RESUMO
The endothelial cell adhesion molecule, CD146, is expressed on ≈ 2% of normal circulating T cells, correlating with T cell activation, endothelial interactions and T helper type 17 (Th17) effector functions. In this study, we have characterized CD146 expression in circulating T cells from healthy controls and patients with stable, well-controlled autoimmune connective tissue diseases (CTDs). In vitro, anti-CD3/anti-CD28 stimulation induced CD146 expression in both CD4 and CD8 T cells. In healthy controls and CTD patients, CD146 was associated with expression of recent and chronic activation markers (CD25(+), OX-40(+), CD69(+), CD27(-)) and was confined to CD45RO(+)/RA(-)/CD28(+) populations within the CD4 subset. Except for CD69, these markers were not associated with CD146 in the CD8 subset. Surprisingly, most CTD patients exhibited no T cell hyperactivation ex vivo. In five of five patients with secondary Sjögren's syndrome circulating T cells appeared activated despite therapy, and CD146 up-regulation, associated with activation markers, was observed both on CD4 and CD8 T cells. There was no association between CD146 and putative pro-atherogenic T cell subsets. In conclusion, the relationship of CD146 expression to T cell activation differs between T cell subsets in healthy subjects and correlates with systemic hyperactivity, where present, in patients with CTDs, as exemplified by the patients with secondary Sjögren's syndrome in this study.
Assuntos
Doenças do Tecido Conjuntivo/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Aterosclerose/imunologia , Aterosclerose/patologia , Antígeno CD146/biossíntese , Antígeno CD146/sangue , Doenças do Tecido Conjuntivo/metabolismo , Doenças do Tecido Conjuntivo/patologia , Feminino , Humanos , Imunofenotipagem , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Adulto JovemRESUMO
Antigen-specific B and T cell responses against myelin basic protein, as well as responses against beta-islet-cells or joint tissue, are commonly found both in patients with autoimmune disease and in normal control subjects with disease-associated HLA-DR/DQ alleles. Thus, autoreactive immune responses are not disease-specific; however, the presence of certain autoantibodies may have prognostic value and may aid in disease management.
Assuntos
Autoantígenos/imunologia , Animais , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Humanos , PrognósticoRESUMO
Eosinophilic myositis is a rare entity accompanying parasitic infection or other inflammatory disorders. Two cases are reported in which myalgia and eosinophilic infiltration of muscle occurred in the absence of associated disease, and twelve previously published cases of idiopathic eosinophilic myositis are reviewed. A classification system for idiopathic eosinophilic muscle disease is proposed, describing three distinct groups. Comparisons are drawn between these and other causes of eosinophilic muscle disease, outlining the differential diagnoses for each group.
Assuntos
Eosinofilia/patologia , Miosite/patologia , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Miosite/classificação , Miosite/diagnósticoRESUMO
We examined HLA-DR genotype risk in 288 patients with rheumatoid arthritis who were carefully categorized for disease severity. Five hundred ethnically-matched bone-marrow donors were controls. A hierarchy of positive allelic associations was noted with DRB1*0401 (p < 10(-38), *0404,8 (p < 10(-43), *0405 (p < 10(-8), *10 (p < 10(-3) and *0101,2 (p < 10(-2), while DRB1*0403 was negatively associated (p = 0.02). The DRB1 genotype relative risks (and 95% CIs) for RA were: *0404,5,8/*0404,5,8 = 36.2 (15-87), *0401/*0404,5,8 = 31.3 (18-55), *401/*0401 = 18.8 (11-35), *0101,2/*0404,5,8 = 6.0 (2-14), *0101,2/*0401 = 6.4 (3-12), *0101,2/*0101,2 = 1.3 (0.3-6), *10/*0404,5,8 = 27.8 (5-148), *10/*0401 = 20.8 (5-89), *10/*0101,2 = 22.3 (5-96), *0404,5,8/DRX = 5.0 (3-8), *0401/DRX = 4.7 (3-7), *0101,2/DRX = 2.3 (1.4-4), *10/DRX = 3.4 (0.8-14). No significant correlation of DRB1 genotypes was found with severity of RA as judged by nodules or articular erosions.
Assuntos
Artrite Reumatoide/genética , Antígeno HLA-DR1/genética , Artrite Reumatoide/patologia , Mapeamento Cromossômico , Suscetibilidade a Doenças , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Conformacional de Fita Simples , Estudos Prospectivos , RiscoRESUMO
OBJECTIVE: To study the association between coxsackie B virus infection and the postviral fatigue syndrome and to assess the immunological abnormalities associated with the syndrome. DESIGN: Case-control study of patients with the postviral fatigue syndrome referred by local general practitioners over one year. SETTING: General practitioner referrals in Dunbartonshire, Scotland. PATIENTS: 254 Patients referred with the postviral fatigue syndrome (exhaustion, myalgia, and other symptoms referable to postviral fatigue syndrome of fairly recent onset--that is, several months) and age and sex matched controls obtained from same general practitioner; 11 patients were rejected because of wrong diagnoses, resolution of symptoms, and refusal to participate, leaving 243 patients and matched controls. MAIN OUTCOME MEASURES: Detailed questionnaire (patients and controls) and clinical examination (patients) and blind analysis of blood sample at entry and after six months for determination of coxsackie B virus IgM and IgG antibodies and other variables (including lymphocyte protein synthesis, lymphocyte subsets, and immune complexes). RESULTS: Percentage positive rates for coxsackie B virus IgM at entry were 24.4% for patients and 22.6% for controls and for coxsackie B virus IgG 56.2% and 55.3% respectively; there were no significant differences between different categories of patients according to clinical likelihood of the syndrome nor any predictive value in a fourfold rise or fall in the coxsackie B virus IgG titre in patients between entry and review at six months. The rates of positive antibody test results in patients and controls showed a strong seasonal variation. Of the numerous immunological tests performed, only a few detected significant abnormalities; in particular the mean value for immune complex concentration was much higher in 35 patients and 35 controls compared with the normal range and mean value for total IgM was also raised in 227 patients and 35 controls compared with the normal range. CONCLUSIONS: Serological tests available for detecting coxsackie B virus antibodies do not help diagnose the postviral fatigue syndrome. Percentage positive rates of the antibodies in patients simply reflect the background in the population as probably do the raised concentrations of total IgM and immune complexes.
Assuntos
Anticorpos Antivirais/análise , Enterovirus Humano B/imunologia , Síndrome de Fadiga Crônica/diagnóstico , Adulto , Complexo Antígeno-Anticorpo/análise , Estudos de Casos e Controles , Infecções por Coxsackievirus/diagnóstico , Síndrome de Fadiga Crônica/imunologia , Feminino , Humanos , Imunoglobulina G/análise , Imunoglobulina M/análise , MasculinoAssuntos
Infecções por Escherichia coli/complicações , Hidrocefalia/complicações , Meningites Bacterianas/complicações , Osteomielite/complicações , Estreitamento Uretral/complicações , Idoso , Cateterismo , Cefuroxima/uso terapêutico , Ciprofloxacina/uso terapêutico , Humanos , Hidrocefalia/tratamento farmacológico , Masculino , Meningites Bacterianas/tratamento farmacológico , Osteomielite/tratamento farmacológico , Estreitamento Uretral/terapiaRESUMO
Inflammatory rheumatic diseases are associated with a substantial increase in accelerated atherosclerosis, with complex interactions between traditional and disease-related risk factors. Therefore, cardiovascular risk reduction should be considered as integral to the control of disease activity in the care plans of patients with RA, SLE and, arguably any chronic inflammatory disease. Shared care structures, already established for the monitoring of DMARDs, could be adapted to communicate and monitor cardiovascular risk reduction objectives. We review the evidence for the efficacy of a range of therapeutic strategies, the majority of which impact on both disease activity and cardiovascular risk. The algorithm proposed here attempts to distil the latest advice from specialist panels at the National Cholesterol Education Program and the British Hypertension Society, as well as incorporating the existing data on SLE and RA patients. The algorithm is structured to minimize clinic time and resources necessary to stratify patients into groups for ROUTINE, SUBSTANTIAL or INTENSIVE risk management; the associated table summarizes optimal therapeutic objectives in each of these groups. The implication of this algorithm is that management of cardiovascular risk should be much more aggressive than is currently the norm in patients with chronic inflammatory diseases, such as RA and SLE. Long-term studies of such interventions are needed to further clarify the benefits of intensive cardiovascular risk management in these patients.
Assuntos
Antirreumáticos/uso terapêutico , Aterosclerose/etiologia , Doenças Reumáticas/complicações , Algoritmos , Artrite Reumatoide/complicações , Aterosclerose/prevenção & controle , Humanos , Lúpus Eritematoso Sistêmico/complicações , Doenças Reumáticas/tratamento farmacológicoRESUMO
OBJECTIVES: In addition to its vasoactive effects, angiotensin II has proinflammatory properties. Angiotensin-converting enzyme (ACE) inhibitors reduce the production of angiotensin II and could therefore act as anti-inflammatory agents. Here we investigated the capacity of the ACE inhibitor quinapril to modulate inflammatory arthritis. METHODS: We studied the effect of quinapril on disease activity in mice with collagen-induced arthritis (CIA). Mice received oral quinapril (10 mg/kg/day) at the time of arthritis induction (prophylaxis protocol) or at the onset of mild arthritis (therapy protocol). Concentrations of immunoglobulin G (IgG) subtypes specific for bovine Type II collagen and TNF-alpha were measured by enzyme-linked immunoassay. RESULTS: Quinapril significantly diminished the activity of CIA when given as prophylaxis or therapy (prophylaxis protocol, P<0.001; therapy protocol P=0.002). Antigen-specific IgG2a antibodies were reduced by 52% (P=0.02) in the quinapril prophylaxis protocol. Suppression of arthritis by quinapril was associated with reduced articular expression of TNF-alpha by 68% (P=0.01) in the prophylaxis protocol and 27% (P=0.06) in the therapy protocol. Quinapril therapy also inhibited expression of splenocyte TNF-alpha production following lipopolysaccharide (LPS) in vitro stimulation by 59% (P=0.02). In parallel human in vitro experiments, ACE inhibition suppressed LPS-stimulated production of TNF-alpha by monocytes. In order to confirm that the action of quinapril occurred predominantly through suppression of angiotensin II, parallel experiments with the angiotensin receptor antagonist candesartan cilexetil demonstrated that this agent also inhibited disease activity in CIA. CONCLUSIONS: These data suggest that angiotensin II is a mediator of chronic inflammation and that ACE inhibition may have therapeutic effects in human inflammatory arthritis.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Artrite Experimental/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Artrite Experimental/enzimologia , Artrite Experimental/imunologia , Artrite Experimental/prevenção & controle , Colágeno Tipo II/imunologia , Citocinas/biossíntese , Epitopos , Imunoglobulina G/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos DBA , Monócitos/imunologia , Peptidil Dipeptidase A/sangue , Quinapril , Fator de Necrose Tumoral alfa/biossínteseRESUMO
OBJECTIVE: To investigate the effect of CD25+ or CTLA-4(+) cell depletion on the natural history of collagen-induced and spontaneous arthritis in male DBA1/J mice. METHODS: Male DBA/1J mice were treated with anti-CD25 depleting antibody (PC61) or isotype control (GL113), or with anti-CTLA-4 depleting antibody (4F10) at various time-points peri- and post-immunization with bovine collagen type II, emulsified in adjuvant. In order to develop a model system in which long-term depletion of CD25+ regulatory T cells can be achieved prior to immunization, adult male DBA/1J mice were thymectomized prior to administration of either PC61 or GL113. An ELISA demonstrated that PC61 and GL113 antibodies were undetectable by 21 days after administration and FACS analysis confirmed the long-term depletion of CD25+ cells in peripheral blood. RESULTS: In the thymectomized mice treated with PC61, the CD25+ population was depleted and a spontaneous arthritis developed (P = 0.03). In the non-thymectomized mice, administration of CTLA-4-depleting antibody prior to immunization exacerbated arthritis in mice immunized with bovine collagen type II emulsified in incomplete Freund's adjuvant (P < 0.01). However, no significant difference in the natural history of arthritis was evident in mice treated with CD25-depleting antibody (PC61) compared with control antibody (GL113). CONCLUSIONS: Two separate models implicate CD25+ CTLA-4(+) constitutive cells in suppression of arthritis in susceptible DBA/1 males: exacerbation of collagen-induced arthritis following CTLA-4 depletion at the start of induction and spontaneous arthritis in the thymectomy/CD25+ depletion model.
Assuntos
Artrite/imunologia , Dermatite/imunologia , Receptores de Interleucina-2/imunologia , Animais , Antígenos CD , Antígenos de Diferenciação/imunologia , Área Sob a Curva , Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4 , Colágeno/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Adjuvante de Freund/imunologia , Imunoglobulina G/sangue , Imunossupressores/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Camundongos Nus , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To compare the TCR beta repertoire of peripheral blood CD8 enriched (CD8+) and depleted (CD8-) T cells in rheumatoid arthritis (RA) patients and controls using CDR3 length analysis (spectratyping). METHODS: CD8+ and CD8- T cells were separated from 14 RA patients and 12 controls, using magnetic beads coated with anti-CD8 monoclonal antibodies. cDNA was prepared as the template for amplification with 22 V beta-C beta primer pairs. The products were resolved by electrophoresis in an ABI373 sequencer using GENESCAN software. Expansions were identified as dominant CDR3 lengths, where the area underlying the corresponding peak exceeded the sum of the areas of the two adjacent peaks. This method was validated by sequencing 10 samples displaying dominant peaks. The expansion frequencies in RA patients and controls were compared using the chi 2 test statistic. RESULTS: Dominant peaks were evident in several V beta families. They were more frequent in RA patients in both the CD8+ subset (RA normalised frequency 10.6; control normalised frequency 8.0; p = 0.03) and the CD8- subset (RA normalised frequency 2.9; control normalised frequency 1.5; p = 0.02). Sequencing of 10 samples exhibiting dominant peaks revealed an unequivocal clonal expansion in nine (90%). CONCLUSIONS: RA patients exhibited a significantly increased frequency of T cell expansions both in the CD8+ and CD8- subsets. This phenomenon may reflect the proliferation of autoreactive cells, a nonspecific expansion of memory T cells in response to pro-inflammatory cytokines or a defect of T cell regulation that predates the onset of RA and may itself predipose to disease.
Assuntos
Artrite Reumatoide/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/sangue , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Sequência de Aminoácidos , Linfócitos T CD8-Positivos/imunologia , Divisão Celular/imunologia , Células Clonais/imunologia , Feminino , Antígenos HLA-DR/análise , Cadeias HLA-DRB1 , Humanos , Região Variável de Imunoglobulina/química , Masculino , Pessoa de Meia-Idade , Dados de Sequência MolecularRESUMO
Oligoclonal or clonal T-cell expansions, presumed to be antigen driven, are frequently sought and followed for diagnostic and prognostic purposes, as well as to understand more about their natural history. Techniques based on conservation of T-cell receptor CDR3 length are increasingly widely used, often without assessment of sensitivity or specificity. We present a comparative evaluation of a novel modified heteroduplex technique and a CDR3-length-based assay. Dilution of a known clone in a mixed T-cell population shows that in our hands the heteroduplex technique is at least 10-fold more sensitive than the CDR3-length-based assay. However, even with this level of sensitivity, we do not detect clonal expansions in unstimulated CD4+ T cells. This contrasts with the frequent detection of CD8+ clones in fresh samples and suggests different mechanisms of clonal homeostasis in the two subsets. We show that both techniques detect functional expansions after in vitro stimulation with a recall antigen. The distinct molecular footprint seen with the heteroduplex technique allows reproducible follow up of specific clonal expansions. We have exploited this to demonstrate that the repertoire of clones expanded by in vitro tetanus toxoid stimulation shows stability within an individual, implying long-term maintenance of multiple CD4+ clones.
Assuntos
Complexo CD3/análise , Linfócitos T CD4-Positivos/imunologia , Receptores de Antígenos de Linfócitos T/análise , Células Clonais , Humanos , Células Jurkat , Ativação Linfocitária , Ácidos Nucleicos Heteroduplexes , Fito-Hemaglutininas/farmacologia , Reação em Cadeia da Polimerase , Receptores de Antígenos de Linfócitos T/genética , Sensibilidade e Especificidade , Superantígenos/farmacologia , Toxoide Tetânico/farmacologiaRESUMO
It is hypothesized that autoimmune diseases manifest when tolerance to self-Ags fails. One possible mechanism to break tolerance is presentation of self-Ag in an altered form. Most Ags are presented by APCs via the traditional presentation pathway that includes "epitope editing" by intracellular HLA-DM, a molecule that selects for stable MHC-peptide complexes. We were interested in testing the hypothesis that autoreactive MHC-peptide complexes may reach the cell surface by an alternate pathway without being edited by HLA-DM. We selected a cartilage autoantigen human cartilage glycoprotein 39 to which T cell responses are observed in rheumatoid arthritis (RA) patients and some DR(*)04 healthy subjects. RA is genetically associated with certain DRB1 alleles, including DRB1(*)0401 but closely related allele DRB1(*)0402 is either neutral or mildly protective with respect to RA. We generated human B lymphoblastoid cell line cells expressing DR(*)0401 or DR(*)0402 in the presence or absence of intracellular HLA-DM and assessed their ability to present a candidate autoantigen, human cartilage glycoprotein 39. Our results show that the presence of intracellular HLA-DM is critical for presentation of this autoantigen to CD4(+) T cell hybridomas generated from DR(*)04-transgenic mice. Presentation of an autoantigen by the traditional HLA-DM-dependent pathway has implications for Ag presentation events in RA.
Assuntos
Apresentação de Antígeno , Autoantígenos/metabolismo , Linfócitos B/metabolismo , Epitopos de Linfócito B/metabolismo , Glicoproteínas/imunologia , Antígenos HLA-D/fisiologia , Adipocinas , Animais , Apresentação de Antígeno/genética , Linfócitos B/imunologia , Cartilagem Articular/imunologia , Cartilagem Articular/metabolismo , Linhagem Celular Transformada , Proteína 1 Semelhante à Quitinase-3 , Glicoproteínas/metabolismo , Antígenos HLA-D/biossíntese , Antígenos HLA-D/genética , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Hibridomas , Lectinas , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , TransfecçãoRESUMO
OBJECTIVE: To examine whether the T cell receptor (TCR) A or TCRB loci exhibit linkage with disease in multiplex rheumatoid arthritis (RA) families. METHODS: A linkage study was performed in 184 RA families from the UK Arthritis and Rheumatism Council Repository, each containing at least 1 affected sibpair. The microsatellites D14S50, TCRA, and D14S64 spanning the TCRA locus and D7S509, Vbeta6.7, and D7S688 spanning the TCRB locus were used as DNA markers. The subjects were genotyped using a semiautomated polymerase chain reaction-based method. Two-point and multipoint linkage analyses were performed. RESULTS: Nonparametric single-marker likelihood odds (LOD) scores were 0.49 (P = 0.07) for D14S50, 0.65 (P = 0.04) for TCRA, 0.07 (P = 0.29) for D14S64, 0.01 (P = 0.43) for D7S509, 0.0 (P = 0.50) for Vbeta6.7, and 0.0 (P = 0.50) for D7S688. By multipoint analysis, there was no evidence of linkage at TCRB (LOD score 0), and the maximum LOD score at the TCRA locus was 0.37 (at D14S50). The presence of a susceptibility locus (LOD score < -2.0) was excluded, with lambda > or = 1.8 at TCRA and > or = 1.4 at TCRB. CONCLUSION: These linkage studies provide no significant evidence of a major germline-encoded TCRA or TCRB component of susceptibility to RA.
Assuntos
Artrite Reumatoide/genética , Mapeamento Cromossômico , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Ligação Genética , Alelos , Humanos , Escore Lod , Repetições de MicrossatélitesRESUMO
This review examines the field of current HLA class II transgenic mouse models and the individual approaches applied in production of these mice. The majority of these mice have been created with the objective of obtaining a disease model with clinical features mimicking human autoimmune disease. The development process of a different type of HLA class II transgenic mice, which are designed to function as a substitute for a normal human immune system in studies of human autoantigens, is described. Several HLA-DR4 transgenic lines with normally expressed HLA-DR4 molecules have been produced. To obtain adequate positive selection of the HLA-DR4-restricted CD4+ T-cell repertoire in these mice it is essential both to introduce a human CD4 transgene, and to delete the murine major histocompatibility complex (MHC) class II molecules. These HLA-DR4 transgenic mice have been used to determine the immunogenic CD4+ T-cell epitopes of several human autoantigenic proteins.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígeno HLA-DR4/genética , Camundongos Transgênicos/genética , Camundongos Transgênicos/imunologia , Animais , Autoantígenos/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Modelos Animais de Doenças , Antígeno HLA-DR4/metabolismo , Humanos , Camundongos , Modelos BiológicosRESUMO
Major depressive disorder and dysthymia are twice as prevalent in women as in men, and the lifetime risk of a woman's developing a major depressive disorder is about 20%. Yet depression is often unrecognized or misdiagnosed in women, and only about one quarter of women who meet criteria for major depressive disorder receive appropriate therapy. Until recently, women were generally excluded from clinical drug trials because of concerns of inadvertent pregnancy and risk of teratogenicity. Thus, information on safety and efficacy in those most likely to require antidepressant therapy is lacking. Studies have shown that the antidepressant fluoxetine, a selective serotonin reuptake inhibitor (SSRI) has a more tolerable side effect profile than do tricyclic amine (TCA) antidepressants, but few data have been reported on the efficacy and tolerability of fluoxetine or other SSRIs in female patients. In this study, a retrospective analysis of 11 randomized, double-blind, well-controlled trials was done to compare data from 427 female patients on fluoxetine and 423 female patients on TCAs. Both fluoxetine and TCAs significantly reduced the HAMD17 total mean score from baseline to end point, week 5 (fluoxetine, 24.35 to 14.37; TCAs, 24.57 to 14.43; p < 0.001). Both treatment groups were associated with significant reductions in the HAMD17 anxiety/somatization and insomnia subfactor scores. Abnormal vision, constipation, dizziness, dry mouth, and somnolence occurred more frequently (p < 0.05) in the TCA group. Insomnia and nausea were the only adverse events more common (p < 0.05) in the fluoxetine group. This study demonstrates that fluoxetine is an effective and tolerable agent for the treatment of major depressive disorder in women.