RESUMO
Mixed cryoglobulinemic vasculitis is associated with the monoclonal expansion of pathognomonic B cells in chronic hepatitis C. Recently, treatment with B-cell depletion, including rituximab, a CD20 monoclonal antibody, has been successful in achieving remission from the active disease. We investigated whether B-cell depletion therapy has an impact on activation of non-B cells in the periphery. Results demonstrated that B-cell depletion therapy is associated with a statistically significant decline in activated T cells, from pretherapy to follow-up while on rituximab therapy: CD4+ CD38+ HLA-DR+ (DR+), CD8+ CD38, CD8+ CD38+ DR+, and CD8+ DR+. Birmingham Vasculitis Activity Score and cryoglobulin had a strong correlation coefficient (R) of 0.72 (P=.0005), while cryoglobulin showed moderate correlation with CD8+ DR+ (R=.61), CD3+ CD38+ DR+ (R=.57), CD3+ DR+ (R=.50), CD4+ CD38+ DR+ (R=.53), CD4+ DR+ (R=.52), and CD8+ CD38+ DR+ (R=.67). These results suggest B-cell expansion has a direct and indirect effect on the pathogenesis of Hepatitis C-associated mixed cryoglobulinemic vasculitis.
Assuntos
Crioglobulinemia/tratamento farmacológico , Hepatite C Crônica/complicações , Fatores Imunológicos/administração & dosagem , Ativação Linfocitária , Rituximab/administração & dosagem , Vasculite/tratamento farmacológico , Humanos , Fatores Imunológicos/efeitos adversos , Depleção Linfocítica , Rituximab/efeitos adversosRESUMO
Changes in CD4+ T-cell surface marker phenotype and antigen receptor (TCR) repertoire were examined during the course of HIV infection and following therapy. A preferential decline in naive CD4+ T cells was noted as disease progressed. Following protease inhibitor therapy, naive CD4+ T cells increased only if they were present before initiation of therapy. Disruptions of the CD4+ TCR repertoire were most prevalent in patients with the lowest CD4+ T-cell counts. Antiviral or IL-12 therapy-induced increases in CD4+ T-cell counts led to only minor changes in previously disrupted repertoires. Thus, CD4+ T-cell death mediated by HIV-1 infection may result in a preferential decline in the number of naive CD4+ T cells and disruptions of the CD4+ T-cell repertoire that are not immediately corrected by antiviral or immune-based therapies.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , Inibidores da Protease de HIV/uso terapêutico , Indinavir/uso terapêutico , Interleucina-2/uso terapêutico , Progressão da Doença , Infecções por HIV/tratamento farmacológico , Humanos , Antígenos Comuns de Leucócito/sangue , Fenótipo , RNA Mensageiro/sangue , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Gêmeos MonozigóticosRESUMO
In mice, the two distinct autosomal recessive genes lpr and gld can induce a syndrome characterized by autoantibody formation and the progressive accumulation of an unusual CD4-CD8- T cell population in peripheral lymphoid tissue. This phenotype does not precisely mirror any human disease. In this report we describe two patients with a progressive lymphoproliferative disorder associated with autoimmunity. The peripheral blood and lymph nodes of these patients contained large numbers of an unusual CD4-CD8- T cell population. These CD4-CD8- T cells express surface markers characteristic of mature peripheral blood T cells (CD3, CD2, CD5), express the alpha/beta form of the T cell receptor, and do not express surface markers characteristic of immature thymocytes (CD1) or NK cells (CD16, CD56). Functionally, these cells exhibited deficient proliferation and lymphokine production upon stimulation with mitogenic antibodies to CD3 or CD2. Both proliferation and lymphokine production could be augmented by co-stimulation with an antibody directed at the CD28 determinant. The clinical and immunological features of this syndrome resemble the lymphoproliferative/autoimmune disease seen in lpr and gld mice.
Assuntos
Doenças Autoimunes/imunologia , Transtornos Linfoproliferativos/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Doenças Autoimunes/patologia , Antígenos CD4/análise , Antígenos CD8/análise , Citometria de Fluxo , Humanos , Hipergamaglobulinemia/patologia , Interferon gama/biossíntese , Interleucina-2/biossíntese , Linfonodos/patologia , Ativação Linfocitária , Transtornos Linfoproliferativos/patologia , Camundongos , Camundongos Mutantes , Receptores de Antígenos de Linfócitos T alfa-beta/análiseRESUMO
AIM: To describe the clinical characteristics of orbital socket contracture in patients with Wegener's granulomatosis (WG). METHODS: A retrospective cohort study The medical records of 256 patients with WG examined at the National Institutes of Health from 1967 to 2004 were reviewed to identify patients with orbital socket contracture. Details of the orbital disease including Hertel exophthalmometry readings, radiological findings, and results of eye examinations were recorded. Orbital socket contracture was defined as orbital inflammation with proptosis followed by the development of enophthalmos and radiographic evidence of residual fibrotic changes in the orbit. To examine for risk factors in the development of a contracted orbit, patients with orbital socket contracture were compared to patients without contracture with respect to multiple variables including history of orbital surgery, orbital disease severity, and major organ system involvement. The main outcome measures were the clinical characteristics of orbital socket contracture associated with inflammatory orbital disease in patients with WG. RESULTS: Inflammatory orbital disease occurred in 34 of 256 (13%) patients and detailed clinical data on 18 patients were available and examined. Orbital socket contracture occurred during the clinical course in six patients; the features included restrictive ophthalmopathy (five), chronic orbital pain (three), and ischaemic optic nerve disease (two) resulting in blindness (no light perception) in one patient. The orbital socket contracture occurred within 3 months of treatment with immunosuppressive medications for inflammatory orbital disease in five patients and was not responsive to immunosuppressive medications. The median degree of enophthalmos in the contracted orbit compared with the fellow eye was 2.8 mm (range 1.5-3.5 mm) by Hertel exophthalmometry. There were no risk factors that predicted development of orbital socket contracture. CONCLUSIONS: In six patients with WG and active inflammatory orbital disease, orbital socket contracture occurred during the treatment course with systemic immunosuppressive medications. The orbital socket contracture, presumably caused by orbital fibrosis, led to enophthalmos, restrictive ophthalmopathy, chronic orbital pain, and optic nerve disease and was not responsive to immunosuppressive therapy. Orbital socket contracture has not been previously reported as a complication of inflammatory orbital disease associated with WG and was an important cause of visual morbidity in our cohort of patients.
Assuntos
Contratura/etiologia , Granulomatose com Poliangiite/complicações , Doenças Orbitárias/etiologia , Adolescente , Adulto , Contratura/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Orbitárias/diagnóstico por imagem , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
In order to study T cell regulation of B cell isotype differentiation we have developed a model system consisting of clonal populations of T and B cells. Using this system we have shown that the murine B cell lymphoma, 70Z/3, can be induced to express membrane IgG2b by exposure to a T cell hybridoma derived from the Peyer's patch (termed HAJ-3). The membrane bound IgG2b (mIgG2b) expression is associated with induction of gamma 2b-mRNA, but switch region rearrangement and C mu deletion does not occur. While LPS-stimulated 70Z/3 B cells also express considerable amounts of gamma 2b-mRNA they do not express detectable mIgG2b, indicating that T cell influence is necessary for the production of translatable gamma 2b-specific mRNA. Both the LPS and T cell induced gamma 2b mRNA transcripts lack VH sequences, implying that the surface IgG2b detected lacks a variable region. These findings lend support to a two step model of B cell isotype switching and provide evidence that T cells can regulate early events involved in B cell isotype differentiation.
Assuntos
Linfócitos B/imunologia , Cadeias Pesadas de Imunoglobulinas/biossíntese , Cadeias gama de Imunoglobulina/biossíntese , Linfócitos T/imunologia , Animais , Separação Celular , Deleção Cromossômica , Citometria de Fluxo , Hibridomas/imunologia , Regiões Constantes de Imunoglobulina/imunologia , Imunoglobulina G/biossíntese , Camundongos , Camundongos Endogâmicos , Polimorfismo de Fragmento de Restrição , RNA Mensageiro/biossíntese , Receptores de Antígenos de Linfócitos B/biossíntese , Células Tumorais Cultivadas/imunologiaRESUMO
Immunodeficiency with thymoma (Good syndrome, GS) is a rare, adult-onset condition that is characterized by thymoma, hypogammaglobulinemia, and low numbers of peripheral B cells. CD4+ T lymphopenia and an inverted CD4:CD8+ T-cell ratio may be present. Here we report 5 patients with GS and infectious complications who were seen at 3 institutions between 1983 and 1999. Three patients had recurrent sinopulmonary infections, 3 had severe cytomegalovirus (CMV) disease, and 1 had Pneumocystis carinii pneumonia. Review of the literature identified 46 other reports of infections in GS patients. The infections reported in all 51 patients included recurrent sinopulmonary infection (19 cases with documented respiratory pathogens), generally with encapsulated bacteria, most often Haemophilus influenzae (11 cases); CMV disease (5 cases); bacteremia (7 cases); oral or esophageal candidiasis (6 cases); persistent mucocutaneous candidiasis (5 cases); chronic diarrhea (5 cases with documented stool pathogens); urinary tract infections (4 cases); P. carinii pneumonia (3 cases); tuberculosis (2 cases); Kaposi sarcoma (1 case); disseminated varicella (1 case); candidemia (1 case); wound infection with Clostridium perfringens (1 case); Mycoplasma arthritis (1 case); and other infections. Patients with GS present with a spectrum of sinopulmonary infections and pathogens similar to common variable immunodeficiency (CVID). Compared with patients with CVID, opportunistic infections, including severe CMV disease, P. carinii pneumonia, and mucocutaneous candidiasis, appear to be more common in patients with GS, and patients with GS may have a worse prognosis. GS should be ruled out in patients with thymoma or CVID who develop severe, especially opportunistic, infections. Treatment with intravenous immune globulin is recommended for all patients with GS.
Assuntos
Agamaglobulinemia/complicações , Infecções Oportunistas/etiologia , Timoma/complicações , Neoplasias do Timo/complicações , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/etiologia , Agamaglobulinemia/terapia , Idoso , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/terapia , Recidiva , Timoma/diagnóstico , Timoma/terapia , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/terapia , Resultado do TratamentoRESUMO
We reviewed our experience with 30 nodal and extranodal lymphoid lesions from 17 patients with common variable immunodeficiency (CVID). Immunohistochemical studies were performed on biopsies from 15 patients, in situ hybridization for Epstein-Barr virus in nine cases, and gene rearrangement analysis on seven lesions. The biopsies were classified into four groups: malignant lymphoma (two cases); atypical lymphoid hyperplasia (eight cases); reactive lymphoid hyperplasia (14 cases); and chronic granulomatous inflammation (six cases). The two malignant lymphomas were diagnosed using histologic criteria; tissue was not available for the assessment of clonality. In one neoplasm, Epstein-Barr virus was identified in the tumor cells by in situ hybridization. The cases of reactive lymphoid hyperplasia and chronic granulomatous inflammation had no atypical architectural, cytologic, or immunohistochemical features. The cases of atypical lymphoid hyperplasia were of particular interest, as these patients had either widespread involvement or massive disease. The diagnosis of lymphoma was considered likely by the clinicians and, in three cases, the histologic slides were originally interpreted as malignant lymphoma by the referring pathologists. Although the architecture of these lesions appeared to be effaced on hematoxylin and eosin-stained sections, immunohistochemical analysis demonstrated preserved architecture with florid expansion of B-cell and T-cell compartments. In addition, clinical follow-up of these patients was benign, and gene rearrangement analysis in three lesions revealed no evidence of clonality. We conclude that the majority of lymphoid lesions in patients with CVID are benign. Immunohistochemical and gene rearrangement studies are particularly helpful in the assessment of cases of atypical lymphoid hyperplasia.
Assuntos
Imunodeficiência de Variável Comum/patologia , Linfonodos/patologia , Linfoma/patologia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Criança , Pré-Escolar , DNA Viral/análise , Feminino , Rearranjo Gênico , Herpesvirus Humano 4 , Humanos , Hiperplasia , Imuno-Histoquímica , Hibridização In Situ , Inflamação , Linfoma/tratamento farmacológico , Masculino , Pessoa de Meia-IdadeRESUMO
Among the immunomodulatory cytokines that have been evaluated for the treatment of HIV disease, alpha-interferon and interleukin-2 (IL-2) have been the most extensively studied. Monotherapy with alpha-interferon is effective therapy for HIV-associated Kaposi's sarcoma (KS) in patients with CD4 counts > 150 cells/mm3. However, the doses necessary to achieve a significant anti-tumor effect are often poorly tolerated. Combination therapy with alpha-interferon and zidovudine is associated with dose-limiting toxicities and an anti-tumor effect similar to that of higher dose alpha-interferon monotherapy. The combination of alpha-interferon and zidovudine can synergistically inhibit HIV replication in vitro; however, in vivo results suggest the anti-HIV effect of this combination is no greater than that seen with zidovudine monotherapy. Whether combination of interferon-alpha and other antiviral drugs will be useful in the treatment of HIV infection remains to be seen. Recent studies employing intermittent courses of IL-2 combined with continuous antiretroviral therapy indicate that sustained rises in CD4 counts can be achieved. The ability of IL-2 therapy to result in a sustained rise in CD4 counts is critically dependent on the pre-treatment CD4 count. The immunologic and clinical significance of these IL-2-induced increases in CD4 counts is unknown. Larger, controlled trials are currently underway to evaluate the role of intermittent IL-2 therapy in HIV infection.
Assuntos
Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Interferon-alfa/uso terapêutico , Interleucina-2/uso terapêutico , Zidovudina/uso terapêutico , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Antivirais/efeitos adversos , Contagem de Linfócito CD4 , Ensaios Clínicos como Assunto/estatística & dados numéricos , Quimioterapia Combinada , Humanos , Interferon-alfa/efeitos adversos , Interleucina-2/efeitos adversos , Sarcoma de Kaposi/tratamento farmacológico , Zidovudina/efeitos adversosRESUMO
Infection continues to be a significant cause of morbidity and mortality in patients with rheumatic diseases, and, consequently, early diagnosis and treatment of infection is critical to the successful medical management of these patients. The intensity of immunosuppressive therapy is the dominant risk factor for infection in this patient population. Because the manifestations of infection in patients with rheumatic diseases are highly variable, the clinician must always be vigilant about the possibility of infection even if the clinical presentation is highly suggestive of an exacerbation of the underlying disease. We have stressed a systematic and individualized approach in the diagnostic evaluation of suspected infection in these patients. The first part of the evaluation involves forming a list of the most likely pathogens based on a detailed history and physical examination and the intensity and type of immunosuppressive therapy the patient is receiving. The physician must then formulate a plan designed to establish a diagnosis expeditiously and with the least morbidity.
Assuntos
Doenças Transmissíveis/induzido quimicamente , Imunossupressores/efeitos adversos , Doenças Reumáticas/tratamento farmacológico , Doenças Transmissíveis/tratamento farmacológico , Doenças Transmissíveis/patologia , Glucocorticoides/efeitos adversos , Humanos , Sistema Imunitário/efeitos dos fármacos , Hospedeiro Imunocomprometido , Doenças Reumáticas/complicações , Doenças Reumáticas/mortalidadeRESUMO
Although GS and CYC have been important agents in improving the outcome and survival of patients with systemic vasculitis, they carry their own risk of drug-induced morbidity and mortality. It has also become apparent that these medications are not the final answer in disease management because some forms of vasculitis have the potential to relapse or be treatment resistant. For these reasons, the pursuit of effective, less toxic therapeutic alternatives is critical. Initial results from the use of MTX in systemic vasculitis have been encouraging. Although drug-related toxicity and disease relapse have still been found to occur, MTX appears to be a valuable addition in the treatment of vasculitis. Further studies will be necessary to determine the optimal way that this agent may be used to safely and effectively manage vasculitic disease.
Assuntos
Antirreumáticos/uso terapêutico , Arterite de Células Gigantes/tratamento farmacológico , Granulomatose com Poliangiite/tratamento farmacológico , Metotrexato/uso terapêutico , Arterite de Takayasu/tratamento farmacológico , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Estudos Prospectivos , Resultado do TratamentoRESUMO
We describe two cases of pituitary involvement by Wegener's granulomatosis. At initial presentation, or during subsequent disease "flares," a pattern of pituitary abnormality was suggested. During periods of remission, we found the pituitary returned to a nearly normal appearance. Loss of the normal posterior pituitary T1 hyper-intensity matched a clinical persistence of diabetes insipidus, suggesting there is permanent damage to this structure by the initial disease process.
Assuntos
Granulomatose com Poliangiite/patologia , Imageamento por Ressonância Magnética , Doenças da Hipófise/patologia , Adolescente , Adulto , Anti-Inflamatórios/uso terapêutico , Diabetes Insípido/patologia , Progressão da Doença , Feminino , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/fisiopatologia , Humanos , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Doenças da Hipófise/tratamento farmacológico , Doenças da Hipófise/fisiopatologia , Neuro-Hipófise/patologia , Prednisona/uso terapêutico , Indução de RemissãoRESUMO
The pathogenesis of vasculitis is complex and involves a variety of mechanisms acting in concert to bring about necrotizing inflammation of blood vessel walls. In recent years, there has been considerable progress in dissecting the immunologic abnormalities present in specific vasculitis syndromes. The primary immunopathogenic events that initiate the process of vascular inflammation and blood vessel damage, however, are still largely unknown. Although the cause of most vasculitis syndromes remains a mystery, advances in molecular and cellular immunology have defined many of the effector mechanisms that mediate inflammatory vascular damage. In this regard, modulation of the inflammatory response by specific cytokine and adhesion molecule antagonists is now possible and may prove beneficial in the treatment of vasculitis.
Assuntos
Vasculite/etiologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Complexo Antígeno-Anticorpo/imunologia , Autoanticorpos/imunologia , Vasos Sanguíneos/imunologia , Vasos Sanguíneos/patologia , Moléculas de Adesão Celular/imunologia , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Biologia Molecular , Necrose , Síndrome , Linfócitos T/imunologia , Vasculite/tratamento farmacológico , Vasculite/imunologia , Vasculite/patologiaRESUMO
Common variable immunodeficiency (CVI) is a heterogeneous immunodeficiency syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections, and a variety of immunological abnormalities. In addition to recurrent infections, patients with this syndrome also suffer from an increased incidence of autoimmune disease and malignancy. Because the spectrum of associated diseases is broad, patients with CVI are seen by a variety of medical specialists. In this review, the pathogenesis, clinical manifestations, diagnosis, and treatment of CVI are discussed.
Assuntos
Imunodeficiência de Variável Comum/fisiopatologia , Autoimunidade , Infecções Bacterianas/etiologia , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/epidemiologia , Imunodeficiência de Variável Comum/terapia , Europa (Continente)/etnologia , Doença Granulomatosa Crônica/etiologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Incidência , Transtornos Linfoproliferativos/etiologia , Recidiva , Estados Unidos/epidemiologia , População BrancaAssuntos
Linfócitos B/imunologia , Isotipos de Imunoglobulinas/fisiologia , Linfócitos T/fisiologia , Animais , Linfócitos B/citologia , Diferenciação Celular , Linhagem Celular , Genes de Imunoglobulinas , Cadeias Pesadas de Imunoglobulinas/genética , Nódulos Linfáticos Agregados/citologia , Nódulos Linfáticos Agregados/imunologiaRESUMO
Infection continues to be a major cause of morbidity and mortality in patients with systemic vasculitis. The recognition and treatment of infections in these patients is a particularly difficult task because the spectrum of potential pathogens is broad and the clinical manifestations of infection often mimic those of the underlying disease. This article provides 1) a general overview of the immunosuppressive properties of agents commonly used in the treatment of systemic vasculitis, and 2) a framework for the diagnostic evaluation and treatment of various infectious syndromes in patients with systemic vasculitis.
Assuntos
Infecções/etiologia , Infecções/terapia , Vasculite/complicações , Vasculite/terapia , Estudos de Avaliação como Assunto , Humanos , Imunossupressores/uso terapêutico , Controle de Infecções/métodos , Resultado do TratamentoRESUMO
Thy-1 exhibits marked differences in expression in various tissues in many species; therefore, it is of interest to define possible mechanisms that may regulate Thy-1 expression. We produced Thy-1 negative variants of the murine T cell lymphoma EL-4 by mutagenesis with ethylmethanesulfonate (EMS), negative selection with anti-Thy-1 monoclonal antibodies (mAb) plus complement, and fluorescence-activated cell sorting (FACS). Thy-1 surface negative (Thy-1-) mutants produced in this manner were shown to produce no detectable Thy-1 mRNA, but contained an intact Thy-1 gene as determined by Southern blotting. 5' CG sequences, which had been demethylated in the parent EL-4 clone, were completely methylated in the EMS-induced Thy-1-variant. In addition, a DNase I hypersensitive site that mapped to the 5' end of the Thy-1 gene in EL-4 was absent in the Thy-1- variant. Treatment of this Thy-1- clone with 5-azadeoxycytidine (5-dAZA) resulted in re-expression of surface Thy-1, demethylation of the 5' CG sequences, and regeneration of the DNase I hypersensitive site. These studies indicate that methylation of certain critical DNA sequences in the 5' region of the Thy-1 gene can alter local chromatin structure and regulate expression of this gene.
Assuntos
Antígenos de Superfície/biossíntese , Cromatina/ultraestrutura , DNA de Neoplasias/análise , Regulação da Expressão Gênica , Linfócitos T/metabolismo , 5-Metilcitosina , Animais , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Linhagem Celular , Citosina/análogos & derivados , Citosina/análise , Decitabina , Metanossulfonato de Etila/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Linfoma , Metilação , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/biossíntese , Linfócitos T/imunologia , Antígenos Thy-1RESUMO
The biochemistry and pharmacology of corticosteroids are reviewed as related to their clinical use, inclusive of head and neck disease. Complications and their management are discussed, as is a dosage regimen considered useful for most patients. Alternate-day corticosteroid therapy is stressed, especially in the long-term management of autoimmune and inflammatory disorders.