摘要:

We investigated the presence of nerve growth factor (NGF) autoantibodies and NGF in the synovial fluid (SF) of patients with different forms of chronic arthritis such as spondylarthropathy (SPA), rheumatoid arthritis (RA), calcium pyrophosphate dihydrate crystal deposition disease (CPPD) and osteoarthritis (OA) and compared them to their levels in serum. NGF autoantibodies were detected by ELISA and by their capacity to immunoprecipitate NGF and to inhibit its biological activity. NGF was measured with a two-site enzyme-linked immunosorbent assay. Significantly high NGF autoantibody levels (p<10−4) and high frequency of detectable NGF (p<0.01) were observed in the SF of SpA patients and to a lesser degree in RA patients as compared to CPPD and OA patients. In the serum high frequency of detectable NGF was observed only in RA patients. These results suggest a role of NGF autoantibodies and NGF in joint inflammation especially in spondylarthropathies.

ISSN:0891-6934    

DOI:10.3109/08916939608995352

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

The diversity of the immunoglobulin heavy (H) and light (L) gene libraries used to construct a combinatorial library is an important parameter in determining the characteristics of antigen-specific Fab obtained from the library. To investigate the role of library diversity, we compared Fab specific for the autoantigen thyroid peroxidase (TPO) isolated from two different combinatorial libraries. Both libraries contained the same H chain genes. The original combinatorial library (H/R) utilized kappa chains generated using a single kappa variable region oligonucleotide primer. We constructed a second combinatorial library (H/D) containing kappa chains amplified with a diverse panel of variable region primers. From the the original H/R library, only two groups of TPO-specific Fab had been obtained, involving two H chain types (V1-3B and hvlL1) but only one kappa chain type (012). In contrast, among the seven TPO Fab characterized from the second library (H/D) we observed five different VH/VL combinations, comprising three types of H chains (V1-3B, VH26 and DP7) and four types of kappa chains (O12, L12, L2/hv328H5 and B3). Besides differences in VH and VL genes, as well as VH/VL combinations, the new TPO Fab used different D regions and JH and JK elements. Nevertheless, the new kappa Fab resembled previously isolated TPO Fab in terms of their affinity for TPO (Kd~10−9M) and preferential recognition of conformationally intact autoantigen. In summary, our studies demonstrate that the diversity of the L chain library repertoire, while having little effect on immunological properties, has a major influence on the genes encoding antigen-specific Fab selected from a combinatorial library. For the successful isolation of rare but clinically important autoantibodies (such as to the TSH receptor) by the combinatorial library approach, library diversity is likely to be a major factor.

ISSN:0891-6934    

DOI:10.3109/08916939608995353

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

By virtue of their functional antagonism, Thl cells or cells producing the same cytokines as Thl cells may behave as 'suppressor cells' with respect to Th2 cells and vice versa. An excessive Th1- or Th2-like response may favor the development of different autoimmune diseases. As can be expected from their physiological role, Th-1 cytokines participate in autoimmune diseases with a preferential delayed type hyper-sensitivity component, i.e. in those diseases in which cytotoxic T cells attack organ-specific target cells. Autoimmune diseases with a predominant Thl component include experimental autoimmune encephalitis and insulin-dependent diabetes mellitus. In contrast, Th2-type responses participate in systemic autoimmune diseases with a strong humoral component. Such diseases probably include certain drug-induced states of autoaggression, namely mercury-induced autoimmune disease and chlorpromazine-induced autoimmunity. It is tempting to speculate that therapeutic interventions designed to recover a normal Thl/Th2 balance will provide a useful etiological strategy for the re-establishment of self-tolerance.

ISSN:0891-6934    

DOI:10.3109/08916939608995354

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

Abnormalities in postthymic T cell development in the BB/W rat model of autoimmune insulin-dependent diabetes mellitus (IDDM) result in part from a lymphopenia (lyp) gene defect. To better characterize these abnormalities, the phenotypes of T cells from diabetes-prone (DP) and diabetes-resistant (DR) coisogenic rats were analyzed by multiparameter flow immunocytometry (FCM). Marked decreases in the numbers of Thyl−RT6+T cells, most of which are CD8+, were documented in DP rats by live-gating. Conversely, an approximately 3-fold increase was observed in the percentage of Thy1+RT6−T cells, which normally serve as the precursors of both Thy1−RT6+and Thy1−RT6−T cell subsets in rats. These results suggested that, at a minimum, an arrest in maturation of the Thy1+precursors of RT6+T cells occurs postthymically in DP rats. To determine more precisely the stage(s) in T cell development at which lymphopenia occurs, the export and fate of recent thymic emigrants (RTE's) and their immediate descendants in DP rats was traced after intrathymic (i.t.) labelling with fluorescein isothiocyanate (FITC). The results showed that in DP, as compared with DR, rats: 1) 5-fold fewer RTE's are exported from the thymus per 24 hr; 2) more than 80% of the RTE's are CD4+; 3) most of the immediate descendants of RTE's disappear from the peripheral lymphoid tissues within one week after export from the thymus; and 4) few of the descendants of the RTE's that do survive differentiate into RT6+T cells. Staining with propidium iodide revealed that a significantly higher proportion of Thy1+T cells in DP than in DR rats are in cycle (S/G2/M), thereby accounting for their disproportionately high numbers relative to RTE's. These results indicate that, in addition to defective thymic export, most of the immediate descendants of RTE's in DP rats undergo non-productive proliferation and death at the time (3-7 days postthymic) at which their counterparts in DR rats differentiate into Thy1−RT6 T cells. The resulting deficiency of immunoregulatory T cells, acting in concert with defective intrathymic selection of effector T cell precursors, appears to conspire to markedly enhance the predisposition of DP rats to autoimmunity.

ISSN:0891-6934    

DOI:10.3109/08916939608995355

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

Using a syngeneic Wistar rat model we have shown that the Wistar rat thyroid (WRT) cell line causes significant and specific proliferation of lymph node T cells from normal Wistar rats, and of splenic T cells from a thyroiditis prone line of BB/W rats, when cultured in the presence of irradiated feeder cells. These T cell responses were associated with a marked increase in the number of CD8+T cells. However, using normal Wistar rat T cells which had been previously exposed to WRT cells, rested and then re-exposed to WRT cells as antigen, we consistently found that the T cell population had been rendered unreactive, or anergic, to further thyroid cell stimulation. However, if recombinant rat IL-2 was added to the cultures, then T cell responsivity was seen on re-exposure to WRT cells. The lymphopenic BB/W rat also had T cells which showed a primary T cell response to the WRT cell line accompanied by a marked increase in CD8+T cells. In contrast to the Wistar rat T cells, the BB/W T cells retained a proliferative responsiveness to WRT cells on re-exposure although such responsiveness could also be markedly enhanced with IL-2. These data suggested that antigen-mediated inhibitory signals were induced in normal Wistar rat T cells by the syngeneic WRT cell line, independent of the presence of co-stimulatory molecules. Furthermore, the thyroiditis prone BB/W rat T cells appeared to be less responsive to such anergy induction, perhaps contributing to their susceptibility to autoimmune thyroid disease.

ISSN:0891-6934    

DOI:10.3109/08916939608995356

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

In the past few years, there has been considerable progress in the identification and characterization of B and T cell idiotypes associated with autoimmunity1,2. The identification of human VHand VLfamilies and the more widely available techniques for sequencing the genes encoding these regions is beginning to help elucidate the structural basis of idiotypy. Awareness of these structures has stimulated experiments designed to suppress, specifically, aberrant immune responses. Such therapy is an attractive prospect but its clinical utility remains unproved. While the concept of the idiotype network as originally defined by Jerne2has been modified since it was first proposed over 20 years ago, we share the view of Coutinho3that its manipulation may well contribute solutions to autoimmune disease. In this article, we will outline some of the more recently described links between idiotypes and certain autoimmune conditions and examine the possibilities for the management of these disorders by modulation with antibodies on peptides targeted to these structures.

ISSN:0891-6934    

DOI:10.3109/08916939608995357

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

ISSN:0891-6934    

DOI:10.3109/08916939608995358

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor