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1.
Splenic T cells from Coombs'-positive New Zealand Black (NZB) mice proliferated consistently in vitro in response to the integral red blood cell (RBC) membrane protein Band 3, the antigen previously shown to be the target for the pathogenic RBC autoantibodies. The responding cells predominantly express CD4 and the proliferative response is blocked by antibodies to the NZB major histocompatibility complex class II but not by antibodies to an irrelevant H-2 haplotype. NZB splenic T cells also proliferated in response to the internal membrane skeleton protein spectrin. By contrast, T cells from BALB/c and DBA2 mice, which bear the same H-2 haplotype as NZB mice, but which do not develop autoimmune hemolytic anemia (AIHA), fail to respond to Band 3. It is considered that these results support the hypothesis that Band 3-reactive T cells provide help for the production of pathogenic anti-Band 3 autoantibodies in NZB mice. T cells from Coombs'-negative NZB mice as young as 3 weeks old proliferated in response to Band 3; moreover, the RBC from Coombs'-negative mice bore elevated levels of autoantibody as judged by a sensitive direct enzyme-linked anti-globulin test. Thus, the pathology of AIHA develops at a much earlier age than was thought previously.  相似文献   

2.
Summary Band 3 is the major membrane protein of erythrocytes, which binds membrane skeletal proteins, glycolytic enzymes, and hemoglobin and transports various kinds of anions. Band 3-Memphis is a variant of Band 3, the amino terminal fragment of which depicts a slow electrophoretic mobility on sodium dodecyl sulfate-polyacrylamide gel. The frequency of Band 3-Memphis varies among populations, with a higher frequency among the Japanese. We investigated the frequency of Band 3-Memphis in a western Japanese island which is relatively isolated from the main islands, finding that the frequency of Band 3-Memphis of the inhabitants of this island is significantly higher than the frequency of the Japanese based on the survey in Kyushu Island. This indicates that there may be differences of population in the frequency of Band 3-Memphis in Japan and that Band 3-Memphis may be a good marker to genetically differentiate each population.  相似文献   

3.
NZB mice spontaneously develop haemolytic anaemia as the result of production of erythrocyte autoantibodies. The mechanisms leading to breakdown in tolerance to erythrocyte autoantigens are unknown. Antibodies to CD4 have been successfully used to treat several murine models of autoimmune disease. In this study we injected NZB mice with non-depleting CD4 antibodies and were able to prevent and abrogate erythrocyte autoantibody production in young (Coombs' negative) and old (Coombs' positive) mice, respectively. Our data indicate the dependency of autoantibody production on CD4+ T cells. However, withdrawal of anti-CD4 antibodies resulted in the appearance of erythrocyte autoantibodies, showing that under these conditions we were unable to re-establish tolerance to autoantigens on erythrocytes using anti-CD4 treatment.  相似文献   

4.
We established two clones of monoclonal hybridoma, from a non-immunized NZB mouse, which produce IgM class hemagglutinating autoantibodies reactive with the exposed murine erythrocyte autoantigens. Absorption studies revealed that one monoclonal antibody exhibits cross-reactivity to chick erythrocytes and mouse liver, and the other antibody to rat erythrocytes and mouse brain. Optimal temperatures for the hemagglutination were 22 degrees C with the former and 4 degrees C with the latter. The specificity and nature of the autoantibodies are apparently distinct from any of the erythrocyte autoantibodies described to date in NZB mice, anti-X, anti-HB, anti-HOL or anti-I antibodies. Implantation of these hybridoma cells in BALB/c mice induced autoimmune hemolytic anemia associated with a marked splenomegaly. These findings provide evidence that the erythrocyte autoantibodies in NZB mice are more heterogenous than generally assumed and suggest that varieties of erythrocyte autoantibodies may be involved in the development of a naturally occurring hemolytic disease in NZB mice.  相似文献   

5.
The pathogenesis of autoantibody-mediated cellular and tissue lesions in autoimmune diseases is most straightforwardly attributable to the combined action of self-antigen binding properties and effector functions associated with the Fc regions of the different immunoglobulin (Ig) isotypes. The analysis of two different sets of monoclonal autoantibodies derived from lupus-prone mice revealed remarkable differences in the pathogenic potentials of different IgG subclasses: (1) the IgG2a and IgG2b subclasses of anti-red blood cell (RBC) autoantibodies are the most pathogenic and efficiently activate two classes of activating IgG Fc receptors (FcγRIII and FcγRIV) and complement; (2) the IgG3 subclass is less pathogenic and activate only complement; and (3) the IgG1 subclass is the least pathogenic and interact only with FcγRIII. In addition, because of the unique property of IgG3 to form self-associating complexes and generate cryoglobulins, this subclass of rheumatoid factor and anti-DNA autoantibodies became highly pathogenic and induced lupus-like nephritis and/or vasculitis. Since the switch to IgG2a and IgG3 is promoted by Th1 cytokine interferon γ, these results strongly suggest that Th1 autoimmune responses could be critically involved in the generation of more pathogenic autoantibodies in systemic lupus erythematosus. This finding is consistent with the observation that the progression of murine lupus nephritis is correlated with the relative dominance of Th1 autoimmune responses. Finally, the analysis of IgG glycosylation pattern revealed that more sialylated IgG autoantibodies remained poorly pathogenic because of limited Fc-associated effector functions and loss of cryoglobulin activity. This suggests that the terminal sialylation of the oligosaccharide side chains of IgG could be a significant factor determining the pathogenic potential of autoantibodies. Our results thus underline the importance of subpopulations of autoantibodies, induced by the help of Th1 cells, in the pathogenesis of autoantibody-mediated cellular and tissue injuries.  相似文献   

6.
Female NZB/W F1 mice develop an autoimmune disease similar to human systemic lupus erythematosus (SLE), and ultimately die of glomerulonephritis. Starting at the age of 16 weeks NZB/W F1 mice were treated for a period of 19 weeks with soluble interferon-γ receptor (sIFN-γR), anti-IFN-γ monoclonal antibody (mAb) or IFN-γ. All mice treated with sIFN-γR or anti-IFN-γ mAb were alive 4 weeks after the treatment was discontinued, whereas 50% of mice died in the placebo groups and 78% of the mice died in the IFN-γ-treated group. Histologically, there was severe membrano-proliferative glomerulonephritis in IFN-γ- and placebo-treated mice, and minimal or no mesangioproliferative disease in mice receiving sIFN-γR or anti-IFN-γ mAb. The renal mononuclear infiltrate (T lymphocytes and monocytes), expression of major histocompatibility complex class II antigen and glomerular immunoglobulin and complement deposition were reduced in those mice. These data suggest that an IFN-γ inhibitor, such as the soluble IFN-γR, can be used for SLE therapy in the early stages of the disease.  相似文献   

7.
C3HeB/FeJ mice infected with the docile strain of lymphocytic choriomeningitis virus (LCMV-d) develop a persistent infection with a transient haemolytic anaemia. Immunoglobulin can be eluted from the red blood cells (RBC) of these mice but it cannot be detected on the RBC by a conventional antiglobulin test. The present study demonstrates that RBC from such mice bear erythrocyte autoantibodies which are predominantly of the IgG2a subclass, with lower levels of autoantibodies of the IgG1, IgG2b and IgG3 subclasses. To identify the target antigen the autoantibodies were eluted from the RBC of LCMV-infected mice. The eluted autoantibody bound to intact normal RBC and precipitated a 105000 MW component that corresponds to murine Band 3 protein. A monoclonal antibody derived from mice infected with LCMV-d also precipitated mouse Band 3, and reacted specifically by enzyme-linked immunosorbent assay against a purified preparation of Band 3. This study has shown that in C3H mice infected with LCMV-d which develop autoimmune haemolytic anaemia, the target autoantigen is erythrocyte membrane Band 3.  相似文献   

8.
Monoclonal IgM anti-erythrocyte autoantibody produced by a NZB-derived hybridoma has been found to react with trimethylammonium-containing compounds. Such compounds are able to prevent the lysis of bromelain-treated mouse erythrocytes (BrMRBC) by those autoantibodies. Using a column of insolubilized betaine hydrazine (BH) the monoclonal anti-erythrocyte antibody has been specifically retained. Elution of this antibody was accomplished by 0.15 M choline (Ch).  相似文献   

9.
10.
ObjectivesRed blood cell autoantibodies (RBC autoAbs) of IgG class are found in the majority of patients with warm autoimmune hemolytic anemia (wAIHA) but sometimes also during the pretransfusion testing of patients with different diagnoses but without hemolysis. The aim of the study was to identify the main differences between these two groups of patients according to age, gender, subclass and titer of IgG RBC autoAbs and diagnosis.Material and methodsIn the 9-year retrospective study, data were collected from records of 291 patients with IgG RBC autoAbs detected by gel technique, from which 111 with wAIHA.ResultsMore than 85% of patients in both groups were over 40 years old, with male to female ratio 1:1.9 in wAIHA vs 1:1.3 in patients without hemolysis (P = 0.0916). The main characteristics of patients with wAIHA vs patients without hemolysis were: IgG only 38% vs 70%, IgG + Complement 62% vs 30%, total IgG1 79% vs 55%, IgG1 + IgG3 35% vs 11%, titer of 100 for IgG1 + IgG3 17% vs 3% (P < 0.0001), respectively, while titer of 100 for IgG1 18% vs 9% (P = 0.0241). The underlying diagnosis in wAIHA vs patients without hemolysis: hematologic disorders 41% vs 22% (P = 0.0006), autoimmune disorders 12% vs 13% (P = 0.8033), solid tumors 5% vs 14% (P = 0.0154) and surgery procedures 6% vs 26% (P < 0.0001).ConclusionWe observed more wAIHA patients with high titer of IgG1 and high prevalence of IgG1 + IgG3 and consider that patients without hemolysis having identical results might be interesting to find out how they are protected from damage by RBC autoAbs.  相似文献   

11.
Primary malignant lymphoma of the liver occupying the right lobe, 14x9x7 cm in size, developed in a 30-year-old man with a 4-year history of autoimmune hemolytic anemia. The diagnosis of systemic lupus erythematosus (SLE) accompanying thrombocytopenia had been made clinically 10 months earlier. The liver biopsy specimen revealed diffuse proliferation of large lymphoma cells expressing the activated helper/inducer T-cell phenotype (LCA+, UCHL1+, OPD4+, LN3+, MT1-, L26-, MB1-, Leu M1-, Ki-1- KP1-). The lymphoma was successfully treated by chemotherapy and irradiation. Intractable thrombocytopenia provoked fatal esophageal hemorrhage. At autopsy, no lymphomatous lesion was identified, and the hepatic right lobe contained an encapsulated necrotic lesion with-out any viable tumor cells. The bone marrow revealed marked hyperplasia of erythroid and megakaryocytic series. Extramedullary hematopoiesis was demonstrated in the liver, spleen and lymph nodes. This is the second case of primary hepatic T-cell lymphoma associated with SLE.  相似文献   

12.
The effects of the nonpseudoautosomal region of the Y chromosome (Y NPAR ) on hippocampal morphology have been investigated in the inbred mouse strains NZB/B1NJ and CBA/H, using comparisons between the two parentals and their respective congenics N.H-Y NPAR and H.N-Y NPAR . Results obtained depend upon the hippocampal variable measured. Y NPAR had no effect on the sizes of the stratum oriens, hilus, or mossy fiber terminal fields (both suprapyramidal and intra- and infrapyramidal). However, in interaction with the strain background, it affected the strata lacunosum-moleculare, radiatum, and pyramidale. Possible relationships among gene(s), mossy fiber terminal fields, and intermale aggression are discussed.  相似文献   

13.
In 1988 and in 1989 consensus workshops were organized in order to define the interlaboratory concordance in detecting autoantibody specificities in selected sera from patients with rheumatoid disorders and to determine the possible causes of discrepancies. In total 20 sera were tested for the presence of antibodies against nRNP, Sm, Ro (SS-A), La (SS-B), Scl-70, centromeric antigens, ribosomal RNP and Jo-1. The methods used for detection by the 28 European laboratories who participated included immunofluorescence, counter-immunoelectrophoresis, immunodiffusion, immunoblotting and ELISA.

The results showed that only a combination of two or more techniques was able to detect all specificities with an adequate efficiency. Recommendations to improve the efficiency of autoantibody detection and to standardize laboratory protocols are given.  相似文献   


14.
An immunoblotting procedure is described which makes it possible to screen multiple blood samples for the presence of glycophorin and band 3 variant forms with altered electrophoretic mobility. The procedure can be simplified by using whole red blood cell hemolysates instead of membranes for SDS-polyacrylamide gel electrophoresis. The use of hemolysates also has the advantage that antigens sensitive to proteolysis are not degraded in vitro. The same nitrocellulose blots were used for immunoenzymatic detection of glycophorins with a set of anti-glycophorin monoclonal antibodies, and for autoradiographic detection of band 3-derived bands with 125I-labeled anti-band 3 monoclonal antibody. The screening of 157 Caucasian blood samples revealed the presence of a slower-migrating form of band 3 in seven cases and variant glycophorin in one case. The variant glycophorin exhibited the features of hybrid glycophorin of B-A type.  相似文献   

15.
To determine the effect of indole-3-acetic acid (IAA), known as natural auxin, on developing fetus, pregnant mice were injected with 500 or 1000 mg/kg on various gestation days (Days). With the repeated treatment during Days 7-15, the fetal brains exhibited a reduction in size and weight in a dose-dependent manner on Day 18. Histopathologically, hypoplasia of the cortical plate, piriform cortex, hippocampus and thalamus were observed. From the single treatment on 1 day during Days 9-14, the sensitive period of IAA-induced microencephaly was found to be during Days 10-13 and the most significant response in the fetuses was seen on Day 11 or 12. With the repeated treatment during Days 11-13, apoptotic cells mainly increased in the medial and dorsal layer of the neuroepithelium and prepalate with a reduction in cell density in the telencephalon, diencephalon, mesencephalon and metencephalon on Day 12.5. p53-positve cells were detected associated with apoptotic cells in neuroepithelium. Therefore, IAA administration to pregnant mice induces apoptosis mediated by p53 in the embryo's neuroepithelium, decreases formation of neurons and leads to microencephaly in the fetuses.  相似文献   

16.
Pemphigus vulgaris (PV) is an antibody-mediated autoimmune disease of the skin and mucous membranes. Desmoglein-3 (dsg-3) expressed in the suprabasal layer of the skin serves as an autoantigen in PV. Passive transfer of sera, either from patients with PV or from experimental animals immunized with a recombinant human dsg3 (hdsg3) into neonatal BALB/c mice results in blister formation, suggesting strongly that there is significant cross-reactivity between the mouse dsg3 (mdsg3) and the hdsg3. However, efforts to induce disease in adult mice through active immunization using hdsg-3 have not been successful, suggesting that the epitopes required for the induction of pathogenic antibodies in adult mice might not be present in hdsg3. Therefore, in this study, we expressed a full-length mdsg3 in insect cells and compared its serological reactivity with that of the hdsg3 using species specific polyclonal sera and a panel of seven monoclonal antibodies (MoAbs) with unique binding specificities to hdsg3. Studies using sera demonstrated a considerable cross-reactivity, while studies using MoAbs exhibited specific epitope differences between the two proteins. Because of these differences, we reasoned that immunization with mdsg3 might induce disease in adult mice. Immunization of four strains of mice (i.e. BALB/c, DBA/1, HRS/J and SJL/J) with mdsg3 resulted in considerable antibody response, but failed to induce lesions. However, sera from immunized BALB/c mice induced acantholysis of neonatal mouse skin in vitro. These studies indicated that our inability to induce lesions in adult mice through active immunization is not due to differences in the ability of mouse and human dsg3 to induce acantholytic antibodies, but due probably to structural differences between adult and neonatal mouse skin. Alternatively, immunization with a combination of dsg3 protein along with other proteins might be necessary to induce pemphigus disease in adult mice. Nevertheless, our current studies show that molecular mechanisms leading to the production of acantholytic antibodies in mice can now be studied using homologous mdsg3.  相似文献   

17.
Summary Permeability of the erythrocyte membrane for sodium and potassium ions was studied in 8–10-week old spontaneously hypertensive rats (SHR, Kyoto Wistar strain), normotensive Wistar and Sprague-Dawley rats.The rate constant of Na/Na exchange was considerably greater in the SHR than in the normotensive Wistar and Sprague-Dawley rats. This difference remained the same in the rats adrenalectomized 7 days prior to the experiment. The maximum difference in the constants was found when the sodium pump was blocked by ouabain.The accumulation of42K in the erythrocytes of the SHR (the sodium pump being blocked) took place at a considerably slower rate, and the K+ washout into a potassium-free medium was faster than in the normotensive Wistar and Sprague-Dawley rats.These results seem to indicate a higher permeability of the SHR's erythrocyte membrane for Na+ and K+ions, as compared to normotensive Wistar and Sprague-Dawley strains. It is suggested that the increased permeability of the erythrocyte membrane for Na+ and K+ in the SHR may reflect a more widespread cell membrane defect, which could serve as a general cause for activating the mechanisms maintaining high blood pressure.  相似文献   

18.
A detailed restriction map of a 430-kb contig comprising the single Cκ, the 5 Jκ and the adjoining 22 Vκ gene segments is presented. The first 12 Vκ genes following the JκCκ region belong to the Vκ21 family, the subsequent ones to the closely related families Vκ8 and Vκ19/28. Previous difficulties in cloning all Vκ21 genes can now be explained by the presence of a duplicated region in this part of the locus. The structure was established by analysis of yeast artificial chromosome, bacterial artificial chromosome and cosmid clones and by the so-called long template PCR technique. The distance between Cκ and the proximal Vκ21 gene is 22 kb and the average distances between the Vκ genes are about 20 kb. Of the 12 Vκ21 genes 5 were sequenced for the first time and 8 of the 12 genes were found to be expressed. Of the 10 Vκ8 and Vκ19/28 germline genes 9 are new; expression products of 8 of the 10 genes were known. The known 5 ′ , 3 ′ polarities allow to specify for the 22 Vκ genes whether they are rearranged to the JκCκ element by a deletion or an inversion mechanism. Also the formation of interesting rearrangement products in classical cell lines as MPC11, MOPC41 and PC 7043 can be explained now. The non-Vκ sequence L10 whose rearrangement by inversion has been described earlier (Hoechtl and Zachau, Nature 1983. 302:260 – 263) was now localized downstream of JκCκ.  相似文献   

19.
Although numerous solitary germ-line V? genes and two small V? contiguously cloned gene regions (contigs) are known, no attempts to systematically elucidate the structure of the ? locus of the mouse have been reported so far. As a first step to this aim we screened a cosmid library of C57BL/6J mouse DNA with 18 probes that are more or less specific for the different V? gene families. Ninety-one V? gene-containing cosmid clones were characterized by detailed restriction mapping and hybridizations. Several contigs were constructed from overlapping clones. The contigs and the still unlinked cosmid clones cover 1.6 Mb. Many of the cosmid clones were localized on chromosome 6 where the ? locus is known to reside; no evidence for the existence of dispersed V? genes (orphons) was obtained. Eighty-five strong hybridization signals were assigned to distinct V? gene families, while for 11 weak signals the assignment was less definite. As to the distribution of gene families within the locus the following situation emerged: there are both, groups of genes which belong to one V? gene family (“clusters”) and groups in which genes of different families are interspersed. The interspersion of gene families seems to be more pronounced than has been assumed so far. Additional V? genes which are known to exist will have to be isolated from other gene libraries of the same mouse Ig? haplotype.  相似文献   

20.
IL‐17, produced by a distinct lineage of CD4+ helper T (Th) cells termed Th17 cells, induces the production of pro‐inflammatory cytokines from resident cells and it has been demonstrated that over‐expression of IL‐17 plays a crucial role in the onset of several auto‐immune diseases. Here we examined the role of IL‐17 in the pathogenesis of autoimmune gastritis, a disease that was previously believed to be mediated by IFN‐γ. Significantly higher levels of IL‐17 and IFN‐γ were found in the stomachs and stomach‐draining lymph nodes of mice with severe autoimmune gastritis. Unlike IL‐17, which was produced solely by CD4+ T cells in gastritic mice, the majority of IFN‐γ‐producing cells were CD8+ T cells. However, CD8+ T cells alone were not able to induce autoimmune gastritis. T cells that were deficient in IL‐17 or IFN‐γ production were able to induce autoimmune gastritis but to a much lower extent compared with the disease induced by wild‐type T cells. These data demonstrate that production of neither IL‐17 nor IFN‐γ by effector T cells is essential for the initiation of autoimmune gastritis, but suggest that both are required for the disease to progress to the late pathogenic stage that includes significant tissue disruption.  相似文献   

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