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1.
Sazuku Nisitani Takeshi Tsubata Masao Murakami Tasuku Honjo 《European journal of immunology》1995,25(11):3047-3052
Activation mechanisms of B-1 (Ly-1 B) cells have been suggested to be different from those of conventional B cells. To assess the role of various interleukins (IL) in the activation of B-1 cells, we injected IL-4, IL-5 or IL-10 into nonanemic anti-red blood cells (RBC) autoantibody-transgenic mice, in which conventional B cells are clonally deleted but peritoneal B-1 cells persist without secreting Ig. Intraperitoneal or intramuscular injection of IL-5 or IL-10, but not IL-4, increased the number of antibody-producing peritoneal B-1 cells by four- to five-fold, resulting in increased anti-RBC serum autoantibody and induction of hemolytic anemia. These results suggest that IL-5 or IL-10 may play an important role in the terminal differentiation of B-1 cells into antibody-producing cells in vivo. 相似文献
2.
Requirement of IL-5 for induction of autoimmune hemolytic anemia in anti-red blood cell autoantibody transgenic mice 总被引:2,自引:0,他引:2
Sakiyama Toshio; Ikuta Koichi; Nisitani Sazuku; Takatsu Kiyoshi; Honjo Tasuku 《International immunology》1999,11(6):995-1000
IL-5, IL-10 and lipopolysaccharide (LPS) are known to activateB-1 cells in vivo in normal mice and anti-red blood cell autoantibodytransgenic mice (HL mice). To assess the exact role of IL-5in proliferation and activation of peritoneal B-1 cells, weanalyzed IL-5 receptor chain-deficient HL (IL-5R/x HL) mice generated by the cross between IL-5R/and HL mice. In IL-5R/ x HL mice, Ig-producingB-1 cells in the peritoneal cavity were negligible, althoughthe total number of B-1 cells in the peritoneal cavity wereas many as 30% of that in HL mice. Moreover, LPS- or IL-10-induceddifferentiation of B-1 cells into antibody-producing cells wasseverely impaired in IL-5R/ x HL mice. We alsoused in vivo 5-bromo-2'-deoxyuridine labeling to estimate theproliferation of B-1 cells in IL-5R/ mice. Theabsence of IL-5R did not affect spontaneous proliferation ofperitoneal B-1 cells. However, induced proliferation of peritorealB-1 cells by oral administration of LPS was markedly impairedin IL-5R/ mice. These results suggest that IL-5is required for activation-associated proliferation of B-1 cellsbut not for their spontaneous proliferation and support theidea that IL-5 plays an important role on the induction of autoantibodyproduction from B-1 cells. 相似文献
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Bruton's tyrosine kinase is required for signaling the CD79b-mediated pro-B to pre-B cell transition 总被引:1,自引:0,他引:1
Kouro T Nagata K Takaki S Nisitani S Hirano M Wahl MI Witte ON Karasuyama H Takatsu K 《International immunology》2001,13(4):485-493
Formation of the pre-BCR complex is a critical check point during B cell development and induces the transition of pro-B to pre-B cells. CD79b (Igbeta) is a signaling component in the pre-BCR complex, since differentiation to the pre-B phenotype is induced by cross-linking the CD79b expressed on developmentally arrested pro-B cells from recombination-activating gene (RAG)-2-deficient mice. Bruton's tyrosine kinase (BTK) plays important roles in B cell development. However, its molecular mechanisms in early B cell development are not fully understood. To examine whether BTK functions in CD79b-mediated signaling for the pro-B/pre-B transition, we utilized RAG2/BTK double-knockout (DKO) mice. Pro-B cells from RAG2/BTK-DKO mice did not differentiate into pre-B cells following CD79b cross-linking, although tyrosine phosphorylation of cellular proteins including Erk1/2 and phospholipase C-gamma2 was induced in the same manner as RAG2-KO mice. BTK is phosphorylated after cross-linking of CD79b on RAG2-deficient pro-B cells. These findings suggest that BTK-dependent pathways downstream of CD79b are critical for the pro-B/pre-B transition and BTK-independent signaling pathways are also activated via the pre-BCR complex. 相似文献
6.
In situ detection of activated Bruton's tyrosine kinase in the Ig signaling complex by phosphopeptide-specific monoclonal antibodies
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Nisitani S Kato RM Rawlings DJ Witte ON Wahl MI 《Proceedings of the National Academy of Sciences of the United States of America》1999,96(5):2221-2226
Bruton's tyrosine kinase (Btk) is a critical transducer of signals originating from the B cell antigen receptor (BCR). Dosage, sequential phosphorylation, and protein interactions are interdependent mechanisms influencing Btk function. Phosphopeptide-specific mAbs recognizing two distinct phosphotyrosine modifications were used to quantify Btk activation by immunofluorescent techniques during B cell stimulation. In a population of cultured B cells stimulated by BCR crosslinking and analyzed by flow cytometry, transient phosphorylation of the regulatory Btk tyrosine residues (551Y and 223Y) was detected. The kinetics of phosphorylation of the residues were temporally distinct. Tyrosine 551, a transactivating substrate site for Src-family kinases, was maximally phosphorylated within approximately 30 seconds of stimulation as monitored by flow cytometry. Tyrosine 223, an autophosphorylation site within the SH3 domain, was maximally phosphorylated at approximately 5 minutes. Btk returned to a low tyrosine phosphorylation level within 30 minutes, despite persistent elevation of global tyrosine phosphorylation. Colocalization of activated Btk molecules with the crosslinked BCR signaling complex was observed to coincide with the period of maximal Btk tyrosine phosphorylation when stimulated B cells were analyzed with confocal microscopy. The results of these in situ temporal and spatial analyses imply that Btk signaling occurs in the region of the Ig receptor signaling complex, suggesting a similar location for downstream targets of its activity. 相似文献
7.
The src-family protein tyrosine kinase, Lyn, has been reported to play a crucial role in the regulation of B-cell antigen receptor (BCR)-mediated signalling. To elucidate the role of Lyn in the maintenance of immunological tolerance and the prevention of B-1 cell activation and its autoantibody production, Lyn-deficient mice were crossed with transgenic mice carrying the immunoglobulin heavy and light chain genes encoding an autoantibody against mouse red blood cells. In the transgenic mice, most peripheral B cells expressed the B-1 cell phenotype. When the transgenic mice were bred in specific pathogen-free (SPF) conditions, B-1 cells were anergic and did not produce any autoantibody. In contrast, Lyn-deficient transgenic mice kept in the same SPF conditions revealed markedly increased numbers of activated B-1 cells and developed severe autoimmune haemolytic anaemia. Moreover, the mice had a huge splenomegaly containing a remarkable accumulation of erythroblasts, resulted from extramedullary erythropoiesis, in addition to the increased numbers of lymphoblast-like cells of the B-1 cell lineages. The present study demonstrates a crucial role of Lyn kinase in the regulation of B-1 cell activation and maintenance of tolerance. 相似文献
8.
Involvement of IL-10 in induction of autoimmune hemolytic anemia in anti-erythrocyte Ig transgenic mice 总被引:3,自引:2,他引:3
Activation of peritoneal B-1 cells triggers autoimmune anemia in anti-
erythrocyte Ig transgenic mice (HL mice). Numbers of peritoneal B-1 cells
and Ig-producing cells were negligible in the T cell-deficient HL mice
generated by the cross with RAG-2-/- mice (RAG-2-/- x HL mice).
Proliferation and activation of B-1 cells in RAG-2-/- x HL mice were
recovered by fetal thymus transfer, indicating involvement of T cells in
B-1 cell-mediated autoimmune hemolytic anemia. Involvement of T cells in
proliferation and activation of B-1 cells could be by-passed by
administration of lipopolysaccharide (LPS), IL-5 or IL-10 to RAG-2-/- x HL
mice. Administration of LPS elevated the serum IL-10 level in HL, RAG-2-/-
x HL and normal mice. Proliferation and activation of B-1 cells were
blocked by an anti-IL-10 antibody in conventionally bred as well as
LPS-treated HL mice. Taken together, IL-10 plays a pivotal role in
activation of peritoneal B-1 cells.
相似文献
9.
N Watanabe S Nisitani K Ikuta M Suzuki T Chiba T Honjo 《The Journal of experimental medicine》1999,190(4):461-469
Surface-expressed immunoglobulin (Ig) has been shown to have a critical role in allelic exclusion of Ig heavy (H) and light (L) chains. Although various degrees of suppression of endogenous Ig expression are observed in Ig transgenic (Tg) mice, it was not clear whether this difference is due to different onsets of Tg expression or to different levels of Tg expression, which are obviously affected by integration sites of the transgene. In this study we generated antierythrocyte antibody Tg mice that carry tandem joined H and L chain transgenes (H+L) and confirmed that homozygosity of the transgene loci enhances the level of transgene expression as compared with heterozygosity. Suppression of endogenous H and L chain gene expression was stronger in homozygous than in heterozygous Tg mice. Similar results were obtained in control Tg mice carrying the H chain only. These results suggest that there is a threshold of the B cell receptor expression level that induces allelic exclusion. In addition, despite the same B cell receptor specificity, the size of Tg autoreactive B-1 cell compartment in the peritoneal cavity is larger in homozygous than in heterozygous mice, although the number of the Tg B-2 cell subset decreased in the spleen and bone marrow of homozygous Tg mice as compared with heterozygous Tg mice. By contrast, homozygosity of the H chain alone Tg line, which does not recognize self-antigens, did not increase the size of the peritoneal B-1 subset. These results suggest that the size of the B-1 cell subset in the Tg mice may depend on strength of signals through B cell receptors triggered by self-antigens. 相似文献
10.
In summary, there are two pathways for activation of peritoneal B-1 cells in HL mice: T cell-dependent and T cell-independent pathways. In both pathways, IL-10 is suggested to play an important role (Fig. 1). We have not yet known what type of cells secrete IL-10 by and whether other soluble factors are involved in each pathway. These questions are to be elucidated by further studies on HL mice. 相似文献