The adjuvant monophosphoryl lipid A increases the function of antigen-presenting cells

The induction of immune responses in vivo is typically performed with antigens administered in external adjuvants, like alum, complete Freund's adjuvant, LPS and, more recently, monophosphoryl lipid A (MPL). However, the role of the adjuvant is still poorly defined. The aim of this study was to test whether the MPL affects the function of antigen-presenting cells (APC) in vitro and in vivo. Antigen-pulsed APC [including macrophages, B cells and dendritic cells (DC)] were incubated or not with MPL, and their ability to sensitize naive T cells was tested in vitro and in vivo. The data show that MPL enhances the ability of macrophages and B cells to sensitize naive T cells, and confers to them the capacity to induce the development of T(h)1 and T(h)2. Administration of MPL i.v. in mice results in the redistribution of fully mature DC in the T cell area of the spleen. These observations suggest that MPL may induce an antigen-specific primary immune response by provoking the migration and maturation of DC that are the physiological adjuvant of the immune system.     

Comprehensive Assessment of Pain in Juvenile Rheumatoid Arthritis: An Empirical Model

A comprehensive assessment model of variables hypothesized toinfluence pediatric pain perception was empirically investigatedin 23 families who had a child with juvenile rheumatoid arthritis.To determine the effects of family environment, child psychologicaladjustment, and disease parameters on child pain perception,a developmentally appropriate model was developed. Childrenbetween the ages of 5 and 15 were found to be reliable judgesof their pain intensity. Several family environmental and childpsychological factors were found to interact with specific diseaseparameters in determining pediatric pain perception and report.A multidimensional age-appropriate assessment model is suggestedfor use in the further examination of pediatric chronic andrecurrent pain.     

A Morphological and Immunohistochemical Study of Lymphoid Germinal Centers in Synovial and Lymph Node Tissues from Rheumatoid Arthritis Patients with Special Reference to Complement Components and Their Receptors

Rheumatoid arthritis (RA) is one of the immune complex (IC) diseases in which lymphoid germinal centers (GCs) are found in the synovial tissue. Simultaneously, patients with RA often show swelling of lymph nodes. The morphology and function of the lymph node GCs in patients with RA is not clear. The aim of this study was to evaluate the differences in morphology and immunoreactions to complement (C) components, their receptors, and lgM-rheumatoid factor (RF) between synovial GCs and lymph-node GCs in RA. Furthermore, the relationship between these immuno-reactive substances and follicular dendritic cells (FDCs) in GCs was investigated. The tissues examined were 41 RA synovial specimens, seven RA lymph nodes with massive lymphadenopathy, and 10 non-RA lymph nodes. The number of synovial GCs was relatively decreased in comparison with lymph-node GCs in RA, and the diameter of each synovial GC was smaller than that of each lymph-node GC. The synovial GCs were edematous and less cellular, and moreover, those from RF-seronegative cases were smaller than those from RF seropositive cases. On the other hand, the lymph-node GCs in RA were larger, more cellular and hyperplastic, but contained more tingible-body macro-phages (TBMs) and neutrophils. In the GCs of both synovial tissues and lymph nodes in RA, early C components (C1q, C4, C3c, C3d), IgM RF, and C3b receptor (C3bR) and C3d receptor (C3dR) were expressed as a lacy network by light microscopy, and were demonstrated on the surfaces of FDCs and lymphocytes, and in the intercellular spaces by electron microscopy. Furthermore, immuno-staining for dendritic reticulum cells (DRC, DAKO DRC1) was observed in a lacy pattern by light microscopy and on the cell surface of FDCs by electron microscopy. In the GCs of non-RA lymph nodes, early C components, C3bR, C3dR, and DRC showed a similar reaction pattern, but IgMRF did not. Consequently, no marked difference in immunoreactions in the GCs, except for the immunoreactions of late C components, was found between synovial tissues and lymph nodes in RA. On the basis of these findings, we discuss the possibility of the presence of a RF-IC.     

Heat shock protein 70 gene polymorphisms in rheumatoid arthritis

A role for heat shock proteins (hsp) in rheumatoid arthritis has been suggested. In addition, the specific binding of human HSP70 protein to QKRAA and RRRAA motifs within the HV3 region of disease-associated DRB1*0401 and DRB1*1001 molecules, respectively, has been proposed as being relevant to rheumatoid arthritis. The purpose of this work was to analyze the influence of HSP70 gene polymorphism on the susceptibility to or severity of rheumatoid arthritis and to investigate the possible contribution of these HSP70 polymorphisms in determining HLA-DRB1*0401/*1001 disease association. The frequencies of the HSP70-1, HSP70-2 and HSP70-hom genotypes were analyzed by PCR-RFLP using BsrBI , Pst I and Nco I enzymes, respectively, in patients with heumatoid arthritis and in healthy controls. No significant differences were observed when HSP70 alleled istribution between the groups under study were compared. Moreover, we did not observe any significant difference in HSP70 allele frequencies between patients positive for HLA-DRB1*0401/*1001 alleles and matched controls. Our data indicate that HSP70 gene polymorphisms do not appear to be relevant in the susceptibility to or severity of rheumatoid arthritis.     

Cytokine profile in systemic lupus erythematosus,rheumatoid arthritis,and other rheumatic diseases

We investigated serum levels of interleukin-6 (IL-6), interferon-gamma (IFN-), and tumor necrosis factor alpha (TNF) from patients with systemic lupus erythematosus (SLE) and its various clinical manifestations of disease and from patients with rheumatoid arthritis (RA) and other rheumatic diseases. The serum levels of IL-6 and IFN- were highly elevated from patients with SLE associated with lymphadenopathy (LN) or nephrotic syndrome (NS). On the contrary, the serum levels of TNF were elevated from most patients with SLE associated with thrombocytopenia (TP). However, serum levels of TNF were in the normal range from patients with SLE associated with NS, LN, or central nervous system disease. Of interest, patients with SLE associated with humoral immunodeficiency disorder, hypogammaglobulinemia, had highly elevated levels of serum IL-6. The concanavalin A-stimulated mononuclear cells (MNC) of patients with SLE associated with TP secreted highly elevated levels of TNF compared to other patient groups. We suggest that abnormal production of various cytokines in SLE is an intrinsic defect of MNC and the immune system that may be the key element for a variety of clinical manifestations of this disease.     

Analysis of depressed cell-mediated immunity in asbestos workers

To explore the mechanisms of asbestos-related perturbations of the immune system, we evaluated the in vitro cell-mediated immunity of five asymptomatic asbestos workers with hypergammaglobulinemia and decreased T-cell numbers. These results were compared with those in 10 matched controls. Analysis of T-lymphocyte populations revealed decreased absolute numbers of OKT4+ (helper/inducer) T cells in the peripheral blood and phytohemagglutinin (PHA)-stimulated mononuclear cell cultures of the workers. When chrysotile asbestos was added to PHA cultures, expansion of OKT4+ cell populations was disproportionately inhibited in workers' cultures. Furthermore, control proliferative responses to PHA became indistinguishable from initial worker responses. These effects were incompletely explained by the cytotoxic effects of asbestos on cultured lymphocytes. We conclude that both in vivo and in vitro exposure of mononuclear cell populations to asbestos may lead to a diminution of helper-inducer T-cell numbers. In asbestos-exposed individuals, this latter lymphocyte subpopulation appears to be especially sensitive to in vitro asbestos exposure. Although the clinical implications of these findings are unclear, we hypothesize that many of the immunologic abnormalities that occur in asbestos workers could be explained by direct asbestos effects on the OKT4+ immunoregulatory population.     

风湿性关节炎患者T细胞表达CCR5和CXCR3的三色流式细胞分析

目的 在单细胞水平上，研究类风湿性关节炎（RA）患者滑液及外周血中T淋巴细胞上CCR5及CXCR3的表达，并结合临床资料分析其在RA发病中的可能作用机制及临床应用。方法 分离15例RA患者的滑液单个核细胞（SFMC）、外周血单个核细胞（PBMC），及15正常人PBMC（对照），以三色荧光素标记物进行流式细胞术分析T细胞上CCR5及CXCR3的表达。结果 与PBMC相比较，RA患者SFMC中T细胞上CCR5及CXCR3的表达显著增高（特别是CCR5）；而CXCR3的表达个体差异较大；与正常人相比较，RA患者初发或活动期未治时，PBMC中CCR5及CXCR3的表达明显增多。CCR5及CXCR3的表达率与患者的ESR及CRP相关。结论 CCR5^ T细胞积聚在RA患者的病变关节内，且与RA的病情密切相关。     

类风湿性关节炎患者关节滑膜液浸润的T细胞表达特性

目的 :为研究类风湿性关节炎 (RA)患者关节滑膜液浸润的淋巴细胞介导自身免疫病的特性 ,分析了 2 2例RA患者滑膜液中淋巴细胞的免疫表型、对II型胶原的反应频率及IL 10、IL 12的分泌格局。方法 :用流式细胞术分别测定滑膜液和外周血淋巴细胞表型 ,并采用国际标准半有限稀释法分析了关节滑膜液中浸润的淋巴细胞对II型胶原 (CII)的反应频率 ,同时用ELISA方法检测了滑膜液与外周血中IL 10与IL 12含量。结果 :滑膜液中的T淋巴细胞的表型分别为CD4 (39 6 %±10 5 % )和CD8细胞 (36 4 %± 16 4 % ) ,CD4 CD8细胞比值显著低于外周血 ,且同时表达CD16和CD5 6的活化NK细胞占15 5 %± 11 1%。T细胞受体谱取用表明仍以αβTCR为主 (6 9 6 %± 15 7% )。有意义的是 :滑膜液中的T细胞对CII的反应频率为 15 2× 10 - 6 ,远远高于外周血 (4 0× 10 - 6 )。IL 12含量为 (4 19 9± 89 2 )pg ml,IL 10含量为 (187 7± 34 5 )pg ml,与外周血中这 2种细胞因子的含量〔分别为IL 12 :(6 5 32± 34 2 )pg ml和IL 10 :(85± 12 7)pg ml〕比较 ,具有显著的统计学差异。结论 :上述实验结果表明这种具有表达特性的浸润T细胞介导了RA患者关节滑膜组织的免疫损伤。     

Collagen-induced arthritis in TNF receptor-1-deficient mice: TNF receptor-2 can modulate arthritis in the absence of TNF receptor-1

TNF is a potent proinflammatory cytokine important for the development of arthritis in human and animals. We have investigated the roles of TNF receptor-1 (TNFR1) and TNF receptor-2 (TNFR2) in collagen-induced arthritis (CIA) by inducing CIA in mice genetically deficient in TNFR1. TNFR1-/- mice developed arthritis with similar incidence and severity as TNFR1+/- littermates, indicating that TNFR1 is redundant for the development of CIA. Anti-type II collagen (CII) antibody levels and T cell responses to CII did not differ between TNFR1-/- mice and controls. Neutralization of TNF with soluble TNF binding protein suppressed the development of arthritis in TNFR1+/- mice but not in TNFR1-/- mice, indicating that TNFR2 cannot substitute for TNFR1 for the proinflammatory function. To further investigate the functions of TNFR2, TNFR1-/- mice were injected with murine TNF-alpha at different stages during the course of CIA. Repeated TNF-alpha injection during the early induction phase enhanced the development of arthritis, but inhibited arthritis when administered during the late progression phase. These results show that the engagement of TNFR2 by TNF is involved in the development of CIA in the absence of TNFR1 and that opposing signals can be transduced by TNFR2.     

Recognition of a novel naturally processed, A2 restricted, HCV-NS4 epitope triggers IFN-gamma release in absence of detectable cytopathicity

Using short term CTL lines derived from HLA A2/K^b transgenic mice and IFN-gamma release assays we demonstrate that the NS4.1769 epitope, is generated from natural processing of the NS4 antigen, and presented in the context of the A2/K^b molecules. Interestingly, T cell recognition of the naturally processed form of the NS4.1769 epitope was associated with significant IFN-gamma release, but no direct cytolytic activity. Epitopes of this phenotype might be of interest, in terms of therapy of chronic HCV infection by associating the benefit of localized lymphokine release with low or absent direct cytopathicity.