4 and -7 were increased during the endochondral differentiation sequence in TNFR1–/– mice. The expression of receptor activator of NF-κ B ligand (RANKL) and receptor activator of NF-κ B (RANK), as assessed by quantitative reverse transcription polymerase chain reaction (RT-PCR), was also increased significantly during endochondral ossification in TNFR1–/– mice. In conclusion, signalling through the TNFR1 seems to be a negative regulator of new tissue formation during endochondral but not intramembranous osteogenesis in an adult organism. BMPs and RANKL and its receptor RANK may be involved in the change of local environment in the absence of TNFR1 signalling.
Identification of epithelial auto-antigens associated with periodontal disease
Authors: Ye P , Simonian M , Nadkarni M A , DeCarlo A A , Chapple C C , Hunter N
Published: January 2005

We previously reported evidence that patients with periodontitis have serum antibodies to oral Gram positive bacteria that are cross-reactive with epithelial antigens. In the present report cross-reactive epithelial antigens including CD24, lactate dehydrogenase A [LDM-A], antioxidant protein 2 [AOP 2] and nuclear factor of activated T cells 5 [NFAT 5], were identified by screening a cDNA expression library with pooled patient sera. Titres of antibodies to CD24 peptide correlated negatively with indices of periodontal disease severity. Strong expression of CD24 in the reactive periodontal epithelium and inflamed gingival attachment contrasted with low to undetectable expression in the external gingival epithelium. In periodontitis, a local action of these auto-reactive antibodies could modulate the regulatory potential associated with expression of CD24 in this epithelium.
Phenotypic perturbation of B cells in the Wiskott–Aldrich syndrome
Authors: Park J Y , Shcherbina A , Rosen F S , Prodeus A P , Remold-O’Donnell E
Published: January 2005

Wiskott–Aldrich syndrome (WAS) is an X-linked immunodeficiency/platelet disease due to mutations of WASP, a cytoskeletal regulatory protein of blood cells. Patients exhibit a range of immune defects generally attributed to defective T-cell function, including poor response to immunization, skewed immunoglobulin isotypes, eczema, recurrent infections, autoimmune disease and increased frequency of malignancies. Here we show a deficit of total B-cells in WAS patients of various ages and identify phenotypic perturbations involving complement receptors and CD27. Whereas B-cells of normal healthy donors are overwhelmingly CD21/CD35-positive, B-cells expressing these receptors are significantly reduced in number in WAS patients, and their paucity may cause suboptimal antigen capture and presentation. The frequencies of IgD– and IgG+ patient B-cells were not different from healthy donors (although absolute numbers were decreased), indicating that isotype switching is occurring. In contrast, the frequency of cells positive for CD27, the marker of post germinal centre B-cells, was significantly decreased even among isotype-switched cells, and B-cells resembling germinal centre progenitors (CD10+CD27–CD38bright) were more frequent in adult patients, suggesting impaired germinal centre maturation/differentiation. The documentation of these phenotypic perturbations and deficit of total cells suggest that defects intrinsic to B-cells contribute to the impaired humoral immunity that characterizes this disease.
Taurine attenuates CD3/interleukin-2-induced T cell apoptosis in anin vitromodel of activation-induced cell death (AICD)
Authors: Maher S G , Condron C E M , Bouchier-Hayes D J , Toomey D M
Published: January 2005

Interleukin (IL)-2 immunotherapy is used for the treatment of metastatic melanoma and renal cell carcinoma and mediates its effects through the clonal expansion of lymphocytes. Although IL-2 remains the most effective form of therapy for these cancers, response rates are poor and dose escalation is hampered by side effects, which include vascular leak and lymphopenia. The mechanism underlying T cell loss is currently unidentified but could be the induction of activation-induced cell death (AICD) mediated by FasL. Our previous studies have shown that the amino acid taurine can attenuate apoptosis induced by a number of factors in different cell types. Here, we induced T cell AICD via CD3 and IL-2 stimulation and investigated the effect of taurine on lymphocyte apoptosis. Anti-CD3-activated Jurkat T cells treated with IL-2 significantly increased FasL expression, which was associated with increased apoptosis. Treatment with taurine prior to stimulation down-regulated FasL protein expression and partially inhibited apoptosis. Inhibition of FasL-signalling resulted in an identical reduction in apoptosis. As the kinetics of AICD are completely different in circulating T cells, we repeated these experiments in such cells to confirm our finding. Stimulation of CD4+ circulating T cells induced apoptosis in sensitized, but not freshly isolated T cells, which was abrogated partially by taurine. In Jurkat cells it was determined that taurine-mediated down-regulation of FasL protein expression was associated with decreased FasL mRNA expression and reduced NFκB activation. These results reveal one possible mechanism underlying the lymphopenia observed with IL-2 immunotherapy, involving increased FasL expression leading to apoptosis. Taurine may be of use in reversing the lymphopenia associated with IL-2, thereby augmenting its immunotherapeutic potential.
Estren-mediated inhibition of T lymphopoiesis is estrogen receptor-independent whereas its suppression of T cell-mediated inflammation is estrogen receptor-dependent
Authors: Islander U , Erlandsson M C , Chavoshi T , Jochems C , Movérare S , Nilsson S , Ohlsson C , Gustafsson J-Å , Carlsten H
Published: January 2005

Estrogen has extensive effects on the immune system. The aim of the present experiments was to compare the effects of 17β-estradiol (E2) and 4-estren-3α,17β-diol (estren) on T lymphopoiesis and T cell-dependent inflammation. In order to investigate the role of estrogen receptors (ER) in the effects of E2 and estren on the immune system, ER knock-out mice lacking both ERα and ERβ (DERKO) were used. T lymphopoiesis and T cell-dependent inflammation were studied by investigating thymus cellularity, the delayed-type hypersensitivity (DTH) reaction, CD4+ T cells in spleen and serum levels of interleukin (IL)-6. As expected, the presence of ERs was mandatory for all the effects of E2. In contrast, treatment with estren reduced thymus cellularity in ER knock-out mice, indicating an effect through ER-independent pathways. Interestingly, estren suppressed only DTH, the frequency of CD4+ T cells in spleen and serum levels of IL-6 in wild-type (WT) mice, but not in mice lacking ERs. Thus, our study is the first to show that estren inhibits T lymphopoiesis via ER-independent pathways, whereas its suppressive effects on inflammation are ER-dependent.
Autoantibodies directed against the protease inhibitor calpastatin in psoriasis
Authors: Matsushita Y , Shimada Y , Kawara S , Takehara K , Sato S
Published: January 2005

Psoriasis is believed to be a T cell-mediated autoimmune disease, but also exhibits autoantibody production. Calpastatin is an endogenous inhibitor of calpain, a ubiquitous protease that regulates inflammatory processes. Anti-calpastatin autoantibody was first identified as an autoantibody specific to rheumatoid arthritis, but has been also detected in other autoimmune diseases. In this study, we examined the presence and levels of anti-calpastatin antibody in 77 psoriasis patients by enzyme-linked immunosorbent assay. Compared with normal controls, psoriasis patients exhibited significantly elevated IgG anti-calpastatin antibody levels that were similar to those found in rheumatoid arthritis patients. Remarkably, IgG anti-calpastatin autoantibody in sera from psoriasis patients inhibited calpastatin activity. Calpain II expression was up-regulated in psoriasis skin lesions compared with normal skin while calpastatin expression was normal. The results of this study reveal the presence of anti-calpastatin autoantibody in psoriasis.
Impaired interleukin (IL)-4-associated generation of CCR4-expressing T cells in neonates with hereditary allergy risk
Authors: Haddeland U , Sletten G B , Brandtzaeg P , Nakstad B
Published: January 2005

Reduced microbial exposure in early life may contribute to the increase of atopic diseases in ‘westernized’ societies but the underlying mechanisms remain elusive. The objective of this study was to examine how exposure to bacterial lipopolysaccharide (LPS) during early antigen encounter might influence the maturation of neonatal lymphoid cells, and to define possible differences in this respect between neonates with high risk of allergy due to a family history (FH+) and controls with no apparent hereditary risk (FH–). Cord blood mononuclear cells from the FH+ or FH– group were stimulated with pure LPS or β-lactoglobulin (β-LG) in the presence of LPS. T cell expression of chemokine receptors CCR4 and CXCR3 was determined by flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR). Cellular expression of interleukin (IL)-4 was analysed by quantitative RT-PCR, whereas interferon (IFN)-γ was analysed by both quantitative RT-PCR and immunoassay. Stimulation with LPS, or β-LG together with LPS, induced up-regulation of CCR4 (P < 0·05) and CXCR3 (P < 0·05). For CCR4, such up-regulation was related to the level of IL-4 produced by the same T cells (rS = 0·49, P = 0·03), while CXCR3 expression was negatively correlated with the IL-4 levels (rS = −0·56, P = 0·02). Compared with the FH– group, the FH+ group showed a significantly lower capacity for generation of CCR4+ T cells (mean percentage of total T cells: FH+, 2·42%versus FH–, 5·74%; P < 0·01), whereas induction of CXCR3 and IFN-γ did not differ significantly between the two groups. When the immune system in early life encounters antigen together with LPS, the T cell potential for compartmentalized interaction with other immune cells might be increased by elevated CCR4- and CXCR3-expression levels. In neonates at hereditary allergy risk, this putative homeostatic mechanism could theoretically be jeopardized due to decreased up-regulation of CCR4. Conversely, Th1 responses to antigen in the presence of LPS did not appear to be reduced compared with controls.
Exploiting T cell receptor genes for cancer immunotherapy
Authors: Xue S , Gillmore R , Downs A , Tsallios A , Holler A , Gao L , Wong V , Morris E , Stauss H J
Published: January 2005

Adoptive antigen-specific immunotherapy is an attractive concept for the treatment of cancer because it does not require immunocompetence of patients, and the specificity of transferred lymphocytes can be targeted against tumour-associated antigens that are poorly immunogenic and thus fail to effectively trigger autologous T cell responses. As the isolation and in vitro expansion of antigen-specific lymphocytes is difficult, ‘conventional’ adoptive T cell therapy can only be carried out in specialized centres in small numbers of patients. However, T cell receptor (TCR) genes isolated from antigen-specific T cells can be exploited as generic therapeutic molecules for ‘unconventional’ antigen-specific immunotherapy. Retroviral TCR gene transfer into patient T cells can readily produce populations of antigen-specific lymphocytes after a single round of polyclonal T cell stimulation. TCR gene modified lymphocytes are functionally competent in vitro, and can have therapeutic efficacy in murine models in vivo. TCR gene expression is stable and modified lymphocytes can develop into memory T cells. Introduction of TCR genes into CD8+ and CD4+ lymphocytes provides an opportunity to use the same TCR specificity to produce antigen-specific killer and helper T lymphocytes. Thus, TCR gene therapy provides an attractive strategy to develop antigen-specific immunotherapy with autologous lymphocytes as a generic treatment option.
Adiponectin – journey from an adipocyte secretory protein to biomarker of the metabolic syndrome
Authors: TRUJILLO M. E. , SCHERER P. E.
Published: January 2005

Adiponectin is an adipocyte‐derived hormone that was discovered in 1995. Unlike leptin, which was identified around the same time, the clinical relevance of adiponectin remained obscure for a number of years. However, starting in 2001, several studies were published from different laboratories that highlighted the potential antidiabetic, antiatherosclerotic and anti‐inflammatory properties of this protein complex. Methods to measure the protein with high throughput assays in clinical samples were developed shortly thereafter, and as a result hundreds of clinical studies have been published over the past 3 years describing the role of adiponectin in endocrine and metabolic dysfunction. Furthermore, adiponectin research has expanded to include a role for adiponectin in cancer and other disease areas. Although it is an impossible task to summarize the findings from all these studies in a single review, we aim to demonstrate the utility of circulating adiponectin as a biomarker of the metabolic syndrome. Evidence for this relationship will include how decreased levels of plasma adiponectin (‘hypoadiponectinaemia’) are associated with increased body mass index (BMI), decreased insulin sensitivity, less favourable plasma lipid profiles, increased levels of inflammatory markers and increased risk for the development of cardiovascular disease. Therefore, adiponectin levels hold great promise for use in clinical application serving as a potent indicator of underlying metabolic complications.
Favourable association of leg fat with cardiovascular risk factors
Authors: SAKAI Y. , ITO H. , EGAMI Y. , OHOTO N. , HIJII C. , YANAGAWA M. , SATOH S. , JINGU S.
Published: January 2005

Objectives.  To assess the association of trunk and leg fat mass (FM) and leg lean tissue mass (LTM) with conventional cardiovascular risk factors.

Design. Cross‐sectional study.

Setting and subjects.  We studied 1249 men and 3007 women (age 20–79 years) who attended a research institute for a health checkup between October 1995 and February 2004.

Main outcome measures.  Body mass index, waist circumference (WC), hip circumference (HC), systolic and diastolic blood pressure, total cholesterol, HDL cholesterol, triglycerides, glucose and haemoglobin A1C were measured. Trunk FM, leg FM and leg LTM were obtained by dual‐energy X‐ray absorptiometry. We evaluated the associations between the indices for regional body composition and cardiovascular risk factors, which included hypertension, hypercholesterolaemia, hypo‐HDL cholesterolaemia, hypertriglyceridaemia, dyslipidaemia and diabetes mellitus.

Results.  Increase in WC and HC respectively showed increase and decrease in odds ratios of cardiovascular risk factors. Increase in trunk FM by 1 kg significantly increased the risk of the cardiovascular risk factors with the odds ratios ranging between 1.11 and 1.45. Increase in leg FM by 1 kg significantly decreased the risk with the odds ratios ranging between 0.52 and 0.90, except for the nonsignificant results for hypercholesterolaemia and hypo‐HDL cholestero‐laemia in men. Odds ratios of 1 kg increase in leg LTM were only significant for dyslipidaemia in men and hypercholesterolaemia in women (both 0.93).

Conclusions.  WC and HC showed opposite and independent associations with cardiovascular risk factors. The favourable association of HC was mainly attributable to that of leg FM.
Factors associated with development of stroke long‐term after myocardial infarction: experiences from the LoWASA trial
Authors: HERLITZ J. , HOLM J. , PETERSON M. , KARLSON B. W. , EVANDER M. HAGLID , ERHARDT L. ,   FOR THE LOWASA STUDY GROUP
Published: January 2005

Objective.  To describe factors associated with the development of stroke during long‐term follow‐up after acute myocardial infarction (AMI) in the LoWASA trial.

Patients.  Patients who had been hospitalized for AMI were randomized within 42 days to receive either warfarin 1.25 mg plus aspirin 75 mg daily or aspirin 75 mg alone.

Design.  The study was performed according to the probe design, that is open treatment and blinded end‐point evaluation.

Setting.  The study was performed in 31 hospitals in Sweden. The mean follow‐up time was 5.0 years with a range of 1.7–6.7 years.

Results.  In all, 3300 patients were randomized in the trial, of which 194 (5.9%) developed stroke (4.2% nonhaemorrhagic, 0.5% haemorrhagic and 1.3% uncertain. The following factors appeared as independent predictors for an increased risk of stroke: age, hazard ratio and 95% confidence interval (1.07; 1.05–1.08), a history of diabetes mellitus (2.4; 1.8–3.4), a history of stroke (2.3; 1.5–3.5), a history of hypertension (2.0; 1.5–2.7) and a history of smoking (1.5;1.1–2.0). Most of these factors were also predictors of a nonhaemorrhagic stroke whereas no predictor of haemorrhagic stroke was found.

Conclusion.  Risk indicators for stroke long‐term after AMI were increasing age, a history of either diabetes mellitus, stroke, hypertension or smoking.
Effects of long‐term treatment with loop diuretics on bone mineral density, calcitropic hormones and bone turnover
Authors: REJNMARK L. , VESTERGAARD P. , HEICKENDORFF L. , ANDREASEN F. , MOSEKILDE L.
Published: January 2005

Background.  Loop diuretics (LD) are widely used in the treatment of cardiovascular diseases and disorders with fluid accumulation. LD are known to increase renal calcium losses and may thereby affect calcium homeostasis and bone metabolism.

Objective.  We studied to what extent long‐term treatment with LD affects calcium homeostasis and bone metabolism.

Design and subjects.  In a cross‐sectional design we compared 140 postmenopausal women treated with a LD for more than 2 years with 140 age‐matched women not in diuretic therapy.

Results.  Treatment with LD was associated with significantly increased urinary calcium, plasma parathyroid hormone (PTH) and 1,25‐dihydroxyvitamin D levels. Per 40 mg day−1 of furosemide, urinary calcium was increased by 17% (P < 0.05) and plasma PTH levels were increased by 28% (P = 0.04). Users of LD had a 17% higher body weight (P < 0.001) compared with nonusers. This was due to a 32% higher fat mass (P < 0.001) and a 6% higher lean tissue mass (P < 0.001). Moreover, users of LD had a higher bone mineral density (BMD) at the spine (+7.5%, P < 0.001), hip (+4.8%, P = 0.004), forearm (+3.7%, P = 0.01) and whole body (+2.5%, P = 0.06). However, after adjustment for body weight differences, BMD did not differ between groups. Nevertheless, duration of LD treatment was positively associated with BMD at the spine (P = 0.03) and whole body (P < 0.05). BMD at the spine increases by 0.3% per 1 year of treatment.

Conclusions.  The increased renal calcium losses in users of LD are compensated for by a PTH‐dependent increase in 1,25(OH)2D levels. Thereby calcium balance remains neutral without major effects on bone metabolism.
The G‐250A substitution in the promoter region of the hepatic lipase gene is associated with the conversion from impaired glucose tolerance to type 2 diabetes: the STOP‐NIDDM trial
Authors: ZACHAROVA J. , TODOROVA B. R. , CHIASSON J.‐L. , LAAKSO M. ,   FOR THE STOP‐NIDDM STUDY GROUP
Published: January 2005

Objectives.  Dyslipidaemia that includes high levels of triglycerides and low high‐density lipoprotein cholesterol is a risk factor for type 2 diabetes. Hepatic lipase gene encoding a lipolytic enzyme participating in remodelling of plasma lipoproteins and formation of serum lipid profile is a promising candidate gene for type 2 diabetes. The purpose of the study was to investigate whether the G‐250A promoter polymorphism of the LIPC gene predicts the conversion from impaired glucose tolerance (IGT) to type 2 diabetes.

Subjects and design.  Study population comprised of subjects who participated in the STOP‐NIDDM trial aiming to investigate the effect of acarbose compared with placebo on the prevention of type 2 diabetes in subjects with IGT.

Results.  Compared with subjects carrying the G‐250G genotype, subjects with the A‐250A genotype of the LIPC gene had a 2.35‐fold [95% confidence interval (CI) 1.27–4.33, P = 0.006] higher risk of developing type 2 diabetes. Subjects in the placebo group and all women carrying the A‐250A genotype had an especially high risk for the conversion to type 2 diabetes [odds ratio (OR) 2.74, 95% CI 1.14–6.61, P = 0.024 and OR 3.70, 95% CI 1.35–10.1, P = 0.011 respectively].

Conclusion.  The G‐250A promoter polymorphism of the LIPC gene is associated with an increased risk of development of type 2 diabetes in high‐risk subjects with IGT. Therefore, genes regulating atherogenic dyslipidaemia are promising candidate genes for type 2 diabetes.
The inflammatory reflex – Introduction
Authors: ANDERSSON J.
Published: January 2005

Sepsis is the third leading cause of death in the developed world. Despite recent advances in intensive care treatment and the discovery of antibiotics, sepsis remains associated with a high mortality rate. The pathogenesis of sepsis is characterized by an overwhelming systemic inflammatory response that is central to the development of lethal multiple organ failure. This volume of the Journal of Internal Medicine contains three reviews addressing novel aspects of a system we are only beginning to understand – the interactions between the immune and the nervous systems, the ‘neuro‐immune axis’. Tracey (Nature 2002; 420: 853) recently discovered that the nervous system, through the vagus nerve, can modulate circulating TNF‐α levels induced by microbial invasion or tissue injury. This cholinergic anti‐inflammatory pathway is mediated primarily by nicotinic acetylcholine receptors on tissue macrophages – the pathway leads to decreased production of proinflammatory cytokines. The author reports that treatment with the acetylcholine receptor agonist, nicotine, modulates this system and reduces mortality in ‘established’ sepsis. Watkins and Maier (J Intern Med 2005; 257: 139) illustrate that pathological pain (induced by inflammation) is not simply a strict neuronal phenomenon, but is a component of the immune response, and is modulated by peripheral immune cells and spinal cord glia cells. This may be of importance for future development of novel drugs for neuropathic pain as well as our understanding of increased risks for infections in anaesthetic skin areas. Blalock (J Immunol 1984; 132: 1067) elucidates the possibility that the immune system actually functions as the sixth sense, sensing microbes and microbial toxins that we cannot see, hear, taste, touch or smell. Activation of the sympathetic nervous system also has predominantly anti‐inflammatory effects that are mediated through direct nerve to immune cell interaction or through the adrenal neuro‐endocrine axis.
The immune system as the sixth sense
Authors: BLALOCK J. E.
Published: January 2005

One of the truly remarkable discoveries in modern biology is the finding that the nervous system and immune system use a common chemical language for intra‐ and inter‐system communication. This review will discuss some of the pivotal results that deciphered this chemical language. Specifically the nervous and immune systems produce a common set of peptide and nonpeptide neurotransmitters and cytokines that act on a common repertoire of receptors in the two systems. The paper will also review more recent studies that have delineated hardwired and humoral pathways for such bidirectional communication. This is discussed in the context of the idea that the sharing of ligands and receptors allows the immune system to serve as the sixth sense that notifies the nervous system of the presence of entities, such as viruses and bacteria, that are imperceptible to the classic senses. Lastly, this review will suggest ways to apply the newfound knowledge of the sixth sense to understand a placebo effect and to treate human disease.
Autonomic neural regulation of immunity
Authors: CZURA C. J. , TRACEY K. J.
Published: January 2005

The ‘cytokine theory of disease’ states that an overproduction of cytokines can cause the clinical manifestations of disease. Much effort has been expended to determine how cytokines are regulated in normal health. Transcriptional, translational and other molecular control mechanisms protect the host from excessive cytokine production. A recent discovery revealed an unexpected pathway that inhibits macrophage cytokine production. The inflammatory reflex is a physiological pathway in which the autonomic nervous system detects the presence of inflammatory stimuli and modulates cytokine production. Afferent signals to the brain are transmitted via the vagus nerve, which activates a reflex response that culminates in efferent vagus nerve signalling. Termed the ‘cholinergic anti‐inflammatory pathway’, efferent activity in the vagus nerve releases acetylcholine (ACh) in the vicinity of macrophages within the reticuloendothelial system. ACh can interact specifically with macrophage α7 subunits of nicotinic ACh receptors, leading to cellular deactivation and inhibition of cytokine release. This ‘hard‐wired’ connection between the nervous and immune systems can be harnessed therapeutically in animal models of inflammatory disease, via direct electrical stimulation of the vagus nerve, or through the use of cholinergic agonists that specifically activate the macrophage α7 subunit of the ACh receptor. Autonomic dysfunction has been associated with human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis; whether this dysfunction results from the inflammatory component of these diseases, or is actually an underlying cause, is now less clear. The description of the cholinergic anti‐inflammatory now brings to the fore several new therapeutic strategies for inflammatory disease, and suggests that many of these diseases may actually be diseases of autonomic dysfunction.
Immune regulation of central nervous system functions: from sickness responses to pathological pain
Authors: WATKINS L. R. , MAIER S. F.
Published: January 2005

Classically, the central nervous system (CNS) and the immune system are thought to operate independently of each other. This simplistic view has been corrected in recent years, first with the recognition that the brain dynamically modulates the immune system, and later with the reverse; that is, that the immune system modulates the CNS as well. The evidence that the immune system regulates CNS functions is first reviewed. This immune‐to‐brain communication pathway triggers the production of a constellation of CNS‐mediated phenomena, collectively referred to as ‘sickness responses’. These sickness responses are created by immune‐to‐brain signals activating CNS glia to release glial proinflammatory cytokines. The most recently recognized member of this constellation of changes is enhanced pain responsivity. The hypothesis is then developed that pathological, chronic pain may result from ‘tapping into’ this ancient survival‐oriented circuitry, including the activation of immune and glial cells and the release of immune/glial proinflammatory cytokines. This can occur at the level of peripheral nerves, dorsal root ganglia, spinal cord, and likely at higher brain areas. The implications of this model for human chronic pain syndromes and clinical resolution of these chronic pain states are then discussed.