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ID PMID Title PublicationDate abstract
19522538 Biochemical and structural characterization of the human TL1A ectodomain. 2009 Aug 18 TNF-like 1A (TL1A) is a newly described member of the TNF superfamily that is directly implicated in the pathogenesis of autoimmune diseases, including inflammatory bowel disease, atherosclerosis, and rheumatoid arthritis. We report the crystal structure of the human TL1A extracellular domain at a resolution of 2.5 A, which reveals a jelly-roll fold typical of the TNF superfamily. This structural information, in combination with complementary mutagenesis and biochemical characterization, provides insights into the binding interface and the specificity of the interactions between TL1A and the DcR3 and DR3 receptors. These studies suggest that the mode of interaction between TL1A and DcR3 differs from other characterized TNF ligand/receptor complexes. In addition, we have generated functional TL1A mutants with altered disulfide bonding capability that exhibit enhanced solution properties, which will facilitate the production of materials for future cell-based and whole animal studies. In summary, these studies provide insights into the structure and function of TL1A and provide the basis for the rational manipulation of its interactions with cognate receptors.
19365835 Population-based study of autoimmune conditions and the risk of specific lymphoid malignan 2009 Jul 15 Some autoimmune conditions are associated with increased risk of lymphoid malignancies, but information on specific malignancy subtypes is limited. From the U.S. Surveillance Epidemiology and End Results-Medicare database, we selected 44,350 lymphoid malignancy cases (> or =67 years) and 122,531 population-based controls. Logistic regression was used to derive odds ratios (ORs) comparing the prevalence of autoimmune conditions in cases and controls, by lymphoid malignancy subtype, adjusted for gender, age at malignancy/selection, year of malignancy/selection, race and number of physician claims. The strongest associations observed by non-Hodgkin lymphoma (NHL) subtypes were diffuse large B-cell lymphoma with rheumatoid arthritis (OR 1.4, 95%CI 1.2-1.5) and Sjögren syndrome (2.0, 1.5-2.8); T-cell lymphoma with hemolytic anemia (9.7, 4.3-22), psoriasis (3.1, 2.5-4.0), discoid lupus erythematosus (4.4, 2.3-8.4) and celiac disease (5.0, 2.4-14.); and marginal zone lymphoma with Sjögren syndrome (6.6, 4.6-9.5), systemic lupus erythematosus (2.8, 1.7-4.7) and hemolytic anemia (7.4, 3.1-18). Hodgkin lymphoma was associated with systemic lupus erythematosus (3.5, 1.9-6.7). Multiple myeloma was associated only with pernicious anemia (1.5, 1.3-1.7). Several autoimmune conditions were associated with increased risk of lymphoid neoplasms, especially NHLs of diffuse large B-cell, marginal zone and T-cell subtypes. These results support a mechanism whereby chronic antigenic stimulation leads to lymphoid malignancy.
19319143 Antiviral immune responses: triggers of or triggered by autoimmunity? 2009 Apr The predisposition of individuals to several common autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis, is genetically linked to certain human MHC class II molecules and other immune modulators. However, genetic predisposition is only one risk factor for the development of these diseases, and low concordance rates in monozygotic twins, as well as the geographical distribution of disease risk, suggest the involvement of environmental factors in the development of these diseases. Among these environmental factors, infections have been implicated in the onset and/or promotion of autoimmunity. In this Review, we outline the mechanisms by which viral infection can trigger autoimmune disease and describe the pathways by which infection and immune control of infectious disease might be dysregulated during autoimmunity.
19264469 Effects of leukotriene B4 and prostaglandin E2 on the differentiation of murine Foxp3+ T r 2009 Apr Leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) are shown to be potent immunoregulatory lipid mediators. Here, we examined the effects of LTB4 and PGE2 on the differentiation of immunosuppressive CD4+CD25+Foxp3+ T regulatory cells (Treg) and pro-inflammatory IL-17-producing cells (Th17) from murine naïve CD4+ T cells. Using MACS-purified murine CD4+CD62L+ naïve T cells, we found that three days later in the presence of TGF-beta1, (28.65+/-6.83)% cells were converted into Treg cells, the mRNA expression of the key transcription factor Foxp3 peaked at 36h. Both LTB4 and PGE2 dose-dependently decreased the percentage of Treg cells and the mRNA expression of Foxp3. When the CD4+CD62L+ T cells were activated under Th17-promoting conditions in the presence of TGF-beta1 plus IL-6, three days later the production of IL-17 was markedly increased and the key transcription factor RORgammat mRNA peaked at 48h. LTB4 dose-dependently increased the secretion of IL-17 and the expression of RORgammat mRNA, whereas PGE2 decreased the secretion of IL-17 and the RORgammat mRNA expression. Our results suggest a distinct mode of immunoregulative action by PGE2 and LTB4, which may further our understanding of the role for lipid inflammatory mediators in the physiopathology of autoimmune diseases such as rheumatoid arthritis.
19228815 Endogenous suppression of mast cell development and survival by IL-4 and IL-10. 2009 May Mast cell development is an important component of atopic and chronic inflammatory diseases such as asthma, multiple sclerosis, rheumatoid arthritis, and atherosclerosis. In this study, we found that IL-4 and IL-10 were produced constitutively in cultures of developing mast cells, correlating with mast cell purity. Deletion of either gene increased mast cell numbers and Fc epsilon RI expression during culture in IL-3 + stem cell factor (SCF). By adding exogenous IL-4 and IL-10 to bone marrow (BM) cultures containing IL-3 + SCF, we found that IL-4 + IL-10 suppressed mast cell development through mechanisms not used by either cytokine alone. IL-4 + IL-10 elicited a rapid cell death coincidental with reduced Kit receptor expression and signaling and enhanced mitochondrial damage and caspase activation. IL-4 or IL-10 costimulation, unlike either cytokine alone, altered mast cell ontogeny to yield predominantly macrophages in cultures that typically produce mast cells. This effect was observed consistently with unseparated BM cells, purified mouse BM stem cells, and erythrocyte-depleted human umbilical cord blood cells. These experiments demonstrated a major role for Stat6 and Stat3, but not the Stat3-induced transcriptional repressor Ets variant gene 3. Genetic background was also a critical factor, as BALB/c-derived BM cells were completely resistant to IL-10-mediated killing and expressed lower levels of IL-10R. Collectively, these results support the theory that IL-4 and IL-10 function as endogenous regulators of mast cell progenitor development, consistent with a role in immune homeostasis. Loss of this homeostasis, perhaps via genetic polymorphism, could contribute to the etiology of mast cell-associated disease.
19109131 Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IF 2009 Jan 1 Increased IFN-alpha signaling is a primary pathogenic factor in systemic lupus erythematosus (SLE). STAT4 is a transcription factor that is activated by IFN-alpha signaling, and genetic variation of STAT4 has been associated with risk of SLE and rheumatoid arthritis. We measured serum IFN-alpha activity and simultaneous IFN-alpha-induced gene expression in PBMC in a large SLE cohort. The risk variant of STAT4 (T allele; rs7574865) was simultaneously associated with both lower serum IFN-alpha activity and greater IFN-alpha-induced gene expression in PBMC in SLE patients in vivo. Regression analyses confirmed that the risk allele of STAT4 was associated with increased sensitivity to IFN-alpha signaling. The IFN regulatory factor 5 SLE risk genotype was associated with higher serum IFN-alpha activity; however, STAT4 showed dominant influence on the sensitivity of PBMC to serum IFN-alpha. These data provide biologic relevance for the risk variant of STAT4 in the IFN-alpha pathway in vivo.
20633279 Long lasting pain hypersensitivity following ligation of the tendon of the masseter muscle 2010 Jul 15 BACKGROUND: A major subgroup of patients with temporomandibular joint (TMJ) disorders have masticatory muscle hypersensitivity. To study myofacial temporomandibular pain, a number of preclinical models have been developed to induce myogenic pain of the masseter muscle, one of the four muscles involved in mastication. The currently used models, however, generate pain that decreases over time and only lasts from hours to weeks and hence are not suitable for studying chronicity of the myogenic pain in TMJ disorders. Here we report a model of constant myogenic orofacial pain that lasts for months. RESULTS: The model involves unilateral ligation of the tendon of the anterior superficial part of the rat masseter muscle (TASM). The ligation of the TASM was achieved with two chromic gut (4.0) ligatures via an intraoral approach. Nocifensive behavior of the rat was assessed by probing the skin site above the TASM with a series of von Frey filaments. The response frequencies were determined and an EF50 value, defined as the von Frey filament force that produces a 50% response frequency, was derived and used as a measure of mechanical sensitivity. Following TASM ligation, the EF50 of the injured side was significantly reduced and maintained throughout the 8-week observation period, suggesting the presence of mechanical hyperalgesia/allodynia. In sham-operated rats, the EF50 of the injured side was transiently reduced for about a week, likely due to injury produced by the surgery. Somatotopically relevant Fos protein expression was indentified in the subnucleus caudalis of the spinal trigeminal sensory complex. In the same region, persistent upregulation of NMDA receptor NR1 phosphorylation and protein expression and increased expression of glial markers glial fibrillary acidic protein (astroglia) and CD11b (microglia) were found. Morphine (0.4-8 mg/kg, s.c.) and duloxetine (0.4-20 mg/kg, i.p.), a selective serotonin-norepinephrine reuptake inhibitor, produced dose-dependent attenuation of hyperalgesia. CONCLUSIONS: Ligation injury of the TASM in rats led to long-lasting and constant mechanical hypersensitivity of myogenic origin. The model will be particularly useful in studying the chronicity of myogenic pain TMJ disorders. The model can also be adapted to other regions of the body for studying pathology of painful tendinopathy seen in sports injury, muscle overuse, and rheumatoid arthritis.
20641630 (64)Cu-1,4,7-Triazacyclononane-1,4-7-triacetic acid-Glu-c(RGDyK)-bombesin[7-14]. 2004 The amphibian bombesin (BBN or BN, a peptide of 14 amino acids) is an analog of human gastrin-releasing peptide (GRP, a peptide of 27 amino acids) that binds to GRP receptors (GRPR) with high affinity and specificity (1, 2). Both GRP and BBN share an amidated C-terminus sequence homology of seven amino acids, Trp-Ala-Val-Gly-His-Leu-Met-NH(2). BBN-Like peptides have been shown to induce various biological responses in diverse tissues, including the central nervous system (CNS) and the gastrointestinal (GI) system. They also act as potential growth factors for both normal and neoplastic tissues (3). Specific BBN receptors (BBN-R) have been identified on CNS and GI tissues and on a number of tumor cell lines (4). The BBN-R superfamily includes at least four different subtypes, namely the GRPR subtype (BB2), the neuromedin B (NMB) receptor subtype (BB1), the BB3 subtype, and the BB4 subtype. The findings of GRPR overexpression in various human tumors, such as breast, prostate, lung, colon, ovarian, and pancreatic cancers, provide opportunities for tumor imaging by designing specific molecular imaging agents to target the GRPR (5, 6). Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (7). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (8-13). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. A peptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various ligands have been introduced for imaging of tumors and tumor angiogenesis (14). Because breast and prostate cancers express both GRPR and α(v)β(3), Liu et al. (15) designed an RGD-BBN heterodimer in which BBN[7-14] and c(RGDyK) are connected with a glutamate linker (BBN on the Glu side chain γ-carboxylate group and RGD on the Glu side chain α-carboxylate group). A spacer, 11-amino-3,6,9-trioxaundecanoic acid (PEG(3)), was put onto the glutamate α-amino group of Glu-RGD-BBN to increase the hydrophilicity and to relieve the steric hindrance. N-Succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB) was used to synthesize [(18)F]SFB-PEG(3)-RGD-BBN for tumor targeting. Liu et al. used 1,4,7-triazacyclononane-1,4-7-triacetic acid (NOTA) as a bifunctional chelator for labeling RGD-BBN to form (64)Cu-NOTA-RGD-BBN for positron emission tomography (PET) imaging of α(v)β(3) and GRPR in nude mice bearing human tumors (15, 16).
20103603 Identification of a novel Raf-1 pathway activator that inhibits gastrointestinal carcinoid 2010 Feb Carcinoids are neuroendocrine tumors (NET) that secrete hormones, including serotonin, resulting in the malignant carcinoid syndrome. In addition to the significant morbidity associated with the syndrome, carcinoids are frequently metastatic at diagnosis, and untreated mortality at 5 years exceeds 70%. Surgery is the only curative option, and the need for other therapies is clear. We have previously shown that activation of Raf-1 inhibits carcinoid cell proliferation. We investigated the ability of leflunomide (LFN), a Food and Drug Administration-approved medication for the treatment of rheumatoid arthritis, and its active metabolite teriflunomide (TFN) as a potential anti-NET treatment. LFN and TFN inhibit the in vitro proliferation of gastrointestinal carcinoid cells and induce G(2)-M phase arrest. Daily oral gavage of nude mice with subcutaneous xenografted carcinoid tumors confirms that LFN can inhibit NET growth in vivo. Treatment with TFN suppresses the cellular levels of serotonin and chromogranin A, a glycopeptide co-secreted with bioactive hormones. Additionally, TFN reduces the level of achaete-scute complex-like 1 (ASCL1), a NET marker correlated with survival. These effects are associated with the activation of the Raf-1/mitiogen-activated protein kinase kinase/extracellular signal-regulated kinase-1/2 pathway, and blockade of mitiogen-activated protein kinase kinase signaling reversed the effects of TFN on markers of the cell cycle and ASCL1 expression. In summary, LFN and TFN inhibit carcinoid cell proliferation in vitro and in vivo and alter the expression of NET markers. This compound thus represents an attractive target for further clinical investigation.
20100929 Absence of SHIP-1 results in constitutive phosphorylation of tank-binding kinase 1 and enh 2010 Mar 1 Autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, result from a loss of tolerance to self-antigens and immune-mediated injury precipitated by the overproduction of type I IFN and inflammatory cytokines. We have identified the inositol 5' phosphatase SHIP-1 as a negative regulator of TLR3-induced type I IFN production. SHIP-1-deficient macrophages display enhanced TLR-induced IFN-beta production, and overexpression of SHIP-1 negatively regulates the ability of TLR3 and its adaptor, Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta, to induce IFN-beta promoter activity, indicating that SHIP-1 negatively regulates TLR-induced IFN-beta production. Further dissection of the IFN-beta pathway implicates TANK-binding kinase 1 (TBK1) as the target for SHIP-1. Critically, in the absence of SHIP-1, TBK1 appears to be hyperphosphorylated both in unstimulated cells and following TLR3 stimulation. In addition, TBK1 appears to be constitutively associated with Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta and TNFR-associated factor 3 in SHIP-1 deficient cells, whereas in wild-type cells this association is inducible following TLR3 stimulation. In support of a role for SHIP-1 in regulating complex formation, confocal microscopy demonstrates that TBK1 distribution in the cell is significantly altered in SHIP-1-deficient cells, with more prominent endosomal staining observed, compared with wild-type controls. Taken together, our results point to SHIP-1 as a critical negative regulator of IFN-beta production downstream of TLR3 through the regulation of TBK1 localization and activity.
20087753 Construction of a recombinant adenovirus vector expressing IL-18BP/IL-4 fusion gene and th 2010 Feb OBJECTIVE: To construct a recombinant adenovirus vector for expressing the IL-18 binding protein (IL-18BP)/IL-4 fusion gene and confirm the anti-inflammatory effect of this gene. MATERIALS AND METHODS: The recombinant virus expressing IL-18BP/IL-4 fusion protein (AD-IL-18BP/IL-4) was constructed. AD-IL-18BP/IL-4 was used to infect synovial fibroblasts (SF). ELISA and Western blot analysis were used to determine the expressions of the proteins IL-4 and IL-18BP. To investigate the protective effects of this vector on rheumatoid arthritis, SF were infected with AD-IL-18BP/IL-4 and stimulated by LPS (1 microg/ml) 4 h later. The expression levels of TNF-alpha, IL-6, IL-8, and IL-18 in the culture supernatant were detected by ELISA and production of PGE2 and NO was estimated. The protein expression of COX-2, iNOS, and NF-kappaB p50 in treated SF was analyzed by Western blot. RESULTS: AD-IL-18BP/IL-4 can effectively express the IL-18BP/IL-4 fusion protein. The expressions of TNF-alpha, IL-6, IL-8, and IL-18 were significantly inhibited in LPS-stimulated SF after treatment with AD-IL-18BP/IL-4. The production of PGE2 and NO was significantly decreased. Moreover, NF-kappaB p50, COX-2, and iNOS levels in SF were markedly suppressed by AD-IL-18BP/IL-4. CONCLUSION: AD-IL-18BP/IL-4 can suppress the production and expression of inflammatory cytokines such as COX-2, iNOS, and NF-kappaB in LPS-stimulated SF.
20083653 Myelin basic protein priming reduces the expression of Foxp3 in T cells via nitric oxide. 2010 Feb 15 Regulatory T cells (Tregs) play a vital role in autoimmune disorders. Among several markers, forkhead box p3 (Foxp3) is the most specific with regard to Treg activity. Therefore, understanding mechanisms that regulate Foxp3 expression is a critical step for unraveling the complicacy of autoimmune pathophysiology. The present study was undertaken to investigate the crosstalk between NO and Tregs. Interestingly, after myelin basic protein (MBP) priming, the expression of Foxp3 decreased in MBP-primed T cells. However, blocking NO either by inhibiting inducible NO synthase with l-N(6)-(1-iminoethyl)-lysine hydrochloride or through scavenging with PTIO or by pharmacological drugs, such as pravastatin, sodium benzoate, or gemfibrozil, restored the expression of Foxp3 in MBP-primed T cells. However, this restoration of Foxp3 by pharmacological drugs was reversed by S-nitrosoglutathione, an NO donor. Similarly, NO also decreased the populations of Tregs characterized by CD4(+)CD25(+) and CD25(+)FoxP3(+) phenotypes. We have further confirmed this inverse relationship between NO and Foxp3 by analyzing the mRNA expression of Foxp3 and characterizing CD25(+)FoxP3(+) or CD4(+)Foxp3(+) phenotypes from inducible NO synthase knockout mice. Moreover, this inverse relation between NO and Foxp3 also was observed during priming with myelin oligodendrocyte glycoprotein, another target neuroantigen in multiple sclerosis, as well as collagen, a target autoantigen in rheumatoid arthritis. Finally, we demonstrate that NO inhibited the expression of Foxp3 in MBP-primed T cells via soluble guanylyl cyclase-mediated production of cGMP. Taken together, our data imply a novel role of NO in suppressing Foxp3(+) Tregs via the soluble guanylyl cyclase pathway.
20641755 (64)Cu-1,4,7,10-Tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid-iron oxid 2004 Magnetic resonance imaging (MRI) maps information about tissues spatially and functionally. Protons (hydrogen nuclei) are widely used in imaging because of their abundance in water molecules. Water comprises ~80% of most soft tissue. The contrast of proton MRI depends primarily on the density of the nucleus (proton spins), the relaxation times of the nuclear magnetization (T(1), longitudinal, and T(2), transverse), the magnetic environment of the tissues, and the blood flow to the tissues. However, insufficient contrast between normal and diseased tissues requires the use of contrast agents. Most contrast agents affect the T(1) and T(2) relaxation times of the surrounding nuclei, mainly the protons of water. T(2)* is the spin–spin relaxation time composed of variations from molecular interactions and intrinsic magnetic heterogeneities of tissues in the magnetic field (1). Cross-linked iron oxide (CLIO) nanoparticles and other iron oxide formulations affect T(2) primarily and lead to decreased signals. On the other hand, the paramagnetic T(1) agents, such as gadolinium (Gd(3+)) and manganese (Mn(2+)), accelerate T(1) relaxation and lead to brighter contrast images. Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (2). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor class affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (3-8). The α(v)β(3) integrin is strongly expressed on tumor cells and activated endothelial cells. In contrast, expression of α(v)β(3) integrin is weak on resting endothelial cells and most normal tissues. The α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents, and the agonists are being studied as angiogenic agents for coronary angiogenesis (7, 9, 10). The tripeptide sequence Arg-Gly-Asp (RGD) is identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins including α(v)β(3). Various radiolabeled cyclic RGD peptides have been introduced for imaging of tumors and tumor angiogenesis (11). (64)Cu-1,4,7,10-Tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid-iron oxide-c(RGDyK) ((64)Cu-DOTA-IO-RGDyK) nanoparticles have been developed as a multimodality probe for positron emission tomography (PET) and MRI of tumor vasculature to study in vivo biodistribution of the tracer in tumor-bearing mice (12). (64)Cu-DOTA-IO-RGDyK has been shown to have a high accumulation in the tumor vasculature with little extravastion and predominant liver and spleen accumulation.
19951419 Confirmation of the genetic association of CTLA4 and PTPN22 with ANCA-associated vasculiti 2009 Dec 1 BACKGROUND: The genetic contribution to the aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is not well defined. Across different autoimmune diseases some genes with immunomodulatory roles, such as PTPN22, are frequently associated with multiple diseases, whereas specific HLA associations, such as HLA-B27, tend to be disease restricted. We studied ten candidate loci on the basis of their immunoregulatory role and prior associations with type 1 diabetes (T1D). These included PTPN22, CTLA4 and CD226, which have previously been associated with AAV. METHODS: We genotyped the following 11 SNPs, from 10 loci, in 641 AAV patients using TaqMan genotyping: rs2476601 in PTPN22, rs1990760 in IFIH1, rs3087243 in CTLA4, rs2069763 in IL2, rs10877012 in CYP27B1, rs2292239 in ERBB3, rs3184504 in SH2B3, rs12708716 in CLEC16A, rs1893217 and rs478582 in PTPN2 and rs763361 in CD226. Where possible, we performed a meta-analysis with previous analyses. RESULTS: Both CTLA4 rs3087243 and PTPN22 rs2476601 showed association with AAV, P = 6.4 x 10-3 and P = 1.4 x 10-4 respectively. The minor allele (A) of CTLA4 rs3087243 is protective (odds ratio = 0.84), whereas the minor allele (A) of PTPN22 rs2476601 confers susceptibility (odds ratio = 1.40). These results confirmed previously described associations with AAV. After meta-analysis, the PTPN22 rs2476601 association was further strengthened (combined P = 4.2 x 10-7, odds ratio of 1.48 for the A allele). The other 9 SNPs, including rs763361 in CD226, showed no association with AAV. CONCLUSION: Our study of T1D associated SNPs in AAV has confirmed CTLA4 and PTPN22 as susceptibility loci in AAV. These genes encode two key regulators of the immune response and are associated with many autoimmune diseases, including T1D, autoimmune thyroid disease, celiac disease, rheumatoid arthritis, and now AAV.
20641311 [(18)F]Fluorobenzyl-PEG(3)-Glu-c(RGDyK)-bombesin[7-14]. 2004 The amphibian bombesin (BBN or BN, a peptide of 14 amino acids) is an analog of human gastrin-releasing peptide (GRP, a peptide of 27 amino acids), which binds to GRP receptors (GRPR) with high affinity and specificity (1, 2). Both GRP and BBN share an amidated C-terminus sequence homology of seven amino acids, Trp-Ala-Val-Gly-His-Leu-Met-NH(2). BBN-Like peptides have been shown to induce various biological responses in diverse tissues, including the central nervous system and the gastrointestinal system. They also act as potential growth factors for both normal and neoplastic tissues (3). Specific BBN receptors (BBN-R) have been identified on central nervous system and gastrointestinal tissues and on a number of tumor cell lines (4). The BBN-R superfamily includes at least four different subtypes, namely the GRPR subtype (BB2), the neuromedin B (NMB) receptor subtype (BB1), the BB3 subtype, and the BB4 subtype. The findings of GRPR overexpression in various human tumors, such as breast, prostate, lung, colon, ovarian, and pancreatic cancers, provide opportunities for tumor imaging by designing specific molecular imaging agents to target the GRPR (5, 6). Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (7). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (8-13). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (12, 14, 15). A peptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various ligands have been introduced for imaging of tumors and tumor angiogenesis (16). Because prostate cancer expresses both GRPR and α(v)β(3), Liu et al. (17) designed an RGD-BBN heterodimer in which BBN[7-14] and c(RGDyK) were connected with a glutamate linker (BBN on the Glu side-chain γ-carboxylate group and on the Glu side-chain α-carboxylate group). A spacer, 11-amino-3,6,9-trioxaundecanoic acid (PEG(3)), was placed on the glutamate α-amino group of Glu-RGD-BBN to increase the hydrophilicity and to relieve the steric hindrance. N-Succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB) was used to synthesize [(18)F]FB-PEG(3)-Glu-RGD-BBN for tumor imaging in vivo.
19850844 Expression of CXCL9, -10, -11, and CXCR3 in the tear film and ocular surface of patients w 2010 Feb PURPOSE: To investigate the expression of CXCL9, -10, -11, and CXCR3 in the tear film and ocular surface of patients with dry eye syndrome. METHODS: Thirty-three patients with dry eye (16 with and 17 without Sjögren's syndrome) and 15 control subjects were recruited. The concentrations of CXCL9, -10, and -11 in tears were measured with enzyme-linked immunosorbent assays. The correlation between chemokine levels and tear film and ocular surface parameters was analyzed. The expression of CXCL9, -10, -11, and CXCR3 in the conjunctiva was evaluated by using immunohistochemistry. Flow cytometry was performed to count CXCR3(+) cells and CXCR3(+)CD4(+) cells in the conjunctiva. RESULTS: The concentrations of CXCL9, -10, and -11 were 1,148 +/- 1,088, 24,338 +/- 8,706, and 853 +/- 334 pg/mL, in the patients with dry eye, and 272 +/- 269 (P = 0.01), 18,149 +/- 5,266 (P = 0.02), and 486 +/- 175 (P < 0.01) pg/mL in the control subjects, respectively. The concentrations significantly increased in tears of the patients with Sjögren's syndrome compared with those of the patients with non-Sjögren's dry eye (P < 0.05). CXCL10 levels correlated significantly with basal tear secretion, and CXCL11 levels correlated significantly with basal tear secretion, tear clearance rate, keratoepitheliopathy score, and goblet cell density (P < 0.05). Staining for CXCL9, -10, -11, and CXCR3 increased in patients with dry eye, especially in the patients with Sjögren's syndrome. Flow cytometry demonstrated an increased number of CXCR3(+) and CXCR3(+)CD4(+) cells in all the patients with dry eye. CONCLUSIONS: Expression of CXCL9, -10, -11, and CXCR3 increased in the tear film and ocular surface of patients with dry eye syndrome, especially in those with Sjögren's syndrome. CXCL11 levels correlated significantly with various tear film and ocular surface parameters. (ClinicalTrials.gov number, NCT00991679.).
19852957 Lymphocytic infiltration leads to degradation of lacrimal gland extracellular matrix struc 2010 Feb We previously reported that lacrimal glands (LGs) of male non-obese diabetic (NOD) mice, an established mouse model of autoimmune inflammatory LG disease that displays many features of human LGs in patients afflicted with Sjögren's syndrome (SjS), exhibit significant degradation of extracellular matrix (ECM) structures as well as increased expression of matrix metalloproteinases (MMPs). The purpose of the current study was to expand the spectrum of proteases identified, to clarify their probable origin as well as to identify the contribution of these changes to disease pathogenesis. We explored in depth the changes in ECM structures and ECM protease expression at the onset of disease (6 weeks) versus late stage disease (18 weeks) in male NOD mouse LGs, relative to LGs of age-matched male NODscid, a severely immunocompromised congenic strain, and healthy BALB/c mice. LG tissues were examined using routine histological, immunohistochemical, Western Blot and gene expression analyses novel multiphoton imaging technologies. We further characterized the profile of infiltrating immune cells under each condition using flow cytometry. Our results show that the initial infiltrating cells at 6 weeks of age are responsible for increased MMP and cathepsin H expression and therefore initiate the LG ECM degradation in NOD mice. More importantly, NODscid mice exhibited normal LG ECM structures, indicating the lymphocytes seen in the LGs of NOD mice are responsible for the degradation of the LG ECM. The disease-related remodeling of LG ECM structures may play a crucial role in altering the acinar signaling environment, disrupting the signaling scaffolds within the cells, which are required to mobilize the exocytotic trafficking machinery, ultimately leading to a loss of LG function in patients afflicted with SjS.
19404025 [Serum sickness induced by rituximab infusion; report of two cases with hematological mali 2009 Apr We report 2 cases of serum sickness after rituximab infusion. Case 1 is a patient with Waldenström's macroglobulinemia, and case 2 is a patient with marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type and Sjögren's syndrome. Both patients had polyclonal hypergammaglobulinemia, were treated with rituximab monotherapy, developed serum sickness between 9 and 17 days after the first rituximab infusion, developed fever and arthralgia, and improved soon after corticosteroid treatment. Serum sickness after rituximab treatment for hematological malignancies is very rare as far as we know. We identified three risk factors of serum sickness after rituximab infusion from previous reports and our cases; administration of rituximab alone, the existence of Sjögren's syndrome, and polyclonal hypergammaglobulinemia.
20673052 Anti-TNF-alpha treatment: a possible promoter in endogenous uveitis? observational report 2010 Aug BACKGROUND: TNF-alpha inhibitory drugs are widely used with beneficial effect in the treatment of rheumatic diseases, such as juvenile idiopathic arthritis and ankylosing spondylitis. Due to the complex immune regulatory function of TNF-alpha, induction of inflammation in several organs including the eye, skin, and gastrointestinal tract has been reported. This report describes the occurrence of intraocular inflammation after treatment with the TNF-alpha antagonist etanercept. METHODS: In this observational case series, we followed and examined six patients receiving etanercept for juvenile idiopathic arthritis, ankylosing spondylitis, adult Still's disease, or psoriasis. RESULT: All patients responded well to their joint affliction, but developed endogenous uveitis for the first time after application of etanercept. Following acute intervention with corticosteroids, etanercept was discontinued and instead an antibody-based anti-TNF treatment using infliximab was instituted. We documented visual acuity before and after change from etanercept to treatment with the anti-TNF-alpha antibody infliximab. Interestingly, prompt long-term remission (mean 34 months) of uveitis without recurrence could be induced in all patients. CONCLUSIONS: Our observations may indicate that immunodysregulatory and even proinflammatory effects of etanercept are of relevance in clinical practice. Further randomized controlled clinical trials are necessary to investigate possible side effects of anti-TNF therapy using etanercept and infliximab.
20535138 STAT4 is a confirmed genetic risk factor for Sjögren's syndrome and could be involved in 2010 Jul Signal transducer and activator of transcription 4 (STAT4) is a transcription factor mainly activated by interleukin 12, which promotes the secretion of type 2 interferon (IFN) by T-helper 1 cells. We assessed the association of STAT4 gene polymorphism and primary Sjögren's syndrome (pSS) and its functional relevance. We analyzed STAT4 rs7582694 polymorphism in an exploratory cohort of 186 pSS patients and 152 controls, and in a replication cohort of 192 pSS patients and 483 controls, all Caucasian. mRNA levels of STAT4alpha, STAT4beta, STAT1, and the type 1 IFN-induced genes PKR, MX1 and IFITM1 were assessed in peripheral blood mononuclear cells (PBMCs) from 30 pSS patients. STAT4 rs7582694 C allele was associated with pSS in both cohorts (odds ratio (OR) 1.57, 95% confidence interval (CI) 1.27-1.93, P=2.3 x 10(-5)). The association was increased for homozygous subjects, which suggests a recessive effect of the STAT4 at-risk allele. STAT4alpha, STAT4beta and STAT1 mRNA levels in PBMCs were not significantly associated with rs7582694 genotypes, however the mRNA levels of STAT4alpha and type 1 IFN-induced genes were strongly correlated: PKR (P=4 x 10(-3), r=0.51), MX1 (P=2 x 10(-4), r=0.63) and IFITM1 (P=8 x 10(-3), r=0.47), suggesting that STAT4 might be involved in not only type 2 IFN production but also in type 1 IFN-mediated effects.