ABSTRACT
STAT5 transcription factors are involved in normal B lymphocyte development and in leukemogenesis. We show that the inhibition of STAT5A expression or activity in the NALM6, 697 and Reh leukemic pre-B cell lines, results in a higher spontaneous apoptosis and an increased FAS-induced cell death. However, the molecular mechanisms underlying the altered pre-B cell survival are unclear. We used a proteomic approach to identify proteins that are differentially regulated in cells expressing (NALM6Δ5A) or not a dominant negative form of STAT5A. Among the 14 proteins identified, six were involved in the control of the oxidative stress like glutathione (GSH) synthetase and DJ-1. Accordingly, we showed increased levels of reactive oxygen species (ROS) in NALM6Δ5A cells and suppression of the increased sensitivity to Fas-mediated apoptosis by the GSH tripeptide. Similar results were observed when NALM6 cells were treated with TAT-STAT5Δ5A fusion proteins or STAT5A shRNA. In addition, the 697 and Reh pre-B cells were found to share number of molecular changes observed in NALM6Δ5A cells including ROS generation, following inhibition of STAT5 expression or function. Our results point out to a hitherto undescribed link between STAT5 and oxidative stress and provide new insights into STAT5 functions and their roles in leukemogenesis.
Subject(s)
Leukemia, B-Cell/metabolism , Oxidative Stress , Precursor Cells, B-Lymphoid/metabolism , STAT5 Transcription Factor/physiology , Apoptosis , Cell Line , Humans , Leukemia, B-Cell/pathology , RNA Interference , STAT5 Transcription Factor/geneticsABSTRACT
INTRODUCTION: Cryofibrinogenemia may be essential, or secondary to diseases such as neoplasia, infection, thrombosis, and collagen vascular diseases. In a previous study, we reported the occurrence of neoplasia in some essential cryofibrinogenemia patients after a short period of follow-up. PURPOSE: We performed a prospective multi-center 5-year follow-up study in essential cryofibrinogenemia patients (2005-2009). RESULTS: 23 patients with essential cryofibrinogenemia were included, mean age 59 years (range: 33-79), 14 males. After a mean follow-up period of 24 months, 11/23 (47%) of cases that were initially diagnosed as essential cryofibrinogenemia were found to have an underlying lymphoma (6 T lymphoma and 5 B lymphoma). CONCLUSION: This prospective study suggests that some cases of cryofibrinogenemia that are initially considered as essential, may have underlying lymphoma. Thus, we further suggest that regular follow-up should be performed in patients with essential cryofibrinogenemia.
Subject(s)
Cryoglobulinemia/etiology , Lymphoma/complications , Adult , Aged , Cryoglobulinemia/diagnosis , Cryoglobulinemia/epidemiology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Outcome Assessment, Health Care , Prospective StudiesABSTRACT
BACKGROUND: Pemphigus is a life-threatening autoimmune blistering disease mediated by autoantibodies against adhesion molecule of the skin. Its concurrence with systemic and organ-specific autoimmune disease was described in case reports. OBJECTIVES: To evaluate the presence of a broad spectrum of organ-specific and non-organ-specific autoantibodies other than anti-desmoglein antibodies in pemphigus patients. PATIENTS AND METHODS: Serum samples were obtained from 105 pemphigus foliaceus (PF) patients, 51 pemphigus vulgaris (PV) patients and 50 controls. Both indirect immunofluorescence assay and ELISA were used to assess the presence of autoantibodies related to connective tissue diseases, autoimmune hepatitis, vasculitis, rheumatoid arthritis, coeliac disease, diabetes and thyroiditis. RESULTS: Significant difference was observed between the three groups for anti-thyroglobulin antibodies in the pemphigus foliaceus group (18% vs. 4%, P=0.03). A significantly higher occurrence of IgM anti-cardiolipin (P=0.03), IgG anti-reticulin (P=0.01) and IgG anti-gliadin antibodies (P=0.008) were observed in the PV group. Cases with more than four autoantibodies were frequently positives for both anti-desmoglein 1 and anti-desmoglein 3. CONCLUSION: Autoantibodies other than anti-desmoglein antibodies are not rare in pemphigus patients. Clinical and serological follow-up of pemphigus patients with positive autoantibodies are needed to clarify their impact in disease evolution.
Subject(s)
Autoantibodies/blood , Desmogleins/immunology , Pemphigus/immunology , Adult , Aged , Aged, 80 and over , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Fluorescent Antibody Technique , Humans , Male , Middle Aged , Pemphigus/blood , Radioimmunoassay , Seroepidemiologic StudiesABSTRACT
Epidermolysis bullosa acquisita is a rare entity belonging to the auto-immune cutaneous blistering disorders of the dermo-epidermal junction. Clinical manifestations are generally cutaneous including the development of sub-epidermal blisters. Mucosal manifestations should be systematically looking for, but laryngeal involvement remains uncommon. We report an 81-year-old woman who presented with dysphagia, dyspnea and dysphonia as the presenting features of laryngeal involvement of an epidermolysis bullosa acquisita. This is the tenth reported case in the literature. We describe our diagnostic approach and the therapeutic management, comparing them with the literature.
Subject(s)
Epidermolysis Bullosa Acquisita/complications , Epidermolysis Bullosa Acquisita/pathology , Laryngitis/etiology , Laryngitis/pathology , Acute Disease , Aged, 80 and over , Anti-Infective Agents/therapeutic use , Dapsone/therapeutic use , Deglutition Disorders/etiology , Drug Therapy, Combination , Dysphonia/etiology , Dyspnea/etiology , Epidermolysis Bullosa Acquisita/diagnosis , Epidermolysis Bullosa Acquisita/drug therapy , Female , Glucocorticoids/therapeutic use , Humans , Laryngitis/complications , Laryngitis/diagnosis , Laryngitis/drug therapy , Prednisone/therapeutic use , Treatment OutcomeSubject(s)
Pemphigus/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Family Characteristics , Female , Genotype , Humans , Male , Middle Aged , Pedigree , Pemphigus/epidemiology , Retrospective Studies , Tunisia/epidemiology , Young AdultABSTRACT
BACKGROUND: Pemphigus foliaceus is an autoimmune blistering skin disease that partly results from genetic factors, especially human leucocyte antigen (HLA) class II genes. OBJECTIVES: The aim of the study was to determine the HLA DR/DQ markers of susceptibility and protection in the Tunisian endemic form. METHODS: Genomic DNA from 90 patients with pemphigus foliaceus recruited from all parts of the country and matched by age, sex and geographical origin with 270 healthy individuals, was genotyped. RESULTS: Firstly, when the whole patient population was studied, DRB1*03, DQB1*0302 and DRB1*04 alleles were significantly associated with the disease while a significant decrease of, in particular, DRB1*11 and DQB1*0301 was observed in patients compared with controls. DRB1*0301 was the dominant allele in DR3-positive patients and controls, while DRB1*0402 was found in 42% of DR4-positive patients. Secondly, when the HLA DR/DQ allele distribution was studied after dividing patients according to their geographical origin, the southern group, which consisted exclusively of patients with the endemic form of the disease, showed the same associations as the whole pemphigus foliaceus population, particularly with DRB1*03. In the northern group, only the DRB1*04 and DQB1*0301 alleles were found to be associated. Interestingly, anti-desmoglein 1 antibody-positive healthy controls did not carry susceptibility alleles but, in contrast, most carried negatively associated alleles. CONCLUSIONS: These observations indicate that a particular genetic background characterizes the Tunisian endemic form of pemphigus foliaceus and that HLA class II genes control the pathogenic properties of the autoimmune response rather than the initial breakage of B-cell tolerance.
Subject(s)
HLA-DR3 Antigen/genetics , Pemphigus/genetics , Adult , Alleles , Antibodies, Anti-Idiotypic/genetics , Antibodies, Anti-Idiotypic/immunology , B-Lymphocytes/immunology , Biomarkers/blood , Desmoglein 1/immunology , Female , Gene Frequency , Genetic Predisposition to Disease , Genotype , HLA-DR3 Antigen/immunology , Humans , Male , Middle Aged , Pemphigus/immunology , Polymorphism, Genetic , Tunisia/epidemiologySubject(s)
Complement C5/genetics , Pemphigus/genetics , Polymorphism, Genetic/genetics , TNF Receptor-Associated Factor 1/genetics , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Sex Factors , Statistics as Topic , Tunisia , Young AdultABSTRACT
BACKGROUND: Pemphigus foliaceus is an autoimmune blistering skin disease characterized by the production of pathogenic IgG autoantibodies directed against desmoglein 1. AIM: To determine the prevalence of anti-desmoglein 1 antibodies in healthy subjects and their distribution in the different regions of Tunisia and to better identify endemic areas of pemphigus foliaceus. METHODS: We tested, by enzyme-linked immunoserbent assay, sera of 270 normal subjects recruited from different Tunisian areas and 203 related healthy relatives to 90 Tunisian pemphigus foliaceus patients. Results Seventy-six patients (84.4%), 20 healthy controls (7.4%), and 32 relatives (15.76%) had anti-desmoglein 1 antibodies. In southern regions where pemphigus foliaceus is associated with a significant sex ratio imbalance (9 female : 1 male in the south vs. 2.3 : 1 in the north) and a lower mean age of disease onset (33.5 in the south vs. 45 years in the north), a higher prevalence of anti-desmoglein 1 antibodies in healthy controls was observed (9.23% vs. 5.71% in the north). Interestingly, the highest prevalence of anti-desmoglein 1 antibodies in healthy relatives (up to 22%) was observed in the most rural southern localities. More than half anti-desmoglein 1-positive healthy controls were living in rural conditions with farming as occupation, which suggests that this activity may expose the subjects to particular environmental conditions. CONCLUSION: These results show that the endemic features of Tunisian pemphigus foliaceus are focused in these southern areas more than in other areas and that both environmental and genetic factors contribute to the disease.
Subject(s)
Antibodies, Anti-Idiotypic/blood , Desmogleins/immunology , Endemic Diseases , Pemphigus/epidemiology , Pemphigus/immunology , Adult , Biomarkers/blood , Case-Control Studies , Desmogleins/genetics , Female , Genetic Predisposition to Disease/genetics , Humans , Immunoglobulin G/blood , Male , Pemphigus/blood , Prevalence , Tunisia/epidemiologyABSTRACT
OBJECTIVE: The objective of this study was to analyze the effects of 3 anti-TNFalpha agents on markers of autoimmunity in rheumatoid arthritis (RA) and spondylarthropathy (SPA) patients. METHODS: First-time anti-TNFalpha biologics (infliximab, etanercept, or adalimumab) were prescribed to 156 RA and 95 SPA (58 ankylosing spondylarthritides, 37 psoriatic arthritides). During 1-2 years of follow-up, clinical, biological [antinuclear (ANA) and anti-double-stranded (dsDNA) antibodies, rheumatoid factors (RF), and anti-cyclic citrullinated peptide (CCP) for RA], and therapeutic data were collected biannually. RESULTS: ANA appeared or ANA and anti-dsDNA titers increased significantly (P < 0.001) more under infliximab than etanercept in both rheumatisms and than adalimumab in RA patients. During the 2-year follow-up, ANA appeared more in RA patients taking adalimumab than etanercept (P = 0.003), but independently of the anti-TNFalpha used; anti-dsDNA titers rarely became positive. Under etanercept or infliximab, ANA and anti-dsDNA were not influenced by the underlying pathology nor were they affected by infliximab intensification over 18 months. Only one case of cutaneous lupus was observed in a patient having IgG anti-dsDNA. The therapeutic responses were independent of ANA and anti-dsDNA titers for all rheumatisms and biologics. In RA patients, RF titers, but not anti-CCP levels, declined with the therapeutic response for all biologics. CONCLUSION: This is the first study that has evaluated the impact of three TNFalpha blockers on ANA and anti-dsDNA antibodies in RA and SPA patients. Autoimmunity was more induced with infliximab than etanercept and to a lesser degree to adalimumab but, more importantly, this emergent autoimmunity was exceptionally associated to clinical manifestations of lupus.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Arthritis, Rheumatoid/drug therapy , Autoantibodies/immunology , Autoimmunity/drug effects , Immunoglobulin G/administration & dosage , Receptors, Tumor Necrosis Factor/administration & dosage , Spondylarthropathies/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab , Adrenal Cortex Hormones/administration & dosage , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized , Antibody Formation/drug effects , Antibody Formation/immunology , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/immunology , Autoantibodies/blood , Autoimmunity/immunology , Dose-Response Relationship, Drug , Drug Therapy, Combination , Etanercept , Female , Follow-Up Studies , Humans , Infliximab , Male , Middle Aged , Peptides, Cyclic/blood , Peptides, Cyclic/immunology , Severity of Illness Index , Spondylarthropathies/blood , Spondylarthropathies/immunology , Tumor Necrosis Factor-alpha/immunologyABSTRACT
OBJECTIVES: To evaluate the predictive value of TNFRII 196R, PTPN22 1858T and HLA-shared epitope (SE) alleles, RFs and anti-citrullinated protein antibodies (ACPAs) for RA diagnosis in a cohort of patients with very early arthritis. METHODS: We followed up 284 patients who had swelling of at least two joints that had persisted for longer than 4 weeks but had been evolving for <6 months. At 2 yrs, patients were classified as having RA or non-RA rheumatic diseases according to the ACR criteria. Patients were genotyped with respect to TNFRII 196M/R and PTPN22 1858C/T polymorphisms and HLA-SE. The presence of IgA, IgG and IgM RF isotypes and ACPA was sought in sera collected at disease onset. RESULTS: HLA-SE alleles alone, concomitant presence of TNFRII 196R and PTPN22 1858T alleles, IgA, IgG and IgM RF alone and ACPA were found to be significantly associated with RA diagnosis. Using logistic regression analysis, the concomitant presence of RF and ACPA at disease onset was the best association to predict RA diagnosis. In patients (n = 34) who did not fulfil the ACR criteria for RA at inclusion but who progressed to ACR positivity, the study of the genetic risk markers did not contribute to predict RA diagnosis at 2 yrs. CONCLUSIONS: PTPN22 1858T, TNFRII 196R and HLA-SE alleles do not improve the predictive value of RF and ACPA for RA diagnosis in our cohort, and do not contribute to an earlier diagnosis in undifferentiated patients initially negative for RF and ACPA.
Subject(s)
Arthritis, Rheumatoid/diagnosis , HLA-DR Antigens/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Receptors, Tumor Necrosis Factor, Type II/genetics , Adult , Aged , Aged, 80 and over , Alleles , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Autoantibodies/blood , Biomarkers/blood , Early Diagnosis , Female , Follow-Up Studies , Genetic Predisposition to Disease , HLA-DRB1 Chains , Humans , Male , Middle Aged , Peptides, Cyclic/immunology , Polymorphism, Genetic , Prospective Studies , Rheumatoid Factor/bloodABSTRACT
A premature atherosclerosis has been presumed in patients with antiphospholipid syndrome. The potential role of antiphospholipid antibodies in the development of atheroma is rather controversial. In this study, we tested the hypothesis that antiphospholipid antibodies could induce atherosclerosis via vascular functional changes. CD1 mice received one single injection of antiphospholipid monoclonal antibodies derived from male (BXSB x NZW) F1 mice with a lupus-like disease associated with an antiphospholipid syndrome and coronary artery disease. One week later, first-order mesenteric arteries (diameter 220-260 microm) were isolated and mounted on a small-vessel myograph for the measurement of the relaxation responses to acetylcholine or the NO donor nitroprusside after precontraction by phenylephrine. Five out of eight antiphospholipid monoclonal antibodies reduced the response to acetylcholine compared with control mice, and this effect was especially marked with one of them. No change in the response to nitroprusside was observed. The impairment was maintained after 3 weeks of treatment and appeared related to a moderate decrease in NO-mediated responses and a marked decrease in prostanoid-mediated relaxations. These vascular functional changes could be prevented by chronic treatment with statins or aspirin. These data could constitute additional elements supporting a direct pathogenic role of antiphospholipid antibodies. We suggest that a sub-population of these autoantibodies could be responsible for the endothelial dysfunction observed in antiphospholipid syndrome.
Subject(s)
Antibodies, Antiphospholipid/toxicity , Antiphospholipid Syndrome/physiopathology , Endothelium, Vascular/physiopathology , Acetylcholine/pharmacology , Animals , Antibodies, Monoclonal/toxicity , Aspirin/pharmacology , Fluorobenzenes/pharmacology , Free Radicals , Immunohistochemistry , Male , Mice , Nitric Oxide/physiology , Prostaglandins/physiology , Pyrimidines/pharmacology , Rosuvastatin Calcium , Sulfonamides/pharmacology , Vasodilation/drug effectsABSTRACT
Desmoglein (Dsg) 1 is a transmembrane glycoprotein of the desmosome allowing cell-cell adhesion between keratinocytes, whose expression is restricted to stratified squamous epithelia-like epidermis. Dsg1 is the target autoantigen of pathogenic autoantibodies produced by pemphigus foliaceus and 50% of pemphigus vulgaris patients in a Dsg1-specific T-cell-dependent pathway. Herewith, we show that mRNA of the DSG1 gene is present in normal human thymus and show by quantitative real-time polymerase chain reaction analysis that the expression of DSG1 transcript increases with age. Although immunoblot analysis on human thymus extracts using different anti-Dsg1 antibodies did not allow to detect the protein, we show by double-immunofluorescence assay that Dsg1 is expressed at protein level by CD19+ CD63+ cells located in the medulla. These data provide another illustration of the thymic expression of a tissue-specific autoantigen involved in an organ-specific autoimmune disease, which may participate in the tolerance acquisition and/or regulation of Dsg1-specific T cells.
Subject(s)
Autoantigens/metabolism , Desmoglein 1/metabolism , Pemphigus/immunology , Thymus Gland/immunology , Adolescent , Adult , Aging , Autoantigens/immunology , Autoimmunity , Child , Child, Preschool , Desmoglein 1/genetics , Desmoglein 1/immunology , Epidermal Cells , Epidermis/immunology , Epidermis/metabolism , Female , Humans , Infant , Infant, Newborn , Keratinocytes/cytology , Keratinocytes/immunology , Keratinocytes/metabolism , Male , Middle Aged , Pemphigus/genetics , Pemphigus/metabolism , Thymus Gland/cytology , Thymus Gland/metabolismABSTRACT
OBJECTIVES: The present study assessed the outcome of several cases of cryofibrinogenaemia detected in our hospitals during a 10-yr period (December 1996-April 2007), and also attempted to evaluate the clinical manifestations and associated diseases. METHODS: We performed a retrospective study in a series of 61 consecutive cryofibrinogenemia patients detected in our hospitals. RESULTS: In the 61 cryofibrinogenaemia patients, 18 had essential cryofibrinogenaemia and 43 secondary cryofibrinogaemia. Five out of the 18 patients with primary cryofibrinogaemia (27%) developed lymphoma after a 5-yr follow-up period. The main manifestations were cutaneous, and there were no differences in clinical presentation and disease severity in both types of cryofibrinogenaemia. A small number of patients (six) had cryofibrinogenaemia associated with cryoglobulinaemia, and in two cases, hepatitis C virus infection was detected; but no differences were observed between these two groups of patients. CONCLUSION: Cryofibrinogenaemia was found in our study with a high prevalence, suggesting that this pathology is rather underestimated. Our data further suggests that these patients should have a regular follow-up because of the high risk of symptom recurrence. We also hypothesize that in some cases essential cryofibrinogenaemia might be a prerequisite for a secondary disease.
Subject(s)
Cryoglobulinemia/drug therapy , Cryoglobulins/analysis , Fibrinogens, Abnormal/analysis , Adult , Aged , Cryoglobulinemia/complications , Cryoglobulinemia/epidemiology , Female , France/epidemiology , Hepatitis C/diagnosis , Humans , Infections/complications , Lymphoma/blood , Lymphoma/epidemiology , Male , Middle Aged , Retrospective Studies , Treatment OutcomeABSTRACT
The aim of our study was (i) to compare the clinical and biological characteristics of 148 (137 women, 11 men) primary Sjögren's syndrome (pSS) patients at diagnosis as a function of their sex and (ii) to assess the prognostic value of anti-calpastatin and anti-alpha-fodrin autoantibodies. In addition, the presence of anti-nuclear antibodies (ANA), anti-52- and 60-kDa Sjögren's syndrome A (SSA), anti-Sjögren's syndrome B (SSB), anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factors (RF) of IgA, IgG and IgM isotypes was sought in sera collected at pSS onset. Raynaud's syndrome, significantly more frequent in women, was the only systemic manifestation of pSS whose frequency differed significantly as a function of the patient's sex (P = 0.02). ANA (P = 0.001) and anti-60-kDa SSA autoantibodies (P = 0.03) were significantly more common in women, while men never synthesized detectable levels of anti-SSB, anti-calpastatin or IgG anti-alpha-fodrin autoantibodies. In addition, anti-CCP autoantibodies were found in low percentages of pSS patients (4% F/18% M). The absence of autoantibodies does not exclude the diagnosis of pSS in men that will be based mainly on the anatomopathological findings of a minor salivary gland biopsy. Positivity of anti-60-kDa SSA, anti-SSB, anti-calpastatin, IgA and IgG anti-alpha-fodrin antibodies is not associated with pSS clinical and biological severity.
Subject(s)
Autoantibodies/blood , Sjogren's Syndrome/immunology , Autoantigens/immunology , Biomarkers/blood , Calcium-Binding Proteins/immunology , Carrier Proteins/immunology , Female , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Male , Microfilament Proteins/immunology , Middle Aged , Prognosis , Retrospective Studies , Ribonucleoproteins/immunology , Severity of Illness Index , Sex Factors , Sjogren's Syndrome/diagnosis , SS-B AntigenABSTRACT
OBJECTIVES: To identify biochemical, immunological and bone markers as predictors of rheumatoid arthritis (RA) patients' responses to infliximab. METHODS: A total of 76 patients with active RA (American College of Rheumatology criteria), refractory to disease-modifying anti-rheumatic drugs, including methotrexate, received infliximab (3 mg/kg) infusions at weeks 0, 2, 6, and then every 8 weeks in combination with methotrexate or leflunomide. At week 14, infliximab efficacy was evaluated using disease activity score (DAS)28. A serum sample, collected just before starting infliximab, was tested by ELISA (unless stated otherwise) for the following immunological markers: rheumatoid factor by agglutination and ELISA (IgA, IgG and IgM isotypes); anti-cyclic citrullinated protein; autoantibodies recognizing calpastatin domain I and its 27 C-terminal fragment, glucose-6-phosphate isomerase, alpha-enolase; anti-keratin and anti-perinuclear factor antibodies (immunofluorescence); biochemical markers: C-reactive protein (nephelometry), metalloproteinase-1 and -3, tissue inhibitors of metalloproteinases-1 and -2, antioxidants (vitamins A and E; selenium); bone resorption markers: pyridinoline, deoxypyridinoline, osteoprotegerin, soluble receptor activator of nuclear factor-kappaB ligand, cartilage oligomeric matrix protein. Each parameter's predictive value of the response to infliximab was analysed using Fisher's exact, Mann-Whitney and chi-square tests. Hierarchical clustering was performed with The Institute for Genomic Research (TIGR) multiple experiment viewer software. RESULTS: Good, moderate and non-responder rates were 6.5, 61.8 and 31.5%, respectively. No significant difference was observed between responders and non-responders, regardless of the serum parameters considered. Analysis of dichotomous or continuous variables failed to identify markers predictive of a good or poor response to infliximab. CONCLUSION: The search for soluble markers in RA patients' sera likely to predict response to infliximab because of their involvement in RA pathogenesis seems disappointing. However, because of the limited power to detect smaller differences in biomarkers, the present study is a preliminary exploratory analysis.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Biomarkers/blood , Adult , Aged , Arthritis, Rheumatoid/blood , Autoantibodies/blood , Bone Resorption , Drug Therapy, Combination , Enzyme-Linked Immunosorbent Assay/methods , Female , Humans , Infliximab , Isoxazoles/therapeutic use , Leflunomide , Male , Metalloproteases/blood , Methotrexate/therapeutic use , Middle Aged , Prognosis , Prospective Studies , Rheumatoid Factor/blood , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
In the systemic autoimmune/inflammatory lupus erythematosus disease, the involvement of the central nervous system is well recognized and frequently includes deficits in neurological function, cognition, and affect. The (NZW x BXSB)F1 lupus-prone mice are model of this pathology, in which a gene located on the Y chromosome provokes a sex specific morbidity in males. The present study examines whether autoimmune (NZW x BXSB)F1 mice develop impairments in learning and memory that correlate with severity of lupus-like disease. For this purpose, spatial and motor abilities were evaluated in 6- and 20-week-old male and female mice, and the immune status of these behaviorally tested mice was assessed by the presence of anti-nuclear antibodies (ANAbs) in the serum. The results showed that none of the animals had motor skill and motor learning disabilities, but that the older males were greatly impaired in their spatial abilities while the young ones and the females, whatever their age, were not. Besides, the ANAbs levels were similar and low in the young males, the young females and the old females, and very much higher in the old males, showing that spatial alterations were correlated to the anti-nuclear antibodies level.
Subject(s)
Lupus Erythematosus, Systemic/immunology , Motor Skills/physiology , Reaction Time/immunology , Space Perception/physiology , Analysis of Variance , Animals , Antibodies, Antinuclear/blood , Brain/immunology , Brain/pathology , Escape Reaction/physiology , Female , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/physiopathology , Male , Maze Learning/physiology , Mice , Mice, Mutant Strains , Reaction Time/genetics , Rotarod Performance Test , Sex Factors , Spatial Behavior/physiology , Statistics as Topic , Transfer, Psychology/physiology , Y Chromosome/geneticsABSTRACT
Brain-reactive auto-antibodies appear as key elements in the progressive CNS disturbances associated with systemic lupus erythematosus. The BxSB lupus prone mice are a model of this pathology, in which a gene located on the Y chromosome provokes a sex specific morbidity in males. This study was aimed to establish and characterize the relationships between behavioral disorders, neurological deficiencies and the aged-related immunological perturbations in this murine model. For this purpose, spatial and motor abilities were evaluated in male and female mice at six and 26 weeks of age. The results showed that the older males were greatly altered in their spatial abilities while the young ones and the females, whatever their age, were not. None of the animals had motor skill and motor learning disabilities. These spatial alterations were associated with modifications of basal neuronal activity measured by the cytochrome oxidase histochemical method in several areas directly or indirectly involved in spatial behavior, such as the hippocampus, the amygdala, the parietal and perirhinal cortex. Immunological study allowed us to correlate the behavioral abnormalities to the appearance of antibodies reactivities against cellular and nuclear components.