High Titers Of Antinuclear Antibodies Research Articles

Molecular Subsetting of Interferon Pathways in Sjögren's Syndrome.

Sjögren's syndrome (SS) is an autoimmune disease that targets the salivary and lacrimal glands. While all patients demonstrate inflammatory infiltration and abnormal secretory function in the target tissues, the disease features, pathology, and clinical course can vary. Activation of distinct inflammatory pathways may drive disease heterogeneity. The purpose of this study was to investigate whether activation of the interferon (IFN) pathway correlates with key phenotypic features. Clinical data and 1 labial salivary gland (stored frozen) were obtained from each of 82 participants (53 patients with primary SS and 29 control subjects) in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. Salivary gland lysates were immunoblotted with markers of type I or type II IFN, and patterns of IFN activity were determined by hierarchical clustering. Correlations between SS phenotypic features and IFN activity in the salivary gland were performed. A total of 58% of the SS participants had high IFN activity and differed significantly from those with low IFN activity (higher prevalence of abnormal findings on sialometry, leukopenia, hyperglobulinemia, high-titer antinuclear antibody, anti-SSA, and high focus score on labial salivary gland [LSG] biopsy). Three distinct patterns of IFN were evident: type I-predominant, type II-predominant, and type I/II mixed IFN. These groups were clinically indistinguishable except for the LSG focus score, which was highest in those with type II-predominant IFN. The SS phenotype includes distinct molecular subtypes, which are segregated by the magnitude and pattern of IFN responses. Associations between IFN pathways and disease activity suggest that IFNs are relevant therapeutic targets in SS. Patients with distinct patterns of high IFN activity are clinically similar, demonstrating that IFN-targeting therapies must be selected according to the specific pathway(s) that is active in vivo in the individual patient.

IFN-γ licenses CD11b+ cells to induce progression of systemic lupus erythematosus

Autoantibodies are a hallmark of autoimmune diseases, such as rheumatoid arthritis, autoimmune hepatitis, and systemic lupus erythematosus (SLE). High titers of anti-nuclear antibodies are used as surrogate marker for SLE, however their contribution to pathogenesis remains unclear. Using murine model of SLE and human samples, we studied the effect of immune stimulation on relapsing of SLE. Although autoantibodies bound to target cells in vivo, only additional activation of CD8+ T cells converted this silent autoimmunity into overt disease. In mice as well as in humans CD8+ T cells derived IFN-γ enhanced expression of Fc-receptors on CD11b+ cells. High expression of Fc-receptors allowed CD11b+ cells to bind to antibody covered target cells and to destroy them in vivo. We found that autoantibodies induce clinically relevant disease when adaptive immunity, specific for disease non-related antigen, is activated.

Differential responses to autoantibody deposition in CD45E613R BALB/c and C57Bl/6-129 F1 glomeruli is mediated by alterations in the autoantibody repertoire and inflammatory renal mononuclear cells (BA3P.110)

Abstract The mechanisms regulating the transition from autoreactivity to autoimmunity are poorly understood. CD45E613R mice express a point mutation in the juxtamembrane wedge that results in dysregulated phosphatase activity. Despite similar hyperactive ITAM-mediated signaling in multiple cell lineages, the phenotypic consequences of this mutation vary with genetic context. While both BALB/c and C57Bl/6-129 F1 CD45E613R mice develop similar high titer anti-nuclear antibodies (ANA) and immune complex deposition in the glomeruli, only F1 mice develop glomerulonephritis (GN). Here, we leverage these distinct phenotypes in the context of a common point mutation to define mechanisms leading to GN. BALB/c ANA are primarily anti-dsDNA while F1 ANA are anti-dsDNA, -H3 and -Sm/RNP. Consistent with this profile, F1 B cells have increased TLR7/9 signaling. Treatment of RAW264.7 cells with aged F1 but not BALB/c CD45E613R sera induces an inflammatory phenotype. Additionally, IL-10, IL-12, MCP-1 and RANTES are elevated in aged F1 CD45E613R mice. Analysis of young, autoantibody-free mice shows increased CD11b+ CD11c+ F4/80+ renal mononuclear cells surrounding F1 but not BALB/c CD45E613R glomeruli. Upon stimulation, only F1 CD45E613R renal mononuclear cells produce TNFα and IFNγ. Together, these data support a model in which an expanded antibody repertoire combined with altered kidney immune cell subsets and altered cytokines mediate the transition from autoreactivity to autoimmunity.

Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease.

IntroductionScurfy mice are deficient in regulatory T cells (Tregs), develop a severe, generalized autoimmune disorder that can affect almost every organ and die at an early age. Some of these manifestations resemble those found in systemic lupus erythematosus (SLE). In addition, active SLE is associated with low Treg numbers and reduced Treg function, but direct evidence for a central role of Treg malfunction in the pathophysiology of lupus-like manifestations is still missing. In the present study, we characterize the multiorgan pathology, autoantibody profile and blood count abnormalities in scurfy mice and show their close resemblances to lupus-like disease.MethodsScurfy mice have dysfunctional Tregs due to a genetic defect in the transcription factor Forkhead box protein 3 (Foxp3). We analyzed skin, joints, lung and kidneys of scurfy mice and wild-type (WT) controls by conventional histology and immunofluorescence (IF) performed hematological workups and tested for autoantibodies by IF, immunoblotting and enzyme-linked immunosorbent assay. We also analyzed the intestines, liver, spleen and heart, but did not analyze all organs known to be affected in scurfy mice (such as the testicle, the accessory reproductive structures, the pancreas or the eyes). We transferred CD4+ T cells of scurfy or WT mice into T cell-deficient B6/nude mice.ResultsWe confirm previous reports that scurfy mice spontaneously develop severe pneumonitis and hematological abnormalities similar to those in SLE. We show that scurfy mice (but not controls) exhibited additional features of SLE: severe interface dermatitis, arthritis, mesangioproliferative glomerulonephritis and high titers of anti-nuclear antibodies, anti-double-stranded DNA antibodies, anti-histone antibodies and anti-Smith antibodies. Transfer of scurfy CD4+ T cells (but not of WT cells) induced autoantibodies and inflammation of lung, skin and kidneys in T cell-deficient B6/nude mice.ConclusionOur observations support the hypothesis that lupus-like autoimmune features develop in the absence of functional Tregs.

Predominant role for activation-induced cytidine deaminase in generating IgG anti-nucleosomal antibodies of murine SLE

Serum IgG anti-nuclear antibodies (ANA) directed to complexes of DNA and histones are a hallmark of systemic lupus erythematosus (SLE) and reflect a failure in lymphocyte self-tolerance. A prior study utilizing spontaneously autoimmune B6.Nba2 mice deficient in terminal deoxynucleotidyl transferase (TdT) and with heterozygous deficiencies in Jh and Igk loci underscored the importance of somatic hypermutation (SHM) as a major generator of SLE-associated ANA. This interpretation had to be qualified because of severely limited opportunities for receptor editing and restricted VHCDR3 diversity. Therefore, we performed the converse study using mice that carried functional Tdt genes and wild type Jh and Igk loci but that could not undergo SHM. Analyses of ANA and ANA-producing hybridomas from B6.Nba2 Aicda−/− mice revealed that few animals produced high titers of the prototypical ANA directed to complexes of histones and DNA, that this response was delayed and that those cells that did produce such antibody exhibited limited clonal expansion, unusual Jk use and only infrequent dual receptor expression. This, together with the additional finding of an intrinsic propensity for SHM to generate Arg codons selectively in CDRs, reinforce the view that most IgG autoimmune clones producing prototypical anti-nucleosome antibodies in wild type mice are created by SHM.

Psoriatic Arthritis Complicating Systemic Sclerosis: Possible Involvement of M2 Macrophages.

Dear Editor: Psoriatic arthritis (PsA) is a seronegative inflammatory arthritis that occurs in the presence of psoriasis. The synovial macrophages are a major source of proinflammatory cytokines1. The subset of macrophages that expresses alternatively activated macrophages (M2 macrophages) is usually greater in number in PsA synovitis than in rheumatoid arthritis synovitis2. Systemic sclerosis (SSc) is a rheumatological disorder characterized by excessive fibrosis and microvascular damage of the skin and various internal organs. The presence of macrophage infiltrates and increased numbers of M2 macrophages in fibrotic areas have been reported3. A 44-year-old Japanese man developed scaly erythema that had been present on the trunk and lower and upper extremities for 40 years. A primary care doctor had diagnosed his condition as psoriasis. His previous treatments included topical corticosteroid therapy, topical psoralen ultraviolet-A therapy, or oral cyclosporin. Sacroiliitis was also associated with the skin symptoms. For the previous 4 years, the scaly erythema had gradually improved but was then complicated by sclerodactylia. On examination, a high anti-nuclear antibody (ANA) titer with homogeneous, speckled, and nucleolar patterns (×640) was present. Detailed analysis of the ANA revealed that there was a significant increase in anti-topoisomerase I antibody (152 U/ml). Rheumatoid factor was negative. From these results, the presumptive diagnosis was SSc complicated by PsA, and the patient was admitted to our hospital. Psoriatic plaque was present on the elbows of the patient (Fig. 1A). The modified Rodnan total skin thickness score value of 22 was used to grade the degree of skin sclerosis (Fig. 1B). The levels of T helper 2 cytokines, such as interleukin (IL)-4 (17.0 pg/ml) and transforming growth factor (TGF)-β1 (15.1 ng/ml), were elevated. The serum Krebs von den Lungen-6 (1,182 U/ml) and surfactant protein D (226 ng/ml) levels were elevated, and high-resolution computed tomography revealed the presence of a bilateral consolidation of both lower lobes with peripheral ground glass opacity. Skin biopsies from the elbow and the forearm revealed the presence of markedly elongated rete ridges with parakeratosis (Fig. 1C), and sclerotic change that ascended from the lower dermis (Fig. 1D). We also performed immunostaining for CD68 (Fig. 1E, F) and CD163 (Fig. 1G, H) in lesional skin biopsy samples. Subequal infiltrated dermal cells expressed CD68, which suggested that macrophages infiltrated both types of samples of lesional skin. Furthermore, the numbers of CD163-positive cells were increased in lesional skin from SSc. This result suggests that M2 macrophages were increased in lesional skin from SSc compared with lesional skin from PsA (Fig. 1E~H). Fig. 1 Clinical and histopathological manifestations in the patient. (A) Psoriatic skin lesion affecting the elbow. (B) Widespread skin thickening, progressing from the fingers to the trunk. (C) The skin biopsy specimen from the elbow has characteristics consistent ... Polarized macrophages have been broadly classified into two groups: M1 and M2 macrophages. Tissue macrophages can exist in different activation states. They can be proinflammatory macrophages (M1; activated by interferon-γ or lipopolysaccharide) or anti-inflammatory macrophages (M2; activated by TGF-β or IL-4)4. They participate in tissue remodeling, immune modulation, parasite clearance, and tumor progression5. In this patient, M2 macrophages may be one of the key regulating cell types involved in the clinical manifestations. However, further investigations are needed for elucidating the involvement of M2 macrophages in skin disorders.

Resveratrol possesses protective effects in a pristane-induced lupus mouse model.

BackgroundSystemic lupus erythematosus (SLE) is a multisystemic autoimmune disease characterized by the production of autoantibodies. To date, no therapy has been found to satisfactorily treat SLE. SIRT1 deficiency results in the development of an autoimmune syndrome in mice, including a high titer of anti-nuclear antibody in serum, immunoglobulin deposition in the kidney, and immune complex glomerulonephritis. Resveratrol is an activator of SIRT1 and possesses anti-inflammation and immune-regulatory properties.ObjectiveTo evaluate the preventative effects of resveratrol on a pristane-induced lupus animal model and assess its putative immune modulation effects.MethodsBALB/c mice received a single intraperitoneal injection of 0.5 ml of pristane on day 1 and then various doses of resveratrol were given to the mice daily starting on day 2 and continuing for seven months. The autoantibodies in serum and supernatants were measured. Single cells isolated from spleen, isolated CD4+ T cells, and CD19+ B cells were cultured with or without resveratrol in vitro and assessed by flow cytometry.ResultsResveratrol attenuated proteinuria, immunoglobuin depositon in kidney, and glomerulonephritis as well as IgG1 and IgG2a in serum in pristane-induced lupus mice. Resveratrol also suppressed CD69 and CD71 expression on CD4+ T cells as well as CD4+ T cell proliferation, induced CD4+ T cell apoptosis, and decreased CD4 IFNγ+ Th1 cells and the ratio of Th1/Th2 cells in vitro. In vitro antibody production and proliferation of B cells were also inhibited.ConclusionResveratrol possesses protective effects in pristane-induced lupus mice and may represent a novel approach for the management of SLE.

Glomerular Diseases Associated With Chronic Graft-Versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation: Case Reports

Chronic graft-versus-host disease (cGVHD) is the major complication following allogeneic stem cell transplantation (allo-SCT). Nephrotic syndrome (NS) and other types of glomerulonephritis have been proposed to be the very rare forms of renal cGVHD. From 1991 to 2011, 253 patients underwent allo-SCT at our center. We report here 4 cases (1.6%) presenting with varieties of glomerular manifestations associated with cGVHD. The first case was typical NS. The renal pathology showed membranous nephropathy (MN). The second case was also MN, but this patient also had the pathology of focal segmental glomerulosclrosis (FSGS) and acute tubular necrosis (ATN). The third case showed lupus nephritis-like glomerular lesions with a high anti-nuclear antibody (ANA) titer. The fourth case presented with rapidly progressive glomerulonephritis (RPGN)-like symptoms. The kidney histology in this case was not available. The patient responded well to immunosuppressive therapy, but NS later recurred. Therefore, overt glomerular diseases after allo-SCT in Thai patients are not very rare. Monitoring urinalysis during withdrawal of immunosuppressive drugs and also during follow-up of patients with cGVHD may be considered.

Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis

Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis

Oral lichenoid lesions and serum antinuclear antibodies in Thai patients

The aim of this study was to investigate the presence of serum antinuclear antibodies (ANA) in Thai oral lichenoid drug reaction (OLDR) and oral lichen planus (OLP) patients. This study comprised 20 patients diagnosed with OLDR, 23 patients with OLP, and 24 healthy control subjects. Participants' blood samples were assayed for ANA staining patterns and serum ANA titer levels by immunofluorescence using human epithelial type 2 (HEp-2) as a substrate. The serum ANA titer levels were defined as low (1:40-1:80), medium (1:160-1:320), and high (>1:640). Serum ANA were detected in 73.9%, 70%, and 25% of OLP, OLDR, and control subjects, respectively. There was a statistically significant difference between the number of serum-ANA-positive subjects in the OLP or OLDR groups and the control group (P < 0.01), but no significant difference between the OLP and OLDR groups. The speckled pattern was the most commonly found staining pattern, present in 60.9%, 55.0%, and 20.8% of the OLP, OLDR, and control subjects, respectively. The number of subjects with low ANA titers in the OLP and OLDR groups was significantly higher than that of the control group (P < 0.01). Medium ANA titers were found in 15%, 4.4%, and 4.2% of the OLDR, OLP, and control subjects, respectively, while high ANA titers were not found in any group. The number of serum-ANA-positive OLP and OLDR patients was significantly higher than the control group. Speckled pattern and low titer levels were the most common findings in both OLP and OLDR groups.

Pregnant woman with non-comatose autoimmune acute liver failure in the second trimester rescued using medical therapy: A case report.

We present the case of a 25-year-old woman at 16 weeks of gestation who presented with non-comatose autoimmune acute liver failure and was at high risk of developing fulminant hepatitis. Predictive formulas indicated a high probability of developing fulminant hepatitis. Unenhanced computed tomography showed marked hepatic atrophy and broadly heterogeneous hypoattenuating areas. The course of her illness was subacute, and the etiology of liver injury was unclear. Considering all of the above, we predicted a poor prognosis. Plasma exchange (PE) and continuous hemodiafiltration (CHDF) therapy were initiated just after admission. A few days after admission, a high titer (×80) of antinuclear antibody was noted. Because autoimmune hepatitis (AIH) was considered a cause of liver failure, treatment with moderate prednisolone (30 mg/day) doses was administrated, with careful consideration of her pregnancy. Thereafter, her laboratory findings and clinical course gradually improved without the need for liver transplantation. A liver biopsy at 18 days after admission indicated a diagnosis of AIH. She continued the pregnancy and delivered a healthy baby without any complications. Eventually, prednisolone doses were decreased to 10 mg, after which her liver function worsened. The second liver biopsy also indicated a diagnosis of AIH. Accordingly, low-dose prednisolone and azathioprine doses (50 mg/day) were administrated to recover her liver function, after which her liver function regained normalcy. This case illustrates that a pregnant woman with non-comatose autoimmune acute liver failure in the first or second trimester of pregnancy and her fetus can be rescued by PE/CHDF therapy and safe moderate doses of prednisolone.

Gemcitabine-induced Hemolytic Uremic Syndrome Mimicking Scleroderma Renal Crisis Presenting with Raynaud's Phenomenon, Positive Antinuclear Antibodies and Hypertensive Emergency

A 58-year-old woman who received gemcitabine for advanced gallbladder cancer developed an impaired renal function, thrombocytopenia, Raynaud's phenomenon, digital ischemic changes, a high antinuclear antibody titer and hypertensive emergency that mimicked a scleroderma renal crisis. A kidney biopsy specimen demonstrated onion-skin lesions in the arterioles and small arteries along with ischemic changes in the glomeruli, compatible with a diagnosis of hypertensive emergency (malignant hypertension). The intravenous administration of a calcium channel blocker, the oral administration of an angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker and the transfusion of fresh frozen plasma were effective for treating the thrombocytopenia and progressive kidney dysfunction. Gemcitabine induces hemolytic uremic syndrome with accelerated hypertension and Raynaud's phenomenon, mimicking scleroderma renal crisis.

A case of sine scleroderma with parenchymal lung disease

Systemic sclerosis sine scleroderma is a subtype of scleroderma, which is characterized by involvement of visceral organs, but no characteristic skin alteration. The involved organs could be kidneys, heart, gastrointestinal system, and lungs. Interstitial lung disease (ILD) is one of the pulmonary manifestations of sine scleroderma. We report a 38-year-old woman presenting with chill, fever, generalized malaise, dyspnea on exertion, and dry cough with a history of Raynaud's phenomenon, who was evaluated by physical examination, spirometry, and computed tomography scan, that all lead to the diagnosis of ILD. Combination of high-titer positive anti-nuclear antibody, high erythrocyte sedimentation rate, positive C-reactive protein, and ILD could be explained by sine scleroderma.

Lupus nephritis with positive myeloperoxidase/proteinase 3-antineutrophil cytoplasmic autoantibody that developed after 17 years of propylthiouracil therapy

Dear Editor, Propylthiouracil (PTU) is a thiouracil-derived drug used to treat hyperthyroidism. A number of adverse effects have been reported in association with this drug, including fever, agranulocytosis, skin rash, and vasculitis. Increasing evidence has recently suggested that PTU can induce autoimmune syndromes with the production of antinuclear antibodies or antineutrophil cytoplasmic autoantibody (ANCA) in patients with Graves’ disease. We herein report a patient who developed lupus nephritis with positive myeloperoxidase (MPO)/proteinase 3 (PR3)-ANCA after taking PTU for 17 years. A 51-year-old man with a history of Graves’ disease, treated with PTU at 50 mg/day for approximately 17 years, presented to another institution with persistent high fever, polyarthralgia, and foot edema and was subsequently referred to our hospital. Upon presentation, he had thrombocytopenia (platelet count, PLT: 3.8 9 10/lL), leukocytopenia (WBC: 2.9 9 10/lL with 47 % neutrophils), microhematuria ([100 red blood cells per highpower field), proteinuria (1.01 g/day, peak value 4.26 g/ day), and an elevated serum creatinine level (1.42 mg/dL, peak value 5.66 mg/dL; Fig. 1). Thyroid function tests were within the normal range. Serological examinations showed a high titer of antinuclear antibodies (1:320, speckled pattern), positive MPO-ANCA (140.0 U/mL), positive PR3-ANCA (19.5 U/mL), positive double-stranded DNA antibody (Ds-DNA IgG Ab: 19.1 IU/mL), positive single-stranded DNA antibody (Ss-DNA IgG Ab: 140.0 IU/mL), and hypocomplementemia (C3: 41.7 mg/dL, C4: 7.1 mg/dL, and CH50: 13.9 U/mL). Renal biopsy showed mesangial proliferative glomerulonephritis, and immunofluorescence revealed positive staining for IgG, IgM, C3, and C1q. The pathological finding of a crescentic lesion indicating ANCA-associated renal vasculitis was not seen. Based on these findings, ANCA-positive lupus nephritis (WHO class II) was diagnosed. PTU treatment was discontinued, and he was effectively treated with plasmapheresis and hemodialysis combined with two pulses of cyclophosphamide and three pulses of methylprednisolone, prednisolone, and intravenous immunoglobulin therapy. After 3 months, his thrombocytopenia, proteinuria, and MPO/PR3-ANCA titer were significantly improved (Fig. 1). Potassium iodide and radioiodine therapy was administered to treat Graves’ disease. At the current time point of 2-years follow-up with low-dose prednisolone, his serum creatinine level is 1.28 mg/dL with no proteinuria and microhematuria. MPO-ANCA is 12.5 IU/mL (normal range is \3.5 IU/ml) without any remarkable findings of vasculitis, and Ds-DNA/Ss-DNA IgG Ab and complement titers are within the normal range. While the renal biopsy showed lupus nephritis, this patient had overlapping clinical and laboratory findings of lupus and vasculitis. In a previous study, ANCA was detected in 37.3 % of patients with idiopathic systemic lupus erythematosus, and patients with this condition are almost always positive for MPO-ANCA [1]. In addition, MPO-ANCA is found in a similar proportion of patients with PTU-induced lupus and patients with vasculitis; however, PR3-ANCA is detected only in patients with PTU-induced vasculitis [2]. In the present case, the regular long-term use of PTU and overlapping clinical findings of lupus and vasculitis with positive PR3-ANCA highly indicated that this patient developed an autoimmune T. Taguchi (&) S. Nakayama S. Fujimoto Y. Terada Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku 783-8505, Japan e-mail: ttagu27k@axel.ocn.ne.jp

Hydroxychloroquine is a good second‐line treatment for adults with immune thrombocytopenia and positive antinuclear antibodies

Treatment of patients with lupus-associated thrombocytopenia (SLE-ITP) is not standardized. We report data on efficacy and safety of hydroxychloroquine (HCQ) in this setting and in ITP patients with positive antinuclear antibodies (ANA) without definite SLE. Inclusion criteria were: definite diagnosis of ITP with a platelet count (PLT) <50 × 10(9) /L, ANA ≥ 1/160 on Hep2 cells with or without a definite diagnosis of SLE, and no sustained response to at least one previous treatment-line and treatment with HCQ. Response criteria were Complete Response (CR) for PLT ≥ 100 × 10(9) /L and Response (R) for PLT ≥30 × 10(9) /L and at least twice the initial value. Forty patients (32 females) with a mean age of 35 ± 17 years and PLT at ITP diagnosis of 14 ± 13 × 10(9) /L were analyzed. Twelve (30%) patients had a SLE-ITP, 28 patients had only positive ANA. All the patients failed to respond to oral prednisone with a median of two treatment-lines (1-5) before HCQ which was initially given in combination with another ITP treatment in 36 patients. Overall response rate was 60% (24/40) including 18 lasting CR and six lasting R maintained with a median follow-up of 64 months (6-146), in ¾ of cases with only HCQ and no concomitant ITP treatment. The response rate (CR+R) was higher in the SLE group vs ANA-positive group (83% vs 50%, P < 0.05). No patient stopped HCQ because of a side-effect. HCQ appears to be a safe and effective second line treatment for patients with SLE-ITP or ITP and high titer of ANA. This trial was registered at www.clinicaltrials.gov as # NCT01549184.

Autoimmune Hepatitis Associated with Sjögrenʼs Syndrome: A Case Report

Purpose: Introduction: Autoimmune hepatitis (AIH) is a chronic necroinflammatory liver disorder characterized by periportal hepatitis and the presence of serum autoantibodies. It can be associated with a number of other autoimmune diseases. Here,we report a case of AIH associated with Sjögren's syndrome, which is rare and seldom reported in literature. Case: A 45-year-old Northeast Chinese female was admitted to our hospital. The patient suffered from fatigue and anorexia, and had persistently high level of serum aminotransferase for twelve months. Over the last six months, she had dry eyes and dry mouth. She denied any family history or illicit drugs. On admission physical examination, mild percussion pain over the liver was identified, and no enlargement of the parotid and submandibular glands. Laboratory data revealed increased levels of alanine aminotransferase (391 U/L), aspartate aminotransferase (202 U/L), and γ-globulin. Serological testing for autoimmune displayed high titer of anti-nuclear antibodies (1/3200), and positive values of anti-SSA and anti-SSB. Histological examination showed a large number of IgG-positive lymphocytes in labial salivary gland biopsy specimen, as well as a lymphoplasmacytic interface hepatitis in liver biopsy specimen. Discussion: In this study, we demonstrated that AIH was concomitant with Sjögren's syndrome, which is rarely reported in literature. Therefore,we should pay attention to possible existence of Sjögren's syndrome when evaluating clinically symptomatic extrahepatic manifestations of AIH.

Autoimmune hepatitis presenting as hyperacute liver failure with severe hepatic encephalopathy: Rescue of the child by auxiliary liver transplantation and complete recovery of the native liver by combined immunosuppression

Background: Acute liver failure (ALF) is a dramatic event. 5% of pediatric cases are determined by autoimmune hepatitis (AIH). When AIH does not respond to immunosuppressive treatment, liver transplantation remains the only therapeutic option. However, after transplantation AIH may recur in 20% of patients.Aim: To report the third pediatric case of ALF due to AIH successfully treated with auxiliary liver transplantation (ALT).Case report and results: A 5-year-old girl was referred to our Center of Pediatric Hepatology for the sudden onset (<7 days) of jaundice and lethargy. Elevated liver enzymes (AST 999 U/L, ALT 1583 U/L), severe coagulopathy (international normalized ratio 3.3) and hyperammoniemia (158 μmol/L) were present at admission. High titers of anti-nuclear and anti-smooth muscle antibodies were retrieved suggesting the presence of type 1 AIH. Despite a prompt steroid treatment, the girl showed a progressive neurological deterioration leading to hepatic coma in less than 24 h after admission. Cerebral edema/hemorrhages were excluded by neurological imaging. 72 h after admission the girl underwent a native left hepatectomy and received a left auxiliary graft implanted orthotopically. Histology of the explanted left lobe confirmed the diagnosis of AIH. Immunosuppression was based on tacrolimus, azathioprine and steroids. The girl showed a complete neurological recovery in the first week after ALT. Liver tests normalized 3 months after transplant. Liver biopsies and volumetric CT scans, performed at 1 and 6 months after ALT, respectively demonstrated a complete remission of AIH and a full volume recovery of the right native lobe. Steroid treatment was interrupted 6 months after ALT. Gradual withdrawal of tacrolimus was started 7 months after ALT. No significant complications have been observed at 10 months of follow up.Conclusions: ALT is an option for the treatment of ALF when the chances for the native liver to recovery are high but temporary support is critical for survival. Less than 50 cases of ALT have been reported in children with ALF so far; the main indications consisted of seronegative non-A- non-G hepatitis, drug toxicity and mushroom poisoning. We have described the third pediatric case of AIH treated by ALT with rapid restoration of liver function and reversal of hepatic encephalopathy. ALT should be always considered as a therapeutic option for AIH in the setting of a rapidly deteriorating liver function despite maximal medical treatment. Background: Acute liver failure (ALF) is a dramatic event. 5% of pediatric cases are determined by autoimmune hepatitis (AIH). When AIH does not respond to immunosuppressive treatment, liver transplantation remains the only therapeutic option. However, after transplantation AIH may recur in 20% of patients. Aim: To report the third pediatric case of ALF due to AIH successfully treated with auxiliary liver transplantation (ALT). Case report and results: A 5-year-old girl was referred to our Center of Pediatric Hepatology for the sudden onset (<7 days) of jaundice and lethargy. Elevated liver enzymes (AST 999 U/L, ALT 1583 U/L), severe coagulopathy (international normalized ratio 3.3) and hyperammoniemia (158 μmol/L) were present at admission. High titers of anti-nuclear and anti-smooth muscle antibodies were retrieved suggesting the presence of type 1 AIH. Despite a prompt steroid treatment, the girl showed a progressive neurological deterioration leading to hepatic coma in less than 24 h after admission. Cerebral edema/hemorrhages were excluded by neurological imaging. 72 h after admission the girl underwent a native left hepatectomy and received a left auxiliary graft implanted orthotopically. Histology of the explanted left lobe confirmed the diagnosis of AIH. Immunosuppression was based on tacrolimus, azathioprine and steroids. The girl showed a complete neurological recovery in the first week after ALT. Liver tests normalized 3 months after transplant. Liver biopsies and volumetric CT scans, performed at 1 and 6 months after ALT, respectively demonstrated a complete remission of AIH and a full volume recovery of the right native lobe. Steroid treatment was interrupted 6 months after ALT. Gradual withdrawal of tacrolimus was started 7 months after ALT. No significant complications have been observed at 10 months of follow up. Conclusions: ALT is an option for the treatment of ALF when the chances for the native liver to recovery are high but temporary support is critical for survival. Less than 50 cases of ALT have been reported in children with ALF so far; the main indications consisted of seronegative non-A- non-G hepatitis, drug toxicity and mushroom poisoning. We have described the third pediatric case of AIH treated by ALT with rapid restoration of liver function and reversal of hepatic encephalopathy. ALT should be always considered as a therapeutic option for AIH in the setting of a rapidly deteriorating liver function despite maximal medical treatment.

SAT0243 Endothelial dysfunction reflected by high S-ICAM-1 and VWF levels accelerates coronary atherosclerosis in systemic lupus erythematosus patients

BackgroundConventional risk factors of coronary artery disease fail to explain accelerated atherosclerosis in systemic lupus erythematosus (SLE) patients. Clinical and experimental studies shows that soluble intercellular adhesion molecule 1 (sICAM-1)...

AB0123 Microrna-mediated regulations in plasmacytoid dendritic cells in lupus mice

BackgroundSystemic lupus erythematosus (SLE) is a chronic autoimmune disease complicated by the involvement of multiple organ systems and its diverse clinical manifestations. Typically, SLE patients have been characterised by the...

MicroRNA-mediated modulations in hyperactive plasmacytoid dendritic cells in systemic lupus erythematosus (P4072)

Abstract Systemic lupus erythematosus (SLE) patients are typically presented by their increased serum type I interferon (IFN) activities. Plasmacytoid dendritic cells (pDCs), the most potent type I IFN-producing cells, are found to be hyperactive in SLE. Using the New Zealand Black/White F1 lupus mouse model, we sought for the regulatory mechanism of IFN production by pDCs in SLE. Mice with lupus symptoms such as high titers of serum anti-nuclear antibodies and persistent proteinuria were compared with the pre-symptomatic ones. Upon toll-like receptor (TLR) 7 and TLR9 stimulations, the up-regulations of co-stimulatory markers CD40, CD86 and MHC class II were significantly heightened in bone-marrow-derived pDCs from the symptomatic mice. Furthermore, the expression profiles of over 700 microRNA (miRNAs) in pDCs upon TLR7 activation were analyzed by low-density arrays. Among those, miRNA-155 was the most highly induced and its induction was consistently higher in pDCs from the symptomatic mice. It was previously found in human studies that miRNA-155 regulates type I IFN production by pDCs and itself inversely regulated by the autocrine/paracrine IFN dynamics. Current investigations pursue on the correlation between up-regulated miRNA-155 induction and aberrant pDC functions in SLE using miRNA mimics and inhibitors. Together, our study should reveal miRNA-mediated modulations in pDC abnormalities in SLE.