High Titers Of Antinuclear Antibodies Research Articles

Autoimmune Hepatitis With Severe Hypergammaglobulinemia and Eosinophilia in a Child

We report here a 7-year-old Afghan girl with autoimmune hepatitis (AIH). Because she showed hepatic dysfunction with markedly high serum immunoglobulin G (IgG) (5,234 mg/dL) and eosinophilia (absolute eosinophil counts: 9,547/µL) at onset, we had difficulty in diagnosing this case by differentiating from various possible diseases. After wedge biopsy of the liver which histologically showed chronic hepatitis pattern as well as high titers (1:640) of anti-nuclear antibody with other negative autoantibodies, the patient was eventually diagnosed as AIH type 1 and successfully managed with a combination of prednisolone (PSL), azathioprine and ursodeoxycholic acid (UDCA), followed by a maintenance therapy with PSL, cyclosporine and UDCA. Int J Clin Pediatr. 2020;9(2):50-54 doi: https://doi.org/10.14740/ijcp372

Unilateral Optic Neuritis in Primary Sjögren Syndrome Onset – a Case Report

"Introduction. Primary Sjogren's syndrome (pSSj) is a chronic, autoimmune disease that predominantly affects the lacrimal and salivary glands but is also responsible for extra-glandular disturbances. Although rare, optic neuritis (ON) may appear as initial manifestation and may be responsible for visual loss if diagnosis is delayed. The aim of the paper is to report a case of pSSj-induced ON as disease debut. Case presentation. A 35-year-old patient with xerophthalmia presented an episode of sudden decrease in visual acuity of the left eye. Examination of the fundus revealed papillary edema, tortuous retinal vessels, non-reflex macula improved after methylprednisolone pulse-therapy. Immunological testing revealed high titer antinuclear antibodies (ANA) and intensely positive anti-Ro antibodies. Schirmer test was positive and parotid gland ultrasound was compatible with pSSj. Central nervous system damage is heterogeneous as clinical phenotypes in patients with pSSj. Prompt distinction between non-specific ON and pSSj-related eye involvement is mandatory for successful therapeutic strategy. Conclusions. pSSj is a rare cause of ON that requires a detailed medical history, autoantibody determination, and minor salivary gland biopsy for confirmation. The ON response to methylprednisolone is promising and may improve patients’ prognosis."

Inflammatory abdominal aortic aneurysms: place of Ig G4related diseases

Aim. Inflammatory abdominal aortic aneurysm may be one of the manifestations of Ig G4-related disease. This study analyzes the clinical manifestations of Ig G4related inflammatory abdominal aortic aneurysm. Material and methods. We examined twenty patients with abdominal aortic aneurysm (AAA). The clinical performance of the disease, the results of laboratory and pathomorphological studies were studied. In 8 cases, Ig G4-related inflammatory AAA criteria were identified. Results. Compared to atherosclerotic AAA, Ig G4-related cases were characterized by a less frequent presence of abdomen or back pain. The concentration of IgG4 in serum in Ig G4-related cases was significantly increased. Patients with Ig G4-related inflammatory AAA often had a history of allergic reactions to drugs, autoimmune diseases, a high concentration of Ig E and a high titer of antinuclear antibodies in blood serum. According to a histological study of intraoperative biopsy samples, Ig G4-related cases were characterized by thickening of adventitia and numerous infiltrates with Ig G4-positive plasma cells. Conclusion. The presence of Ig G4-related disease is diagnosed in the presence of irregular fibrous tissue proliferation with Ig G4 plasma cell infiltrates and with an increase in the concentration of Ig G4 in blood serum. Ig G4-related inflammatory AAA has clinical specifics in comparison with atherosclerotic aneurysm.

Epidemiological survey of antinuclear antibodies in healthy population and analysis of clinical characteristics of positive population.

BackgroundIn China, the incidence of autoimmune diseases is gradually increasing. To decrease the misdiagnosis rate of autoimmune diseases, we conducted an epidemiological investigation about the presence of antinuclear antibody (ANA) in healthy populations and analyzed the clinical characteristics of healthy population with both high titer of ANA and positive anti‐SSA and AMA‐M2.MethodsSerum ANA titers were detected by indirect immunofluorescence (IIF), and other 15 types of ANA‐specific antibodies were detected by line immunoassays.ResultsIn 25 110 individuals for routine examination, the positive rate of ANA titer >1:100 was 14.01%, of which the positive rate of female (19.05%) was higher than that of male (9.04%; P < 0.01). The positive rate of ANA titer >1:320 was 5.93%, of which the positive rate of female (8.68%) was higher than that of male (3.21%; P < 0.01). The specific antibodies were detected in 1489 of ANA‐positive people with titer >1:320, and the top three detected antibodies were anti‐Ro‐52 (212), AMA‐M2 (189), and anti‐SSA (144). The abnormal rate of blood routine test, liver function test, and other clinical indicators in AMA‐M2–positive population was significantly different from those in the control group. The abnormal rate of blood routine test, liver function test, and immune index in anti‐SSA–positive population was higher than those in control group.ConclusionThere was a high prevalence of ANA positive in healthy population. To avoid misdiagnosis, those who had symptoms of abdominal discomfort, pruritus, or fatigue with abnormal results of blood routine and liver function test should be examined for ANA, AMA‐M2, anti‐SSA as early as possible.

Hepatopathy of unknown etiology - is liver biopsy a good tool in differential diagnosis?

IntroductionLiver biopsy is a well-known method for the diagnosis and evaluation of chronic diffuse liver diseases, especially among patients with “hepatopathy of unknown origin”.Material and methodsIn the years 2014–2015 we performed 259 liver biopsies in 28 patients (22 females, 6 males, aged 18–65 years, mean: 45 years) with an initial diagnosis of “hepatopathy of unknown origin”. The liver biopsies of these 28 patients were revised by two independent pathologists.ResultsHistopathological features of autoimmune conditions were found in 11 cases, steatohepatitis with/without Mallory bodies in 7, simple steatosis without inflammation in 2 cases. In the other 8 cases the histopathological features were non-specific but pointed to vanishing bile duct syndrome, hemochromatosis, acute inflammation or fibrosis without inflammation. Surprisingly, only mild fibrosis without inflammatory infiltrates was present in one patient with a high titer of antinuclear antibodies (ANA > 1 : 3200). Mild cholestasis with bilirubinostasis was found in 4 cases. One patient had prominent lobular iron deposits and is now under observation for hemochromatosis. Vanishing bile duct syndrome as ductopenia without any signs of inflammation was found in one patient with suspicion of primary biliary cirrhosis. In one liver biopsy specimen we found normal liver architecture without inflammation or steatosis in a patient with elevated ALT and GGT, negative for viral antibodies and autoantibodies.ConclusionsLiver biopsy – despite the increasing access to new, non-invasive methods – remains a useful method in the differential diagnosis of liver diseases.

BAFF-R and TACI expression on CD3+ T cells: Interplay among BAFF, APRIL and T helper cytokines profile in systemic lupus erythematosus

BackgroundSystemic lupus erythematosus (SLE) is the prototype of systemic autoimmune disease, characterized by loss of immune tolerance against self-antigens where autoantibody production is the hallmark of disease. B-cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) are cytokines that promote autoreactive cell survival, immunoglobulin-class switching and autoantibody responses in human and mouse SLE models. BAFF and APRIL exert their functions through interactions with their receptors BAFF-R and TACI that are differentially expressed in B lymphocyte subsets, monocytes, dendritic cells and T lymphocytes. BAFF stimulation favors T lymphocyte activation and cytokine production through BAFF-R, which could contribute to the Th1, Th17 and/or Th2 response dysregulation observed in SLE patients. ObjectiveTo evaluate the expression of the cytokines BAFF and APRIL and their association with the receptors BAFF-R and TACI on CD3+ T cells and to evaluate Th1/Th2/Th17 cytokine profile in patients with SLE. MethodsFifteen healthy controls (HC) and 36 SLE patients were included, and their demographic and clinical data were assessed. The disease activity index (Mex-SLEDAI) and damage index (SLICC) were applied to the SLE patients. BAFF-R and TACI expression on CD3+ T cells were evaluated by flow cytometry. Serum BAFF and APRIL concentrations were measured by enzyme-linked immunosorbent assays (ELISA). Cytokine levels of Th1 (IL-12, IL-2, IFN-γ, TNF-α), Th2 (IL-4, IL-6, IL-10, IL-13) and Th17 (IL-1β e IL-17) were quantified with a multiplex assay (MAGPIX). Statistical analysis was performed using PASW Statistics v.20 and GraphPad Prism v.6 software. ResultsNo differences in BAFF-R or TACI expression on the CD3+ T cells of SLE and HC were observed. BAFF-R expression correlates inversely with disease activity (r = −0.538, p < 0.01), while TACI correlates with disease activity (r = 0.530, p < 0.05). Serum BAFF and APRIL levels were high in SLE patients and correlated with the disease activity index Mex-SLEDAI (r = 0.621, p < 0.01 and r = 0.416, p < 0.05). SLE patients were found to have significantly higher levels of IL-12, IFN-γ, TNF-α, IL-6, IL-10, IL-13, IL-1β and IL-17 compared to HC (p < 0.05). Cytokines IL-17 (r = 0.526) and TNF-α (r = 0.410) correlate with disease activity (p < 0.05), while APRIL (r = 0.477), IL-10 (r = 0.426) and IFN-γ (r = 0.440) levels were associated with organ damage (p < 0.01). Serum BAFF expression levels correlate with IL-4 (r = 0.424; p < 0.05), IL-6 (r = 0.420; p < 0.05) and IL-10 (r = 0.459; p < 0.01), whereas APRIL levels correlate with IL-2 (r = 0.666; p < 0.01), IL-12 (r = 0.611; p < 0.01) and TNF-α (r = 0.471; p < 0.05) cytokines. A subgroup of SLE patients with high serum BAFF levels (>2 ng/mL) also showed increased APRIL, IL-2, IL-6 and IL-10 levels (p < 0.05). Finally, BAFF, IL-4 and TNF-α serum levels were associated with high titers of antinuclear antibodies. ConclusionsThe study demonstrates an imbalance in the Th1/Th2 cytokine profile, with increased proinflammatory cytokines, as well as BAFF and APRIL serum levels. Associations of BAFF with Th2 profile cytokines and disease activity, as well as APRIL with Th1 profile cytokines and organ damage, suggest that BAFF and APRIL generated in the autoimmunity context could through still unknown mechanisms, modulate the microenvironment, and perpetuate the inflammatory response, autoantibody production and organ damage observed in SLE patients.

RECURRENT ANGIOEDEMA AS A PRESENTING SYMPTOM OF MIXED CONNECTIVE TISSUE DISEASE IN A PEDIATRIC PATIENT

Introduction Idiopathic angioedema without urticaria presents infrequently and warrants investigation for an underlying etiology. Autoimmune conditions are a rare cause of acquired angioedema (AAE). The identification of an underlying cause has significant potential implications for treatment and thus resolution of AAE. We present a patient who was diagnosed with mixed connective tissue disease (MCTD) after initially presenting with recurrent angioedema. Case Description A 17-year-old female with a six-month history of recurrent angioedema without urticaria presented for evaluation to an outpatient pediatric allergy clinic. At initial presentation, she denied musculoskeletal complaints. Laboratory evaluation revealed a significantly elevated sedimentation rate with a normal C-reactive protein. Over the next several months she developed pain and stiffness, particularly in her wrist and elbow joints. These findings triggered rheumatologic referral for further evaluation. She was ultimately diagnosed with MCTD with corresponding U1-ribonucleoprotein antibodies and high titer anti-nuclear antibodies. She was started on mycophenolate mofetil and hydroxychloroquine for MCTD treatment with resolution of her arthritis and no further episodes of angioedema. Discussion The pathophysiology of nonhistaminergic idiopathic angioedema remains unknown. This case highlights the need to asses for concurrent rheumatologic and autoimmune symptoms while evaluating AAE in the absence of urticaria, especially in the pediatric population. To our knowledge, this is the first report of MCTD presenting as acquired angioedema in published literature.

Pediatric systemic lupus erythematosus. Retrospective analysis of clinico-laboratory parameters and their association with Systemic Lupus Erythematosus Disease Activity Index score.

Objectives:To elucidate the clinico-laboratory characteristics associated with pediatric systemic lupus erythematosus (pSLE) patients with higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score in a retrospective cohort of pSLE patients.Methods:A retrospective study involving 32 pSLE patients was conducted at Hospital Universiti Sains Malaysia, Kelantan, Malaysia between 2006 and 2017.Results:Within the group of 32 pSLE patients, 23 were girls and 9 were boys (3:1 ratio). The most common symptom was renal disorder (n=21; 65.6%) followed by malar rash (n=9; 28.1%), oral ulcers (n=7; 21.9%), prolonged fever (n=5; 15.6%) and arthritis (n=4; 12.5%). Antinuclear antibodies (ANA) were detected in all patients and 25 patients (78.1%) were positive for anti-double stranded DNA (anti-dsDNA) antibodies. Eighteen (56.3%) patients had active SLE (SLEDAI ≥6), and these patients were significantly associated with heavy pyuria (p=0.004), a high ANA concentration (1:160; p=0.040, 1:320; p=0.006), elevated ESR (p=0.006), low C3 levels (p=0.008), oral ulcers (p=0.010), heavy hematuria (p=0.017) and heavy proteinuria (p=0.017), lupus erythematosus (LE)-nonspecific lesion manifestations (p=0.019) and malar rash (p=0.044).Conclusion:Pediatric systemic lupus erythematosus patients with higher SLEDAI score were most significantly associated with pyuria, high ANA titers, and elevated ESR.

Undifferentiated Connective Tissue Disease and Interstitial Lung Disease: Trying to Define Patterns

ObjectivesTo identify clinical or immunological features in patients with undifferentiated connective tissue disease (UCTD) associated interstitial lung disease (ILD), in order to group them and recognize different functional and high resolution computed tomography (HRCT) behavior. MethodsRetrospective cohort study. Patients meeting Kinder criteria for UCTD were included. We defined the following predictive variables: ‘highly specific’ connective tissue disease (CTD) manifestations (Raynaud's phenomenon, dry eyes or arthritis), high antinuclear antibody (ANA) titer (above 1:320), and ‘specific’ ANA staining patterns (centromere, cytoplasmic and nucleolar patterns). We evaluated the following outcomes: change in the percentage of the predicted forced vital capacity (FVC%) during the follow-up period, and HRCT pattern. ResultsSixty-six patients were included. Twenty-nine (43.94%) showed at least one ‘highly specific’ CTD manifestation, 16 (28.57%) had a ‘specific’ ANA staining pattern and 29 (43.94%) high ANA titer. Patients with ‘highly specific’ CTD manifestations were younger (mean [SD] 52 years [14.58] vs 62.08 years [9.46], P<.001), were more likely men (10.34% vs 48.65%, P<.001) and showed a smaller decline of the FVC% (median [interquartile range] 1% [−1 to 10] vs −6% [−16 to −4], P<.006). In the multivariate analysis, the presence of highly specific manifestations was associated with improvement in the FVC% (B coefficient of 13.25 [95% confidence interval, 2.41 to 24.09]). No association was observed in relation to the HRCT pattern. ConclusionThe presence of ‘highly specific’ CTD manifestations was associated with female sex, younger age and better functional behavior. These findings highlight the impact of the clinical features in the outcome of patients with UCTD ILD.

Thank God for Lab: Systemic Lupus Erythematosus - A Difficult Diagnosis, a Difficult Disease

Abstract Systemic Lupus Erythematosus (SLE) involves autoimmune mechanisms that affect multiple systems and has variable clinical manifestations. It affects mainly feminine gender, usually of child-bearing age. Very late onset SLE (patients older than 75 years) is rarely met and difficult to diagnose due to the unspecific symptoms. The diagnosis is frequently mistaken for drug-induced SLE or for other age-specific disorders. We present the case of a 78 years old male patient complaining of hemoptysis in small amounts, fever, dyspnea at small efforts, weight loss, and important asthenia. Based on physical examination, severe anemia and thoracic CT aspect, several diagnosis were taken into account: anemic syndrome and pleurisy due to refractory pneumonia, pulmonary neoplasm, pulmonary tuberculosis, congestive heart failure and Wegener granulomatosis. Only when direct Coombs test came positive and all the other serological tests resulted negative, diagnosis of SLE was considered. Confirmation came along with high titers of antinuclear antibodies, anti double strained DNA antibodies and lupic anticoagulant and low levels of C3c and C4. We conclude that the diagnosis of SLE must be taken into consideration even in elder male patients. Therapeutic options in these patients are challenging because of the associated comorbidities and side effects.

Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation

BackgroundLoss-of-function CECR1 mutations cause polyarteritis nodosa (PAN) with childhood onset, an autoinflammatory disorder without significant signs of autoimmunity. Herein we describe the unusual presentation of an autoimmune phenotype with constitutive type I interferon activation in siblings with adenosine deaminase 2 (ADA2) deficiency.Case presentationWe describe two siblings with early-onset recurrent strokes, arthritis, oral ulcers, discoid rash, peripheral vascular occlusive disease and high antinuclear antibody titers. Assessment of interferon signatures in blood revealed constitutive type I interferon activation. Aicardi-Goutières syndrome (AGS) was suspected, but no mutation in the known AGS genes were detected. Whole exome sequencing identified compound heterozygosity for a known and a novel mutation in the CECR1 gene. Functional consequences of the mutations were demonstrated by marked reduction in ADA2 catalytic activity.ConclusionsOur findings demonstrate that ADA2 deficiency can cause an unusual autoimmune phenotype extending the phenotypic spectrum of PAN. Constitutive interferon I activation in patient blood suggests a possible role of type I interferon in disease pathogenesis which may have therapeutic implications.

Intracranial lesion as onset symptom in a patient with early undifferentiated connective tissue disease: a case report

BackgroundUndifferentiated connective tissue disease (UCTD) is widely considered to be a distinct clinical entity, and now divided into two subgroups: stable UCTD and early UCTD. The most frequent onset symptoms of UCTD include arthralgias, arthritis, Raynaud’s phenomenon, mucocutaneous involvement, and sicca symptoms. However, Neurologic involvement is rare, and intracranial lesion as onset symptom in a patient with early UCTD has not yet been reported.Case presentationA 51-year-old Chinese female experienced progressive left leg weakness for 14 days before hospitalizing in our department. The lesion on right parietal lobe was initially detected by brain magnetic resonance imaging. Although the patient declined a cerebral biopsy, the possibility of stroke, cerebral venous sinus thrombosis, NMOSD, MS, autoimmune encephalitis, intracranial infections, and malignant tumors as cause of the lesion was excluded by intracranial angiogram, CSF study, MRI enhancement and MRS examination. Moreover, immunologic studies showed high titer of antinuclear antibody, increased erythrocyte sedimentation rate and C-reactive protein. These results led to a diagnosis of early UCTD with central nerve system (CNS) involvement. After low dose corticosteroid and azathioprine therapy, the patient’s symptoms, abnormalities in immunologic tests and cerebral radiologic examinations were all greatly improved within a short duration.ConclusionsThis is the first report of intracranial lesion as onset symptom in a patient with early UCTD. Our case suggested that central nerve system (CNS) involvement could be the onset symptom in early UCTD, and should be recognized quickly with exclusion of other causative factors in the differential diagnosis. Prompt and adequate treatment with low-dose steroid and immunosuppressive drugs could improve the prognosis of both early UCTD and CNS involvement.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) as a first presentation of systemic lupus erythematosus

Peripheral nervous system involvement frequently occurs in systemic lupus erythematosus (SLE) patients. However, chronic inflammatory demyelinating polyneuropathy (CIDP) is an unusual presentation that can develop before, after, or simultaneously with the onset of SLE. This paper reports the case of a 20-year-old man with diabetes mellitus (DM) and CIDP accompanied by SLE. The patient complained of progressive weakness in the bilateral upper and lower extremities that had begun 2 months prior to this visit. He was diagnosed with CIDP and treated with intravenous immunoglobulin (IVIG), but had little improvement. A plasma exchange was then scheduled, but it was not helpful either. The patient developed polyarthritis, oral ulcer, and a worsening of his muscle weakness two weeks later. A neurologic examination revealed 3/5 muscle strength in the upper and lower extremities, absent deep tendon reflex (DTR), and impaired position sense. The patient was diagnosed with SLE because of pancytopenia, lymphopenia, pleuropericardial effusion, proteinuria, high titer anti-nuclear antibody (ANA), and anti-dsDNA. A kidney biopsy revealed stage IV lupus nephritis. The patient received 3 pulses of methyl prednisolone, 6 months of cyclophosphamide, and a high daily dose of prednisolone. His proteinuria improved, and he regained the ability to ambulate with a normal gait after about 2.5 months. To the best of the authors’ knowledge, the concurrency of CIDP with SLE and DM has not been previously reported.

Lichen Planus in Silicosis Patient with Unusually High Antinuclear Antibody Titer.

Lichen Planus in Silicosis Patient with Unusually High Antinuclear Antibody Titer.

Clinical analysis of 6 patients with drug-induced lupus

To improve the understanding of drug-induced lupus (DIL) and the differences from systemic lupus erythematosus (SLE). Clinical manifestation and treatment of patients with definite DIL were retrospectively analyzed. Six patients with DIL were enrolled in this study, including 4 females and 2 males. Two patients were diagnosed after receiving interferon, one after soluble tumor necrosis factor receptor fusion protein, one after propylthiouracil, one after penicillamine, and one after levofloxacin. High titer of antinuclear antibody was identified in all six patients, including 3 with positive anti-dsDNA antibody. One patient had positive anti-Sm antibody. One patient had positive anti-RNP antibody. One patient had anti-nucleosome antibody. One patient had anti-histone antibody. One patient had antimitochondrial antibodies-M2, and one patient had anticardiolipin antibodies. Patients with DIL are not as severe as those with SLE. After cessation of suspected drugs and administration of standard treatment, the clinical outcome of DIL is satisfying.

Acute Kidney Injury in a Patient with Mantle Cell Lymphoma-Associated Hypocomplementemia

Lymphomatous infiltration of the kidney is a rare manifestation of mantle cell lymphoma (MCL). We present the case of a 54-year-old male with MCL, acute kidney injury, extremely high antinuclear antibody titers, and hypocomplementemia. The diagnosis of MCL was further confirmed by kidney, lymph node, and bone marrow biopsies and immunohistochemical analysis of cyclin D1 expression. Renal ultrasonography demonstrated bilateral renal hypertrophy, and histological examination of renal biopsy revealed lymphomatous infiltration of the tubulointerstitium, with similar antigenic profiles to those observed in bone marrow and lymph node samples. Following a thorough literature search, we believe the present case represents the first report of MCL with abnormally high antinuclear antibody titers, hypocomplementemia, and acute kidney injury.

Lurking in the Wall: Pneumatosis Cystoides Intestinalis with Scleroderma

0002-9343/$ -see front matter 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.12.007 He had a 6-year history of scleroderma, marked by Raynaud phenomenon, characteristic skin-tightening, and high titers of antinuclear antibodies. His vital signs were stable and bowel sounds were present, but his abdomen was diffusely distended, and he had mild epigastric tenderness without rebound or guarding.

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.