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ID PMID Title PublicationDate abstract
23166957 (64)Cu-1,4,7-Triazacyclononane-1,4-diacetic acid-c(RGDyK)-Glu-6-aminohexanoic acid-bombesi 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 receptor (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-Rs) 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 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), Jackson et al. (15) designed an RGD-BBN heterodimer in which c(RGDyK) and BBN[7-14]NH(2) 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, 6-aminohexanoic acid (6-Ahx), was put onto the glutamate α-amino group of RGD-Glu-BBN to increase the hydrophilicity and to relieve the steric hindrance. 1,4,7-Triazacyclononane-1,4-7-triacetic acid (NOTA) was used as a bifunctional chelator for labeling RGD-BBN to form (64)Cu-NO2A-RGD-Glu-6-Ahx-BBN for use in positron emission tomography (PET) imaging of α(v)β(3) and GRPR in nude mice bearing human tumors.
21735593 (111)In-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-MEDI-522. 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). 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 (2-7). 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 the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide 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 radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). In addition to RGD peptides, a humanized anti-human integrin α(v)β(3) monoclonal antibody (MEDI-522) was identified to be unique in that it recognizes either the human α(v) or β(3) subunit. MEDI-522 cross-reacts with integrin α(v)β(3) from rabbits, chickens, and hamsters but not with integrin α(v)β(3) from mice or rats (13). MEDI-522 is being evaluated as an antiangiogenic agent for cancer therapy (14-16). Cai et al. (17) reported the development of (64)Cu-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-MEDI-522 ((64)Cu-DOTA-MEDI-522) for positron emission tomography imaging of α(v)β(3) receptors in nude mice bearing tumors. Liu et al. (18) reported the evaluation of (111)In-DOTA-MEDI-522 for single-photon emission computed tomography (SPECT) imaging α(v)β(3) receptors in nude mice bearing tumors.
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).
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.
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.
20641665 Pyro-Gly-Asp-Glu-Val-Asp-Gly-Ser-Gly-Lys(BHQ3). 2004 Photodynamic therapy (PDT), also known as photochemotherapy, uses light-activated photosensitizers (PS) in the presence of oxygen to kill cells (1). PDT has become a promising modality to treat skin, esophagus, and lung cancers, as well as other diseases such as atherosclerosis, macular degeneration, and rheumatoid arthritis (2). In PDT, light excites the singlet state of the PS, followed by intersystem transition from the singlet state to the triplet state; then, the energy is transferred from the triplet state of the PS to the triplet ground state of oxygen (3)O(2)(X(3)Σ(g)(-)) ((3)O(2) triplet state quenching) to generate singlet oxygen (1)O(2)(a(1)Δ(g)) (3). The produced (1)O(2) is a major cytotoxic agent that has a short life time (<200 ns) and an average diffusion range (~20 nm, which is smaller than the diameter of a cell) (2). Such a short diffusion range requires the delivery of target-specific PS agents into subcellular compartments such as cytoskeletal tubulin, lysosomes, mitochondria, plasma membrane, and the nucleus, where they can generate (1)O(2) efficiently (2). A novel type of PS agents, called a photodynamic molecular beacon (PMB) or killer beacon, has been developed to meet this requirement (2, 4). A typical PMB consists of four modular components: a fluorescent PS, a quencher, a linker, and a delivery vehicle. The target-specific linkers keep the fluorescent PS and the quencher within the effective distance of the Föster radius (3–6 nm) (2), which allows efficient fluorescence resonance energy transfer between the fluorescent PS and the quencher. As a result, the fluorescent PS is silent until the PMB meets the target, where the enzyme cleaves the linker and activates the fluorescence of the PS (4). Thus, the PS performs two functions by producing (1)O(2) to kill cells and by illuminating detectable fluorescence to image its own therapeutic outcome (5). Caspases are cysteine aspartate proteinases (6), and they participate in apoptosis through direct disassembly of cell structure, cleavage of several important proteins (gelsolin, focal adhesion kinase, and p21), shutting down DNA replication and repair, disrupting nuclear structure, and disintegrating cells into apoptotic bodies (7). As a main downstream effector, the caspase subtype-3 (capspase-3) recognizes targets that contain the tetrapeptide sequence Asp-Glu-Val-Asp (7). Proteins with this recognition motif are cleaved specifically with high efficiency (k(cat)/K(m) > 10(6) M(-1)s(-1)). Pyro-Gly-Asp-Glu-Val-Asp-Gly-Ser-Gly-Lys(BHQ3) (PPB) is a PMB specific for caspase-3, and it is detectable with near-infrared (NIR) fluorescence imaging (5). PPB consists of the infrared fluorescence PS pyropheophorbide α (Pyro), a black hole quencher 3 (BHQ3), and a peptide linker (GDEVDGSGK) (5). The peptide contains the tetrapeptide motif DEVD for caspase-3 recognition, and the cleavage site is located between the D and G residues. Pyro acts as the intracellular vehicle and as the PS (absorption, 665 nm; emission, 675 nm and 720 nm) with good (1)O(2) production (50%). Pyro lacks dark toxicity (toxicity in absence of ligh) because of its low absorption between 450–600 nm. BHQ3 (absorption, 672 nm) can efficiently quench Pyro fluorescence via fluorescence resonance energy transfer (FRET). The cleavage of PPB by caspase-3 separates the photosensitizer (Pyro) from the quencher (BHQ3) and restores the Pyro fluorescence for detection.
12472675 Do autoantibodies predict autoimmune liver disease in primary Sjögren's syndrome? Data of 2002 Dec OBJECTIVE: To evaluate the clinical value of autoantibodies as serological markers to predict autoimmune liver diseases in primary Sjögren's syndrome (SS). MATERIALS AND METHODS: 180 patients who met the European diagnostic criteria for SS but without a history of liver disease were studied upon a 5 year follow-up. Sera taken at enrolment were evaluated by immunofluorescence analysis (IF-AMA) on rat liver, stomach and kidney sections, enzyme-linked immunosorbent assay using rat mitochondrial, microsomal and soluble liver antigens and Western blot (WB) analysis using rat mitochondrial antigens. RESULTS: At presentation, 152 (84%) sera had autoantibodies. Antinuclear antibodies (ANA) were expressed in 58% of patients and displayed three distinct patterns (speckled, homogenous and anticentromere). Smooth muscle autoantibodies (SMAs) and parietal cell autoantibodies were found in 39 and 4.5% of patients, respectively. Three patients presented antimitochondrial antibodies by IF-AMA, and two of them developed symptomatic primary biliary cirrhosis (PBC). Two patients without IF-AMA and without evidence of cholestasis had PBC-specific AMA (anti-PDC-E2 and anti-BCKADC-E2). However, these two patients and the third IF-AMA-positive woman remained free from symptoms and biochemical signs of PBC. Autoimmune hepatitis (AIH) (n = 2), 'overlap syndrome' of AIH and chronic hepatitis C (n = 1) and autoimmune cholangiopathy (AIC) (n = 1) were diagnosed in four patients. CONCLUSIONS: Patients with IF-AMA usually develop symptomatic PBC upon a 5 year follow-up. Our findings support the idea that patients without IF-AMA, who express PBC-specific AMA, are in early, asymptomatic stage of the disease. High-titre SMA and IF-AMA are the most specific indicators for AIH and PBC.
15307580 Brain abscesses caused by Abiotrophia defectiva: complication of immunosuppressive therapy 2004 We report the case of a patient who developed brain abscesses caused by Abiotrophia defectiva. The patient was treated with prednisone and cyclophosphamide for connective-tissue disease (lupus-Sjögren's overlap syndrome). A few cases of central nervous system infections due to Abiotrophia species have been previously reported in immunocompetent patients following neurosurgical procedures, suggesting possible introduction of this organism at the time of surgery. This case report is the first report of brain abscesses due to A. defectiva in a pharmacologically immunosuppressed patient.
15490242 Normal but not altered mucins activate neutrophils. 2004 Dec Interactions between leucocytes and their surroundings are mediated through oligosaccharide epitopes, some of which are also expressed on ocular mucins. Neutrophils represent the majority of immune cells in the proinflammatory environment of the ocular surface during sleep. We have tested whether changes in mucin glycosylation, as occur in dry eyes, influence the phenotype and activation of neutrophils. Peripheral blood leucocytes were circulated over equal concentration mats of ocular surface mucins purified from normal volunteers and dry-eye patients, and in sequence over normal and pathological mucins in all combinations. Non-adherent cells were tagged with monoclonal fluorescent antibodies to leucocyte determinants and analysed by flow cytometry. Oxidative burst, assessed with dihydrorhodamine, was followed in cells and supernatant. At a speed similar to that of leucocyte traffic in the retina, normal mucins caused a decrease in neutrophil cathepsin G fluorescence, a decrease that was not observed with mucins from patients with Meibomian gland disease or Sjogren syndrome. No effect was detected at a higher flow. Supernatant and cells collected after circulation over normal mucin showed increased rhodamine fluorescence, indicative of oxidative burst. Fluorescence could also be observed in intact cells adherent to dry-eye mucins. Non-adherent cells could be activated with phorbol 12-myristate 13-acetate after flow over any mucin or combination of mucins. Differences in neutrophil activation after exposure to normal and pathological mucins highlight reciprocal influences at the interface between local and systemic immunity.
15363623 [Acquired C1 inhibitor deficiency associated with lymphoproliferative disorders: four case 2004 Sep INTRODUCTION: Acquired C1 inhibitor deficiency is sometimes associated with lymphoproliferative disorders. EXEGESIS: We report four cases of acquired C1 inhibitor deficiency in association with lymphoproliferative disorders. Three of them were asymptomatic; one was associated with abdominal pain. Four women (median age, 66 years) presented either two non-Hodgkin lymphoma or two chronic lymphocytic leukaemia. C1 inhibitor deficiency was detected fortuitous (n = 1) or during investigation of arthralgia (n = 2), or Gougerot-Sjogren syndrome (n = 1). The deficit was acquired in all cases type I. Auto-immune disorders were associated with: Gougerot-Sjogren syndrome (n = 1), cryoglobulinemia (n = 2), IgM lambda monoclonal gammopathy (n = 1), Coombs positive test (n = 2), IgG anti-cardiolipine antibodies (n = 1). C1 inhibitor deficiency was not modified after lymphoproliferative disorders treatment (radiotherapy, splenic ablation) in two cases but patients were not in complete remission. C1 inhibitor raised normal level in one case, after five chemotherapy regimens, but decreased complement level and C4 split persist. CONCLUSION: Acquired C1 inhibitor deficiency associated with lymphoproliferative disorders is sometimes asymptomatic. Diagnosis could be delay in spite of clinical manifestations. Deficit correction is not constant after lymphoproliferative disorders treatment.
15120756 Autoantibodies in SLE but not in scleroderma react with protein-stripped nucleosomes. 2004 Jun Autoantibodies against nucleosomes (ANuA) are known to be sensitive markers for systemic lupus erythematosus (SLE), but their clinical relevance seemed to be limited because sera from patients with progressive systemic sclerosis (PSS) also showed positive reactions with conventional ANuA ELISA test systems (anti-Nu1 ELISA). It was generally assumed thatANuA were associated with both diseases. Using discontinuous sucrose gradient centrifugation to generate pure nucleosomes, we discovered by chance that at the 30-50% sucrose interface an antigen (Nu2) banded which was demonstrably free of non-histone components and histone H1. The two different nucleosome preparations, Nu1 and Nu2, were used in parallel as antigenic substrates in standardised ELISA tests to analyse sera from SLE (295 patients), PSS (119) and patients with other rheumatic diseases (101). With Nu1, 62% of the SLE and 52% of the PSS sera showed positive reactions. Two sera from patients suffering from Sjögren's syndrome (SS) and one from polymyositis were also positive. Using the Nu2 preparation, 58% of the SLE but none of the PSS sera showed a positive reaction. One serum from a patient with SS was also positive. It could be shown that it was the PSS-specific autoantigen Scl-70 in the nucleosome preparation (Nu1) which contributed to the positive reactions of the PSS sera in conventional ANuA test systems, whereas in the Nu2 preparation no remaining Scl-70 was detectable. The present study definitely proved that ANuA are highly and specifically associated with SLE but not with PSS.
12764074 Oral diseases possibly associated with hepatitis C virus. 2003 Morbidity associated with hepatitis C virus (HCV) infection can involve a variety of extrahepatic conditions, including lichen planus (LP) and sialadenitis, predominantly or exclusively involving the oral region, conditions which have been largely neglected in reviews. The literature suggests that HCV-infected patients may frequently have Sjögren-like sialadenitis with mild clinical symptoms, whereas oral LP may be significantly associated with HCV infections in Southern Europe and Japan but not in Northern Europe. These geographical differences could be related to immunogenetic factors such as the HLA-DR6 allele, significantly expressed in Italian patients with OLP and HCV. Analysis of experimental data suggests that HCV could be involved in the pathogenesis of both these diseases. Moreover, parotid lymphoma may arise in patients with sialadenitis, mainly with type II cryoglobulinemia. Little attention has been paid to oral health needs in HCV-infected patients and the variable effect of interferon-alpha therapy on oral tissues. Further research is needed, because of the potentially great influence of oral diseases possibly linked to HCV on the quality of life of millions of patients.
12695155 Anti-chromatin antibodies in systemic lupus erythematosus: a useful marker for lupus nephr 2003 May BACKGROUND: Anti-chromatin antibodies have recently been described in patients with systemic lupus erythematosus (SLE) and it has been suggested that their presence is associated with lupus nephritis. OBJECTIVE: To assess the prevalence and clinical associations of these antibodies in SLE. METHODS: The presence of anti-chromatin antibodies in 100 patients with SLE was investigated by an enzyme linked immunosorbent assay (ELISA). To determine the specificity of these antibodies, 100 patients with primary Sjögren's syndrome, 30 with primary antiphospholipid syndrome (APS), 10 with systemic sclerosis, and 100 normal controls were also tested. RESULTS: Positive levels were detected in 69/100 (69%) patients with SLE. In contrast, they were found in only 8/100 (8%) of those with primary Sjögren's syndrome, in 1/10 (10%) with systemic sclerosis, in 2/30 (7%) with primary APS, and in none of the 100 healthy controls. Patients with anti-chromatin antibodies had a twofold higher prevalence of lupus nephropathy than those without these antibodies (58% v 29%, p<0.01). A significant correlation was found between the levels of anti-chromatin antibodies and disease activity score as measured by the European Consensus Lupus Activity Measurement (ECLAM; p=0.011). CONCLUSIONS: The measurement of anti-chromatin antibodies appears to be a useful addition to the laboratory tests that can help in the diagnosis and treatment of SLE. These antibodies are both sensitive and specific for SLE, and are a useful marker for an increased risk of lupus nephritis.
12653865 Detection of HHV-8 sequences and antigens in a MALT lymphoma associated with Sjögren's sy 2003 Apr We describe the case of a bilateral parotid mucosa-associated lymphoid tissue (MALT) lymphoma associated with 2 years history of Sjögren's syndrome (SS), which was linked to human herpes virus 8 (HHV-8) infection. Using polymerase chain reaction (PCR) assay HHV-8 sequences were detectable in the lymphoma tissue of both sides. Serologic testing of the patient revealed HHV-8 antibodies in enzyme-linked immunosorbent assay (ELISA) and immunofluorescence assay (IFA). Immunohistologic staining with two antibodies against open reading frame (ORF) 26 and v-cyclin homologues of HHV-8 revealed positive staining of the salivary acinic cells whereas the lymphoma cells were negative. The potential influence of HHV-8 infection for MALT lymphoma development in this case and possible parallels to gastric MALT lymphoma are discussed.
12542832 Alterations of nitrate and nitrite content in saliva, serum, and urine in patients with sa 2003 Feb BACKGROUND: The role of the salivary glands in the maintenance of nitrate and nitrite in saliva is poorly understood. The aim was to study alterations of nitrate and nitrite metabolisms in patients with Sjogren's syndrome (SS) or sialosis. METHODS: Saliva, serum, and urine samples were collected from healthy volunteers (n = 29), patients with SS (n = 31), and patients with sialosis (n = 30). Concentrations of nitrate and nitrite were determined by high-performance liquid chromatography (HPLC). RESULTS: In the healthy group, the highest concentration of nitrate was found in parotid saliva (172 mg/l), followed by urine (160 mg/l), whole saliva (97 mg/l), and serum (33 mg/l). In the SS group, concentration of nitrate was decreased in parotid saliva and whole saliva, and increased significantly in urine. Concentration of nitrite in whole saliva was significantly decreased in the SS group and increased in the sialosis group. CONCLUSION: Hypofunction of the salivary glands is associated with significant changes of nitrate and nitrite levels in the saliva and urine.
12607726 A new disorder of lymphocyte apoptosis: combination of autoimmunity, infectious lymphadeno 2002 Dec A new symptom-complex is described characterized by manifestations of autoimmune disease, infectious lymphadenopathy, double negative T cells, and impaired activation-induced cell death that developed in late adolescence. Similarities, but also significant differences, to autoimmune lymphoproliferative syndromes (ALPS, Canale-Smith syndrome) and autoimmune lymphoproliferative disease (ALD, Dianzani syndrome), were observed. The main clinical features were recurrent bacterial infections with subsequent lymphadenopathy due to autoimmune neutropenia. Laboratory results revealed a large proportion of alphabetaTCR positive, CD4 negative, CD8 negative, peripheral T cells, and a decreased apoptosis upon activation with phytohemagglutinin and interleukin 2, but normal Fas-mediated apoptosis. Genetic investigations excluded mutations in Fas gene death domain and in the 4 exons of Fas ligand gene. Despite unknown pathogenesis, this new syndrome might belong to the growing group of diseases with defects in apoptosis.
12640102 Lymphocytic mastitis and diabetic mastopathy: a molecular, immunophenotypic, and clinicopa 2003 Mar Lymphocytic mastitis and diabetic mastopathy are uncommon fibroinflammatory breast diseases. The lesions seen in these entities are unique in that the associated lymphoid infiltrates are composed of predominantly B cells. In addition, B-cell lymphoepithelial lesions, a finding commonly associated with extranodal marginal zone B-cell/mucosa-associated lymphoid tissue (MALT) lymphomas, are also often present in lymphocytic mastitis and diabetic mastopathy. Although the clinical and immunomorphologic features are well characterized, the clonality of the B-cell infiltrate and the lymphomatous potential of lymphocytic mastitis and diabetic mastopathy have not been emphasized in the literature. We evaluated 11 cases of lymphocytic mastitis/diabetic mastopathy for immunoglobulin heavy chain gene rearrangement and correlated the findings with all available clinical data. A longstanding history of Type I diabetes mellitus was present in seven patients. One nondiabetic patient had Sjogren's syndrome, and two patients had no history of diabetes mellitus or other autoimmune disease. Clinical data were unavailable for one patient. B-cell-predominant lymphoid infiltrates were seen in all cases, and B-cell lymphoepithelial lesions were found in five. No evidence of a B-cell clone was found in any of the 11 cases by appropriately controlled immunoglobulin heavy chain gene rearrangement studies, and none of the patients developed lymphoma during follow-up intervals ranging from 2-126 months. These findings suggest that despite the presence of B-cell-predominant lymphoid infiltrates and lymphoepithelial lesions, lymphocytic mastitis and diabetic mastopathy do not appear to be associated with an increased risk for lymphoma.
12477058 Salivary IgA and IgG subclasses in oral mucosal diseases. 2002 Nov OBJECTIVE: It was hypothesized that serum levels of immunoglobulins may play a role in the pathogenesis of oral mucosal diseases, or reflect clinical changes in these conditions, but little is known about the role of salivary immunoglobulins in the pathogenesis of these diseases. The aim of this study was to investigate possible alterations in salivary immunoglobulin A (IgA) and IgG subclasses in patients with oral mucosal inflammatory diseases. SUBJECTS AND METHODS: Levels of IgG1, IgG2, IgG3 and IgG4 were determined by enzyme-linked immunosorbent assay (ELISA), and IgA1 and IgA2 by radial immunodiffusion in the resting whole saliva of 31 patients with acute recurrent aphthous ulceration (RAU) (and followed in remission), 11 patients with chronic hyperplastic candidal infection (CHC), 12 patients with Sjogren's syndrome (SS), six patients with oral lichen planus (OLP), and 18 healthy volunteers using the normal saliva as a comparison point for all. RESULTS: IgG and IgA subclasses were increased in OLP. In CHC all IgG subclasses were increased while IgA1 was decreased, IgG1, IgG3 and IgG4 levels were increased in SS, while all IgG subclasses as well as IgA2 were increased in acute RAU in comparison with healthy controls. No differences in any immunoglobulin subclasses between major and minor acute RAU were found. In remission, IgG1 and IgG4 returned to normal values while IgG2, IgG3, and IgA2 remained increased in patients with RAU. CONCLUSION: Salivary immunoglobulin subclasses vary in different oral mucosal conditions and may play a role in oral mucosal inflammatory diseases and/or reflect clinical changes in these conditions.
12410797 Immunization with peptides from 60 kDa Ro in diverse mouse strains. 2002 Nov Antibodies binding the Ro (or SSA) and La (or SBB) proteins are commonly found in a high proportion of sera from patients with systemic lupus erythematosus or Sjögren's syndrome. The mechanism by which these autoantibodies arise is not known. Others and we have shown that immunization of nonautoimmune-prone mice with short peptides from the Ro ribonucleoprotein particle can induce autoimmunity to 60 kDa Ro and 52 kDa Ro as well as to the 48 kDa La protein after epitope spreading. We have explored the differences in the epitope spreading after 60 kDa Ro peptide immunization in several strains of mice. There is intra- and intermolecular diversification of the immune response after immunization of DBA/2J animals with a monomer peptide representing the residues 480-494 of the 60 kDa Ro protein, but this peptide does not induce epitope spreading when used as the immunogen in either C57Bl/6J or PL/J mice. Similar to previously studied BALB/c mice, DBA/2J mice have antibodies binding many epitopes of 60 kDa Ro, and some sera bind 52 kDa Ro as well as La. These mice have antinuclear antibody in their sera. These data demonstrate that Ro peptide immunization results in different outcomes depending upon the strain of mouse used. Furthermore, these data suggest that genetic variation is important with regard to responding towards short peptide immunization by epitope spreading.
15341921 IL-1beta induction of IL-6 and LIF in normal articular human chondrocytes involves the ERK 2004 Oct 7 Interleukin-1 (IL-1) is an important catabolic cytokine in rheumatoid and osteoarthritic joint disease. Besides inducing a catabolic response in articular chondrocytes it also strongly induces synergistic mediators such as leukemia inhibitory factor (LIF) and interleukin-6 (IL-6). The molecular basis of this is so far hardly understood. The aim of our study was to evaluate in vitro and in vivo whether IL-6 and LIF are differentially expressed in normal human and osteoarthritic adult articular chondrocytes and to investigate the potential intracellular signaling pathways of IL-1 involved in these gene regulation events. IL-6 and LIF mRNA expressions were found only at low levels in normal adult articular cartilage. Neither IL-6 nor LIF was strongly over-expressed in osteoarthritic cartilage degeneration. Clearly, both IL-6 and LIF can be very efficiently induced by IL-1beta in articular chondrocytes in vitro. However, this induction was somewhat less in osteoarthritic cells, which were overall activated in terms of expression of both cytokines without stimulation. Experiments using pathway selective inhibitors showed that intracellular signaling of IL-1beta for IL-6 and LIF is mediated by a mixture of the IL-1 signaling cascades. However, the ERK-pathway appeared to be particularly important and might be, therefore, of particular potential if one intends to block induction of these molecules by IL-1 in arthritic joint disease.