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ID PMID Title PublicationDate abstract
17127753 Reduced nitric oxide synthase and cyclo-oxygenase activity in the uterus of non-obese diab 2006 Dec A functional interaction between progesterone, Th2 cytokines and a suitable balance between nitric oxide and prostaglandins in the uterus is considered to have a major role in the success of embryo implantation and pregnancy. Non-obese diabetic (NOD) mice offer a suitable model to study the modulatory role of Th1 cytokines on uterus signalling and function, since at the prediabetic stage they develop a spontaneous Th1 autoimmune response against exocrine glands similar to Sjögren's syndrome. Vasoactive intestinal peptide (VIP) is a vasoactive neuro- and immunopeptide that promotes Th2 profiles and contributes to the smooth muscle relaxation and vasodilation. The aim of the present study was to investigate the activities of nitric oxide synthase and cyclo-oxygenase and the effect of VIP in the uterus of NOD mice with an emerging Th1 cytokine response. We present evidence of a reduced basal and VIP-stimulated activity of both enzymes in the uterus of NOD mice compared with normal BALB/c mice in proestrus. An altered functional interaction between both enzymes is also present in NOD mice at the time when increased levels of serum interleukin (IL)-12 and tumour necrosis factor-alpha but not interferon (IFN)-gamma or IL-10 were detected. We conclude that signalling alterations in uteri of NOD mice are simultaneous to the onset of a systemic Th1 cytokine response.
16859527 Hepatocyte growth factor prevents lupus nephritis in a murine lupus model of chronic graft 2006 Chronic graft-versus-host disease (GVHD) induced in (C57BL/6 x DBA/2) F1 (BDF1) mice by the injection of DBA/2 mouse spleen cells represents histopathological changes associated with systemic lupus erythematosus (SLE), primary biliary cirrhosis (PBC) and Sjogren's syndrome (SS), as indicated by glomerulonephritis, lymphocyte infiltration into the periportal area of the liver and salivary glands. We determined the therapeutic effect of hepatocyte growth factor (HGF) gene transfection on lupus using this chronic GVHD model. Chronic GVHD mice were injected in the gluteal muscle with either HVJ liposomes containing 8 microg of the human HGF expression vector (HGF-HVJ liposomes) or mock vector (untreated control). Gene transfer was repeated at 2-week intervals during 12 weeks. HGF gene transfection effectively prevented the proteinuria and histopathological changes associated with glomerulonephritis. While liver and salivary gland sections from untreated GVHD mice showed prominent PBC- and SS-like changes, HGF gene transfection reduced these histopathological changes. HGF gene transfection greatly reduced the number of splenic B cells, host B cell major histocompatibility complex class II expression, and serum levels of IgG and anti-DNA antibodies. IL-4 mRNA expression in the spleen, liver, and kidneys was significantly decreased by HGF gene transfection. CD28 expression on DBA/2 CD4+ T cells was decreased by the addition of recombinant HGF in vitro. Furthermore, IL-4 production by DBA/2 CD4+ T cells stimulated by irradiated BDF1 dendritic cells was significantly inhibited by the addition of recombinant HGF in vitro. These results suggest that HGF gene transfection inhibited T helper 2 immune responses and reduced lupus nephritis, autoimmune sialoadenitis, and cholangitis in chronic GVHD mice. HGF may represent a novel strategy for the treatment of SLE, SS and PBC.
17207605 Novel animal models for Sjögren's syndrome: expression and transfer of salivary gland dys 2006 Dec IL-2 knockout (KO), IL-2Ralpha KO and scurfy mice lack the CD4+CD25+ regulatory T (Treg) cells and develop severe inflammation in multiple organs, although organs affected vary among these strains. We asked if salivary and lacrimal glands, the main organs affected in Sjögren's syndrome, are targeted in these strains. Severe lymphocyte and neutrophil infiltration in the salivary and lacrimal glands and a decrease in salivary secretory function were observed in IL-2 KO and IL-2Ralpha KO mice, but not in scurfy mice. Interestingly, transfer of lymph node cells from scurfy mice to RAG-1 KO recipients rapidly and effectively induced inflammation and loss of function in the salivary glands. Furthermore, we observed that daily LPS feeding in scurfy mice also induced inflammation in the salivary glands. Our study demonstrates several novel models for Sjögren's syndrome, including an adoptive transfer model that shows that scurfy mice have dormant salivary gland-specific autoreactive lymphocytes that can be activated by certain environmental factors, such as those present in RAG-1 KO mice.
16918699 Sjögren's syndrome-like disease of C57BL/6.NOD-Aec1 Aec2 mice: gender differences in kera 2006 Sep Sjögren's syndrome (SjS) is a systemic autoimmune disease in which an immunological attack primarily against the salivary and lacrimal glands results in loss of acinar cell tissue and function leading to stomatitis sicca and keratoconjunctivitis sicca. In recent years, the NOD mouse has become an accepted model of SjS, exhibiting a spontaneously developing disease that strongly mimics the human condition. Two genetic regions, one on chromosome 1 (designated Aec2) and the second on chromosome 3 (designated Aec1) of NOD mice, have been shown to be necessary and sufficient to recapitulate SjS-like disease in non-susceptible C57BL/6 mice. Here we describe a newly derived strain, C57BL/6.NOD-Aec1R1Aec2, in which a recombination in Aec1 has resulted in reducing this genetic region to less than 20 cM from 48.5 cM. Profiling of this recombinant inbred strain has revealed that male mice maintain a full SjS-like disease, whereas female mice exhibit stomatitis sicca in the absence of detectable keratoconjunctivitis sicca. These data suggest SjS-like disease in the NOD mouse shows gender-specific regulation determined by autosomal genes.
15683447 Structurally derived mutations define congenital heart block-related epitopes within the 2 2005 Feb Congenital heart block is a passively transferred autoimmune condition, which affects the children of mothers with Ro/SSA autoantibodies. During pregnancy, the antibodies are transported across the placenta and affect the fetus. We have previously demonstrated that antibodies directed to the 200-239 amino acid (aa) stretch of the Ro52 component of the Ro/SSA antigen correlate with the development of congenital heart block. In this report, we investigated the antibody-antigen interaction of this target epitope in detail at a molecular and structural level. Peptides representing aa 200-239 (p200) with structurally derived mutations were synthesized to define the epitopes recognized by two Ro52 human monoclonal antibodies, S3A8 and M4H1, isolated from patient-derived phage display libraries. Analyses by ELISA, circular dichroism and MALDI-TOF-MS demonstrate that the antibody recognition is dependent on a partly alpha-helical fold within the putative leucine zipper of the 200-239 aa stretch and that the two human anti-p200 monoclonal antibodies, M4H1 and S3A8, recognize different epitopic structures within the p200 peptide. In addition, we investigated the representation of each fine specificity within the sera of mothers with children born with congenital heart block, and in such sera, antibodies of the S3A8 idiotype were more commonly detected and at higher levels than M4H1-like antibodies.
16014535 Anti-endothelial cell antibodies determination by cyto-ELISA: a comparative study between 2005 Jun Cyto-ELISA has been widely used to investigate anti-endothelial cell antibodies (AECAs); however, because various types of endothelial cells have been used, the results among studies differ. The aim of our study was to analyze and compare the results when determining AECAs in patients with connective tissue disease (CTD). We did so using a cyto-ELISA with different cells as antigenic substrates: two different endothelial cells, one microvascular (HMEC-1) and one from human bone marrow (HBMEC), and one epithelial cell line from breast adenocarcinoma as negative controls (MDA-MB-231). In this trial, we performed a retrospective study in 60 patients with CTD [46 with systemic lupus erythematosus, 8 with Sjögren's syndrome, and 6 with systemic sclerosis] and 32 healthy volunteers. Using cyto-ELISA, the antibody against a cell was considered positive when the optical density (OD) obtained was higher than the mean OD obtained in the control group + 2 standard deviations (upper normal range). Patients were classified into three groups according to the OD obtained with the different cell lines: group 1: patients without any antibody; group 2: patients with specific AECAs; and group 3: patients with nonspecific AECAs. According to this classification, we found that 43.3% of patients with CTD have specific AECAs, and 28.3% have nonspecific antibodies. Our study delineates the heterogeneity of AECAs in patients with CTD. The use of HBMEC in cyto-ELISA may increase the sensitivity of the test, and the use of nonendothelial cells as negative controls may improve its specificity.
15650839 Mucosa-associated lymphoid tissue lymphoma of the thymus: a case report with no evidence o 2005 Feb We report a case of thymic mucosa-associated lymphoid tissue (MALT) lymphoma (TML) that presented as an asymptomatic mediastinal mass in a 40-year-old woman with a past history of Sjögren syndrome. This case had the characteristic clinical and pathological features of TML, as found in most of the 24 previously reported cases, i.e., autoimmune context, especially Sjögren syndrome, IgA secretion, large epithelial cysts, lymphoepithelial lesions involving residual Hassal's corpuscles, epithelial cysts, and a marked plasmacytic differentiation with IgA expression. Reverse-transcription polymerase chain reaction for t(11;18)(q21;q21) was negative, in agreement with recently published data. In this case, investigation for t(14;18)(q32;q21) using fluorescent in situ hybridization was also performed and supplied negative results. Neoplastic cells were negative for MAL, a marker of primary mediastinal large B cell lymphoma (PMBL). Altogether, these findings further support that among MALT lymphomas, TML have peculiar clinical and morphological characteristics and appear not to involve MALT1 rearrangement. They also suggest the absence of a relationship between TML and PMBL.
15772600 Multiple bilateral parotid sialoliths in a patient with mucosa-associated lymphoid tissue 2005 Apr Multiple sialoliths in the major salivary glands is uncommon. Sjogren's syndrome (SS) is a chronic autoimmune disorder characterized by lymphocyte-mediated destruction of exocrine glands. There is an increased incidence of malignant lymphoma in patients with Sjogren's syndrome. We present a patient with MALT lymphoma of the salivary glands who also had multiple calculi in the parotid glands. Multiple sialoliths in the major salivary glands in the presence of MALT lymphoma has not previously been reported.
15870389 A novel celecoxib derivative potently induces apoptosis of human synovial fibroblasts. 2005 Aug We have already demonstrated that celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, has a proapoptotic effect on synovial fibroblasts obtained from patients with rheumatoid arthritis (RA). Here we report on the development of two novel derivatives of celecoxib, N-(2-aminoethyl)-4-[5-(4-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (TT101) and 4-[5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (TT201), including whether these compounds have a proapoptotic effect on synovial fibroblasts. Synovial fibroblasts were harvested from the synovial tissues of patients with RA or osteoarthritis (OA). Cell proliferation and cell viability were assessed by the incorporation of 5-bromo-2'-deoxyuridine and by the 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt assay, respectively. Apoptosis was detected by the identification of DNA fragmentation, and activation of caspase-3 was detected by the addition of a caspase-3 substrate to cell lysates. Production of prostaglandin E(2) by RA synovial fibroblasts was analyzed by enzyme-linked immunosorbent assay. TT101 inhibited the proliferation of RA and OA synovial fibroblasts in a concentration-dependent manner. It caused a marked decrease of cell viability and induced DNA fragmentation more potently than either celecoxib or SC-236 (4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide). TT101 also increased caspase-3 activity. The order of potency of the COX-2 inhibitory activity of these drugs in RA synovial fibroblasts was celecoxib = SC-236 > rofecoxib > TT201 > TT101. In conclusion, we developed TT101 with about a 5- to 10-fold stronger proapoptotic effect on RA and OA synovial fibroblasts compared with that of celecoxib. Although the mechanism of action of TT101 remains unclear, it may have potential as a novel antirheumatic agent.
15894513 Increased prevalence of transfusion-transmitted virus and cross-reactivity with immunodomi 2005 Aug OBJECTIVE: Systemic lupus erythematosus (SLE) patients produce autoantibodies to HRES-1/p28, a human endogenous retrovirus-encoded nuclear protein. To identify cross-reactive viral antigens capable of triggering autoreactivity, HRES-1/p28 epitopes were mapped by SLE antibodies. METHODS: Forty-four peptides overlapping HRES-1/p28 and 13 viral peptides were synthesized on cellulose membrane and tested for recognition by antibodies from 16 HRES-1 Western blot seropositive SLE patients. Transfusion-transmitted virus (TTV) was detected by gene amplification in sera of 211 SLE patients, 78 healthy SLE family members, 199 unrelated healthy donors, and 91 rheumatoid arthritis (RA) patients. RESULTS: HRES-1/p28 residues 41-55, 121-135, and 156-170 were recognized by 12/16 (75.0%), 11/16 (68.8%), and 9/16 lupus sera (56.25%) and considered immunodominant. HRES-1/p28 residues 121-135 harbor cross-reactive epitope with retroviral peptides and the 70 K U1snRNP lupus autoantigen. HRES-1/p28 residues 41-55 and 156-170 exhibited the highest prevalence of cross-reactivity with TTV peptide ORF2a (14/16, 87%). Prevalence of TTV DNA was increased in lupus patients (120/211) with respect to healthy (66/199; P < 0.0001) or RA controls (23/91; P < 0.0001). TTV prevalence in healthy lupus relatives (40/78) was decreased with respect to lupus patients (80/121; P = 0.0184) and increased with respect to unrelated healthy donors (66/199; P = 0.0026). HRES-1/p28 Western blot reactivity was observed in 12/23 TTV PCR-negative donors and 43/58 TTV PCR-positive donors (P < 0.0281). CONCLUSIONS: Increased prevalence of TTV and molecular mimicry with HRES-1/p28 may contribute to generation of antinuclear antibodies and pathogenesis of SLE.
16818766 Prostaglandin E2 augments IL-10 signaling and function. 2006 Jul 15 In inflamed joints of rheumatoid arthritis, PGE(2) is highly expressed, and IL-10 and IL-6 are also abundant. PGE(2) is a well-known activator of the cAMP signaling pathway, and there is functional cross-talk between cAMP signaling and the Jak-STAT signaling pathway. In this study, we evaluated the modulating effect of PGE(2) on STAT signaling and its biological function induced by IL-10 and IL-6, and elucidated its mechanism in THP-1 cells. STAT phosphorylation was determined by Western blot, and gene expression was analyzed using real-time PCR. Pretreatment with PGE(2) significantly augmented IL-10-induced STAT3 and STAT1 phosphorylation, as well as suppressors of cytokine signaling 3 (SOCS3) and IL-1R antagonist gene expression. In contrast, PGE(2) suppressed IL-6-induced phosphorylation of STAT3 and STAT1. These PGE(2)-induced modulating effects were largely reversed by actinomycin D. Pretreatment with dibutyryl cAMP augmented IL-10-induced, but did not change IL-6-induced STAT3 phosphorylation. Misoprostol, an EP2/3/4 agonist, and butaprost, an EP2 agonist, augmented IL-10-induced STAT3 phosphorylation and SOCS3 gene expression, but sulprostone, an EP1/3 agonist, had no effect. H89, a protein kinase A inhibitor, and LY294002, a PI3K inhibitor, diminished PGE(2)-mediated augmentation of IL-10-induced STAT3 phosphorylation. In this study, we found that PGE(2) selectively regulates cytokine signaling via increased intracellular cAMP levels and de novo gene expression, and these modulating effects may be mediated through EP2 or EP4 receptors. PGE(2) may modulate immune responses by alteration of cytokine signaling in THP-1 cells.
15763607 Efficacy and tolerability of lumiracoxib in the treatment of osteoarthritis of the knee: a 2005 Jan BACKGROUND: Lumiracoxib is a cyclooxygenase-2-selective inhibitor developed for the treatment of osteoarthritis (OA), rheumatoid arthritis, and acute pain. OBJECTIVES: This study assessed the efficacy and tolerability of lumiracoxib 100 mg QD compared with celecoxib and placebo in patients with OA of the knee. METHODS: In this 13-week, double-blind, double-dummy,placebo-controlled, parallel-group study, patients with primary OA of the knee and pain intensity in the target knee a 40 mm on a 100-mm visual analog scale after a 3- to 7-day washout of nonsteroidal anti-inflammatory drugs were randomized to receive lumiracoxib 100 mg QD, lumiracoxib 100 mg QD with a loading dose of lumiracoxib 200 mg QD for the first 2 weeks, celecoxib 200 mg QD, or placebo. Three primary efficacy variables were assessed at the end of the study: pain intensity in the target knee, the patient's global assessment of disease activity, and functional status (Western Ontario and McMaster Universities Osteoarthritis Index total score). In addition, the treatment response was assessed using the Outcome Measures in Clinical Trials-Osteoarthritis Research Society International (OMERACT OARSI) criteria. The safety profile and tolerability of all treatments were also examined. RESULTS: The study enrolled 1551 patients (primarily white; 62% female; mean age, 60.5 years): 391 were randomized to receive lumiracoxib 100 mg QD, 385 lumiracoxib 100 mg QD with a loading dose, 393 celecoxib 200 mg QD, and 382 placebo. Treatment groups were closely balanced at baseline with respect to demographic and disease characteristics. Lumiracoxib was superior to placebo (P < 0.001) and similar to celecoxib on all primary efficacy variables. Reductions in pain intensity in the target knee were similar in the 2 lumiracoxib groups at week 13 (estimated least square mean difference vs placebo: -6.7 and -8.1 mm for lumiracoxib 100 mg QD and lumiracoxib 100 mg QD with loading dose, respectively; both, P < 0.001); with celecoxib, the estimated least square mean difference was -5.7 mm (P < 0.001). Significant differences compared with placebo were seen in all variables starting at week 2 for all active treatments (all, P < 0.001). No significant differences were seen between the lumiracoxib groups at any time point. Based on OMERACT OARSI criteria, all active treatments were superior to placebo (all, P < 0.001). Lumiracoxib and celecoxib were well tolerated, with an incidence of adverse events similar to that with placebo (64.7% lumiracoxib 100 mg QD, 67.0% lumiracoxib 100 mg QD with loading dose, 58.8% celecoxib, 58.4% placebo). CONCLUSION: In this population of patients with OA of the knee, lumiracoxib 100 mg QD was of similar efficacy to celecoxib 200 mg QD and had similar tolerability to placebo.
16682805 Transcription factor Ets-1 regulates fibroblast growth factor-1-mediated angiogenesis in v 2006 We previously demonstrated that a modified secreted form of fibroblast growth factor 1 (FGF-1), a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis, the so-called chick chorioallantoic membrane assay or CAM. We recently defined the importance of the phosphatidylinositol 3-kinase/AKT pathway in FGF-1-mediated angiogenesis in this model using specific pharmacological inhibitors. In our continuing efforts to define the molecular signaling pathway regulating FGF-1-induced angiogenesis in vivo, we utilized a transcription factor activity assay and identified transcription factor Ets-1 as a critical effector of FGF-1-induced angiogenesis. Both activity and mRNA expression levels of the Ets-1 molecule were increased in response to FGF-1 overexpression in CAMs, as documented by electrophoretic mobility shift assay (gel shift) and reverse transcription real-time PCR techniques, respectively. Furthermore, the delivery of Ets-1 antisense (AS) into CAM tissues effectively reduced angiogenesis in the CAM assay. In addition, both Ets-1 AS-treated chicken CAMs and cultured endothelial cells exhibited a reduction in matrix metalloproteinase 1 gene expression levels. The Ets-1 AS-treated endothelial cells also demonstrated a reduction in migration. These data suggest that Ets-1 activation is a requisite for FGF-1-mediated angiogenesis in vivo. Therefore, Ets-1 might be a potential target for the generation of inhibitor drugs for the treatment of FGF-dependent pathological angiogenesis such as metastatic tumors, rheumatoid arthritis and diabetic retinopathy.
15968885 Safety, tolerability and pharmacokinetics of oral S-3304, a novel matrix metalloproteinase 2005 Jun OBJECTIVE: A novel sulfonamide derivative, S-3304, was discovered as a potent matrix metalloproteinase (MMP) inhibitor. It is a more specific inhibitor to MMP-2 and MMP-9 (in vitro) than to MMP-1, and may therefore lack the musculoskeletal side effects seen with non-specific inhibitors. The aim of the present study was to investigate the safety, tolerability and pharmacokinetics of S-3304 when administered as single and multiple oral doses to healthy male volunteers. MATERIALS AND METHODS: 48 male volunteers received single oral doses ranging from 10 - 800 mg S-3304 or placebo under fasting conditions. At the 200 mg dose level, effects of high-fat diets were studied in a crossover design. In the multiple dose design, 24 male subjects were administered 200 mg, 400 mg or 800 mg S-3304 or placebo b.i.d. after meals for 10 - 17 days. Studies were conducted in a randomized double-blind fashion. Safety assessment was conducted based on blood chemistry, hematology, urinalysis, electrocardiogram and physical examination. Pharmacokinetic parameters were determined for S-3304 and its metabolites. All subjects were enrolled in the studies after obtaining informed consent. RESULTS: Adverse events reported after single dose administration of S-3304 or placebo were all of mild severity. Adverse events reported in the multiple dose treatment with S-3304 or placebo were mostly of mild severity, except for two episodes of moderate headache and two episodes of moderate myalgia. Most commonly reported adverse events in the multiple treatments with S-3304 were headache and somnolence. No clinically significant changes were observed in the clinical laboratory tests, except for reversible elevation of alanine aminotransferase of one subject at 800 mg S-3304 b.i.d. In the single dose administration, Cmax and mean AUC0-infinity linearly increased up to 63,167 ng/ml and 311,960 ng x h/ml at the 800 mg dose level, respectively; tmax and t1/2 ranged from 2 - 3 hours and from 9.5 - 15.5 hours, respectively. High-fat diets reduced Cmax from 21,565 ng/ml to 14,095 ng/ml but did not alter AUC0-infinity. Hydroxylated metabolites were detected in plasma in concentrations less than 1% of S-3304. Less than 1% S-3304 was excreted in urine. The AUC of one dosing interval and Cmax did not change after multiple doses but t1/2 increased from 9.5 - 10.0 hours to 12.5 - 13.5 hours. The 6beta-hydroxycortisol/ cortisol ratio was not changed after multiple doses suggesting no effect on CYP3A4 activity. CONCLUSION: S-3304 demonstrated a good safety profile and good systemic exposure when administered orally up to 800 mg b.i.d. during 10 - 17 days. At the highest dose level of 800 mg b.i.d., it was free of rheumatoid arthritis-like symptoms.
15838068 Brief communication: high incidence of venous thrombotic events among patients with Wegene 2005 Apr 19 BACKGROUND: Venous thrombotic events (VTEs) have been observed in Wegener granulomatosis, but the incidence rate is not known. OBJECTIVE: To measure the incidence of VTEs in patients with Wegener granulomatosis. DESIGN: Prospective, observational cohort study. SETTING: A multicenter, randomized, double-blind, placebo-controlled treatment trial for Wegener granulomatosis. PATIENTS: 180 patients with Wegener granulomatosis enrolled during periods of active disease. MEASUREMENTS: Venous thrombotic events (deep venous thromboses or pulmonary emboli) were documented and confirmed prospectively. Incidence rates were calculated on the basis of time to first VTE. RESULTS: Thirteen patients had VTEs before enrollment. During 228 person-years of prospective follow-up, 16 VTEs occurred in 167 patients with no history of VTE. Median time from enrollment to VTE for patients with an event was 2.1 months. The incidence of VTE among patients with Wegener granulomatosis was 7.0 per 100 person-years (95% CI, 4.0 to 11.4). LIMITATIONS: Although prospectively recorded, screening for VTEs did not occur. CONCLUSIONS: The incidence rate of VTEs in Wegener granulomatosis is high when compared with available rates in the general population, patients with lupus, and patients with rheumatoid arthritis. These results have important implications for clinical care of patients with Wegener granulomatosis.
17001167 Diabetic (lymphocytic) mastopathy with exuberant lymphohistiocytic and granulomatous respo 2006 Oct We report a case of a 66-year-old woman who presented with multiple painless masses in both breasts. Prior bilateral biopsies were diagnosed as Rosai-Dorfman disease (Sinus Histiocytosis with Massive Lymphadenopathy). A recent lumpectomy specimen revealed a gray-white smooth cut surface with a discrete masslike lesion. The histopathology demonstrated a fibrotic breast parenchyma with foci of dense fibrosis and scattered inconspicuous breast epithelium surrounded by lymphocytes that formed aggregates and follicles with germinal centers. The inflammation was in a periductal, perilobular, and perivascular distribution. In addition, an exuberant inflammatory response with histiocytes and fibroblasts was present. This inflammatory response focally surrounded areas of fat necrosis and formed noncaseating granulomas with rare multinucleated giant cells. This process had infiltrative, ill-defined edges and involved the subcutaneous tissues. The overlying epidermis was normal. The final diagnosis was diabetic mastopathy with an exuberant lymphohistiocytic response. The differential diagnosis included Rosai-Dorfman disease, inflammatory myofibroblastic tumor, granulomatous mastitis, sclerosing lipogranulomatous response/sclerosing lipogranuloma, lupus panniculitis, and rheumatoid nodules. Immunohistochemical studies and flow cytometry confirmed the polyclonal nature of the lymphoid infiltrate. After the histologic evaluation, we inquired if the patient had a history of diabetes mellitus, and learned that she did have type 2 noninsulin-dependent diabetes mellitus. In conclusion, we report a case of diabetic mastopathy that presents with bilateral tumorlike masses and an unusual exuberant lymphohistiocytic response with granuloma formation. The pathologist may not be provided with a history of diabetes mellitus, but the characteristic fibrosis, lymphocytic ductitis/lobulitis, and sclerosing lobulitis with perilobular and perivascular lymphocytic infiltrates should provide clues for an accurate diagnosis, even when an exuberant and an unusual lymphohistiocytic response is present. A timely accurate diagnosis can help limit repeat surgeries in this vulnerable group of patients.
16178869 Detection of apoptosis-specific autoantibodies directed against granzyme B-induced cleavag 2005 Oct The objective of this study was to detect autoantibodies against granzyme B cleavage products in sera from patients with primary Sjögren's syndrome (SS). Cell lysates derived from human salivary gland (HSG) cell lines were incubated with granzyme B. The susceptibility to the generation of cleavage fragments of SS autoantigens was assayed by immunoblotting using sera from 57 primary SS patients, 17 primary SS patients with malignant lymphoma (ML), 28 systemic lupus erythematosus (SLE) patients, and 20 healthy controls. A 27 kD protein was recognized by serum autoantibodies in 8 (14.0%) of 57 primary SS patients, 5 (29.4%) of 17 SS patients with ML, 2 (7.1%) of 28 SLE patients, but not in 20 normal subjects. This protein was recognized by anti-SSB (La) monoclonal antibodies. Granzyme B-treated recombinant La protein was also shown to migrate as a discrete 27 kD protein by SDS PAGE. Blocking studies demonstrated the existence of an apoptosis-specific B cell epitope present in sera from 2 of 8 primary SS patients and in 2 of 5 primary SS patients with ML which recognized the 27 kD protein. Granzyme B-induced La fragments are generated during cytotoxicity in vitro. This is the first report describing autoantibodies in sera from primary SS patients that specifically recognize fragments of the La protein that are produced by the granzyme B protease.
15689312 [Analysis of nine autoantibodies associated with systemic autoimmune diseases using the Lu 2005 Jan Luminex technology allows simultaneous detection of several analytes in a single well. Applications have been recently developed for the detection of autoantibodies. PURPOSE: To evaluate the performances and convenience of the Fidis analytical system (BioMedical Diagnostics, Marnes-la-Vallee, France) for the detection of nine autoantibodies associated with connective diseases: SS-A, SS-B, Sm, RNP, Scl-70, Jo-1, CENP-B, P ribosomal and double stranded DNA antibodies. MATERIALS AND METHODS: Three hospital laboratories analysed 366 samples taken from their serum banks and corresponding to the main systemic autoimmune diseases. Control samples included 120 sera from blood donors and 42 sera from patients with dysglobulinemia. RESULTS: In each laboratory, handling of this new analytical system was easy. Results are readily obtained: nine autoantibodies are quantitated in fourty-four sera in less than two hours. A clear-cut discrimination between negative and positive results was observed, due to very low backgrounds. Intra-assay and inter-assay variations were low: coefficients of variation were under 10% in 80 and 64% of the cases, respectively. Results obtained with Fidis correlated satisfactorily with those obtained with the numerous routine techniques used in each laboratory. The overall concordance exceeded 93%. CONCLUSION: Fidis is a reliable and time-saving analytical system for the detection of autoantibodies associated with systemic autoimmune diseases.
16729300 Induction of interferon-alpha by immune complexes or liposomes containing systemic lupus e 2006 Jun OBJECTIVE: To investigate the ability of systemic lupus erythematosus (SLE) autoantigen- and Sjögren's syndrome (SS) autoantigen-associated U1 small nuclear RNA (U1 snRNA) and hY1RNA to induce interferon-alpha (IFNalpha) production. METHODS: In vitro-transcribed U1 snRNA or hY1RNA and lipofectin were added to peripheral blood mononuclear cell (PBMC) cultures. Purified U1 snRNP particles and IgG from SLE patients (SLE-IgG) were added to cultures of PBMCs, enriched monocytes, or natural interferon-producing cells (NIPCs); the latter are also known as plasmacytoid dendritic cells (pDC). Cells were double-stained for IFNalpha and either blood dendritic cell antigen 2 (NIPCs/pDC) or CD14 (monocytes) and then analyzed by flow cytometry. In some experiments, RNase or inhibitors of Fc gamma receptor IIa (Fc gammaRIIa) (specific antibodies), endocytosis (chloroquine, bafilomycin A), or Toll-like receptors (TLRs; oligodeoxynucleotide 2088) were used. The produced IFNalpha was measured by immunoassay. RESULTS: Lipofected U1 snRNA and hY1RNA both induced IFNalpha production in monocytes, but not in NIPC/pDC. In contrast, U1 snRNP combined with SLE-IgG induced IFNalpha production only in NIPCs/pDC, and this response was decreased by RNase treatment or inhibition of the Fc gammaRIIa, the endocytosis pathways, or the TLRs. CONCLUSION: Our finding that U1 snRNA and hY1RNA have IFNalpha-inducing capacity indicates that immune complexes containing such RNA, for example U1 snRNP particles, can be at least partly responsible for the ongoing IFNalpha production seen in SLE and SS. These results may help to explain the molecular mechanisms behind the pathogenesis of these and other autoimmune diseases in which autoantibodies to RNA-binding proteins occur.
16385525 Toll-like receptor 9 signaling protects against murine lupus. 2006 Jan OBJECTIVE: Hypomethylated CpG-containing DNA, which is recognized by Toll-like receptor 9 (TLR-9), has been strongly implicated in the pathogenesis of autoantibody-mediated diseases such as systemic lupus erythematosus. This study was undertaken to determine the role of TLR-9 in the MRL/+ and MRL/lpr models of murine lupus. METHODS: TLR-9-deficient MRL mice were generated by backcrossing a TLR-9-deficient allele against the MRL backgrounds by a speed congenic technique. Parameters of murine lupus were examined by routine methods. Regulatory T cell activity was assessed by autologous mixed lymphocyte reaction (AMLR), an in vitro assay for autoreactivity. RESULTS: Surprisingly, TLR-9-deficient animals of both the MRL/+ and the MRL/lpr backgrounds developed more severe lupus, as judged by anti-DNA and rheumatoid factor autoantibodies, total serum Ig isotypes, lymphadenopathy, inflammatory infiltrates in the salivary gland and kidney, proteinuria, and mortality, in comparison with their TLR-9-sufficient littermates. In vitro, regulatory T cells from TLR-9-deficient animals were impaired in their ability to suppress the AMLR. CONCLUSION: In the MRL model of murine lupus, TLR-9 signaling plays a protective role, perhaps by modulating the activity of regulatory T cells. These results contrast with findings of recent studies that implicate TLR-9 in the pathogenesis of anti-DNA responses, based in part on investigations in incompletely backcrossed TLR-9-deficient MRL/lpr mice in vivo or transgenic B cells in vitro. The present results highlight the need for caution in the assessment of disease paradigms based on the study of isolated cell populations in vitro, as well as in vivo studies of knockout animals involving non-ideal genetic models.