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Moses Rodriguez - One of the best experts on this subject based on the ideXlab platform.

  • monoclonal remyelination promoting Natural Autoantibody sch 94 03 pharmacokinetics and in vivo targets within demyelinated spinal cord in a mouse model of multiple sclerosis
    Journal of the Neurological Sciences, 1997
    Co-Authors: Samuel F Hunter, David J Miller, Moses Rodriguez
    Abstract:

    Abstract Chronic inflammatory demyelination of the central nervous system is usually incompletely repaired. However, we previously reported that in vivo treatment with monoclonal antibody SCH 94.03 (produced using spinal cord homogenate as an immunogen) increased myelin repair 4-fold in the Theiler's virus mouse model of chronic progressive multiple sclerosis ( Miller et al., 1994 ; J. Neurosci. 14: 6230–6238). A major issue regarding site and mechanism of action of this antibody is whether SCH 94.03 enters demyelinated CNS lesions and reacts with oligodendrocytes and myelin. To address this question, we radiolabeled SCH 94.03 and studied its distribution into tissues, pharmacokinetics, and binding to cells within demyelinating spinal cord lesions in vivo. SCH 94.03 distributed widely into extracellular water following intraperitoneal injection and was eliminated with a terminal half-life of 3–4.5 days. Only a portion of the total dose (0.4%) entered brain and spinal cord. SCH 94.03 accumulated 1.5–2.0-fold in brain between 1 and 7 days after injection, but its pharmacokinetics were otherwise similar to those of an isotype control IgMκ antibody. Oligodendrocytes, myelin sheaths and, less frequently, axons were labeled within demyelinating lesions as detected by light and electron microscopic autoradiography. These findings suggest that remyelination-promoting autoantibodies could act within the demyelinating lesion of the central nervous system by binding to the oligodendrocyte, myelin, or axon.

  • successful treatment of established relapsing experimental autoimmune encephalomyelitis in mice with a monoclonal Natural Autoantibody
    Journal of Neuroimmunology, 1997
    Co-Authors: David J Miller, John J Bright, Subramaniam Sriram, Moses Rodriguez
    Abstract:

    We postulated that humoral autoimmunity can play a beneficial role in CNS demyelinating diseases such as multiple sclerosis. We previously demonstrated that monoclonal Natural Autoantibody SCH94.03 suppresses CNS inflammation and promotes remyelination in a virus-induced model of chronic progressive multiple sclerosis. To further investigate the relationship between Natural autoimmunity and CNS demyelination, we examined the effect of SCH94.03 treatment on clinical relapses and pathological disease in SJL/J mice with established adoptive-transfer relapsing experimental autoimmune encephalomyelitis. Treatment with SCH94.03 after recovery from the initial episode of clinical disease reduced relapse rates by half, prolonged relapse onset by 6 days and reduced spinal cord demyelination and meningeal inflammation by 40%. These results are consistent with the hypothesized immunomodulatory function of Natural autoantibodies, and are the first direct demonstration that Natural humoral autoimmunity can be beneficial in an autoimmune T-cell-mediated CNS demyelinating disease.

  • multi organ reactivity of a monoclonal Natural Autoantibody that promotes remyelination in a mouse model of multiple sclerosis
    Journal of Histochemistry and Cytochemistry, 1996
    Co-Authors: David J Miller, M K Njenga, Joseph E Parisi, Moses Rodriguez
    Abstract:

    A contemporary view of autoimmunity suggests that self-reactivity is a normal phenomenon, in contrast to the classical association between autoimmunity and immunopathology. We have previously demonstrated that monoclonal antibody SCH94.03, a Natural Autoantibody with polyreactivity towards several purified protein and hapten antigens, promotes central nervous system remyelination when passively transferred to SJL/J mice chronically infected with Theiler's murine encephalomyelitis virus, an established experimental model of multiple sclerosis. In this study we characterized the autoreactivity of SCH94.03 with endogenous mouse tissue using immunoperoxide and multiple-color immunofluorescence staining techniques on frozen tissue sections. Within the nervous system, SCH94.03 labeled fibrous astrocytes, ependymal cells, ganglion satellite cells, and a sub-population of microglia, oligodendrocytes, and peripheral nervous system neurons. Outside the nervous system, SCH94.03 labeled gastrointestinal tract smooth ...

  • a monoclonal Natural Autoantibody that promotes remyelination suppresses central nervous system inflammation and increases virus expression after theiler s virus induced demyelination
    International Immunology, 1996
    Co-Authors: David J Miller, Kariuki M Njenga, Paul D Murray, Julian L Leibowitz, Moses Rodriguez
    Abstract:

    We have used an established experimental model of multiple sclerosis to investigate the potential beneficial relationship between Natural autoimmunity and remyelination after central nervous system (CNS) demyelination. Intracerebral infection of SJL/J mice with Theiler's murine encephalomyelitis virus (TMEV) produces chronic, progressive, inflammatory CNS demyelination. Chronically infected SJL/J mice show minimal spontaneous remyelination, which is in part due to a T cell-mediated immune response inhibiting myelin repair. We previously identified a monoclonal Natural Autoantibody, designated SCH94.03, that promotes remyelination when passively transferred to chronically infected SJL/J mice. The mechanism whereby SCH94.03 promotes remyelination is unknown, although previous reports suggest that Natural autoantibodies can modulate immune system function. In this report we demonstrate that treatment with SCH94.03 reduced by 2- to 3-fold the number of CD4(+) and CD8(+) cells infiltrating the CNS of SJL/J mice chronically infected with TMEV, in the absence of global lymphocyte depletion. Associated with the decreased inflammation was a 2- to 3-fold increase in virus antigen expression without a significant increase in viral RNA or virus titers. Treatment with SCH94.03 also suppressed the humoral immune response to a T cell-dependent antigen in chronically infected mice. Immunohistochemical staining showed that SCH94.03 labeled MHC class II-positive dendritic cells in peripheral lymphoid organs. These results are consistent with the proposed immunomodulatory function of Natural autoantibodies and suggest that one mechanism whereby SCH94.03 promotes CNS remyelination in chronically infected SJL/J mice is through inhibition of a pathogenic immune response.

  • a monoclonal Autoantibody that promotes central nervous system remyelination in a model of multiple sclerosis is a Natural Autoantibody encoded by germline immunoglobulin genes
    Journal of Immunology, 1995
    Co-Authors: David J Miller, Moses Rodriguez
    Abstract:

    Antibodies directed against self-Ags are frequently considered detrimental, and have been shown to play a pathogenic role in certain autoimmune diseases. However, the presence of autoreactive Abs in normal individuals suggests that some autoantibodies could participate in normal physiology. Our previous studies demonstrated that monoclonal autoantibodies SCH94.03 and SCH94.32, generated from the splenocytes of uninfected SJL/J mice injected with normal homogenized spinal cord, promote central nervous system remyelination when passively transferred into syngeneic mice chronically infected with Theiler's murine encephalomyelitis virus, an established experimental model of multiple sclerosis. In this study we show that these two monoclonal autoantibodies are identical, and have phenotypic characteristics of Natural autoantibodies. By using a solid phase assay system, SCH94.03 and SCH94.32 showed reactivity toward several protein Ags and chemical haptens, with prominent reactivity toward spectrin, (4-hydroxy-3-nitrophenyl)acetyl, and fluorescein. Sequence analysis showed that both SCH94.03 and SCH94.32 were encoded by identical germline Ig light chain V kappa 10/J kappa 1 and heavy chain V23/DFL16.1/JH2 genes, with no definitive somatic mutations. These results indicate that a Natural Autoantibody participates in a beneficial physiologic response to central nervous system injury.

David J Miller - One of the best experts on this subject based on the ideXlab platform.

  • monoclonal remyelination promoting Natural Autoantibody sch 94 03 pharmacokinetics and in vivo targets within demyelinated spinal cord in a mouse model of multiple sclerosis
    Journal of the Neurological Sciences, 1997
    Co-Authors: Samuel F Hunter, David J Miller, Moses Rodriguez
    Abstract:

    Abstract Chronic inflammatory demyelination of the central nervous system is usually incompletely repaired. However, we previously reported that in vivo treatment with monoclonal antibody SCH 94.03 (produced using spinal cord homogenate as an immunogen) increased myelin repair 4-fold in the Theiler's virus mouse model of chronic progressive multiple sclerosis ( Miller et al., 1994 ; J. Neurosci. 14: 6230–6238). A major issue regarding site and mechanism of action of this antibody is whether SCH 94.03 enters demyelinated CNS lesions and reacts with oligodendrocytes and myelin. To address this question, we radiolabeled SCH 94.03 and studied its distribution into tissues, pharmacokinetics, and binding to cells within demyelinating spinal cord lesions in vivo. SCH 94.03 distributed widely into extracellular water following intraperitoneal injection and was eliminated with a terminal half-life of 3–4.5 days. Only a portion of the total dose (0.4%) entered brain and spinal cord. SCH 94.03 accumulated 1.5–2.0-fold in brain between 1 and 7 days after injection, but its pharmacokinetics were otherwise similar to those of an isotype control IgMκ antibody. Oligodendrocytes, myelin sheaths and, less frequently, axons were labeled within demyelinating lesions as detected by light and electron microscopic autoradiography. These findings suggest that remyelination-promoting autoantibodies could act within the demyelinating lesion of the central nervous system by binding to the oligodendrocyte, myelin, or axon.

  • successful treatment of established relapsing experimental autoimmune encephalomyelitis in mice with a monoclonal Natural Autoantibody
    Journal of Neuroimmunology, 1997
    Co-Authors: David J Miller, John J Bright, Subramaniam Sriram, Moses Rodriguez
    Abstract:

    We postulated that humoral autoimmunity can play a beneficial role in CNS demyelinating diseases such as multiple sclerosis. We previously demonstrated that monoclonal Natural Autoantibody SCH94.03 suppresses CNS inflammation and promotes remyelination in a virus-induced model of chronic progressive multiple sclerosis. To further investigate the relationship between Natural autoimmunity and CNS demyelination, we examined the effect of SCH94.03 treatment on clinical relapses and pathological disease in SJL/J mice with established adoptive-transfer relapsing experimental autoimmune encephalomyelitis. Treatment with SCH94.03 after recovery from the initial episode of clinical disease reduced relapse rates by half, prolonged relapse onset by 6 days and reduced spinal cord demyelination and meningeal inflammation by 40%. These results are consistent with the hypothesized immunomodulatory function of Natural autoantibodies, and are the first direct demonstration that Natural humoral autoimmunity can be beneficial in an autoimmune T-cell-mediated CNS demyelinating disease.

  • multi organ reactivity of a monoclonal Natural Autoantibody that promotes remyelination in a mouse model of multiple sclerosis
    Journal of Histochemistry and Cytochemistry, 1996
    Co-Authors: David J Miller, M K Njenga, Joseph E Parisi, Moses Rodriguez
    Abstract:

    A contemporary view of autoimmunity suggests that self-reactivity is a normal phenomenon, in contrast to the classical association between autoimmunity and immunopathology. We have previously demonstrated that monoclonal antibody SCH94.03, a Natural Autoantibody with polyreactivity towards several purified protein and hapten antigens, promotes central nervous system remyelination when passively transferred to SJL/J mice chronically infected with Theiler's murine encephalomyelitis virus, an established experimental model of multiple sclerosis. In this study we characterized the autoreactivity of SCH94.03 with endogenous mouse tissue using immunoperoxide and multiple-color immunofluorescence staining techniques on frozen tissue sections. Within the nervous system, SCH94.03 labeled fibrous astrocytes, ependymal cells, ganglion satellite cells, and a sub-population of microglia, oligodendrocytes, and peripheral nervous system neurons. Outside the nervous system, SCH94.03 labeled gastrointestinal tract smooth ...

  • a monoclonal Natural Autoantibody that promotes remyelination suppresses central nervous system inflammation and increases virus expression after theiler s virus induced demyelination
    International Immunology, 1996
    Co-Authors: David J Miller, Kariuki M Njenga, Paul D Murray, Julian L Leibowitz, Moses Rodriguez
    Abstract:

    We have used an established experimental model of multiple sclerosis to investigate the potential beneficial relationship between Natural autoimmunity and remyelination after central nervous system (CNS) demyelination. Intracerebral infection of SJL/J mice with Theiler's murine encephalomyelitis virus (TMEV) produces chronic, progressive, inflammatory CNS demyelination. Chronically infected SJL/J mice show minimal spontaneous remyelination, which is in part due to a T cell-mediated immune response inhibiting myelin repair. We previously identified a monoclonal Natural Autoantibody, designated SCH94.03, that promotes remyelination when passively transferred to chronically infected SJL/J mice. The mechanism whereby SCH94.03 promotes remyelination is unknown, although previous reports suggest that Natural autoantibodies can modulate immune system function. In this report we demonstrate that treatment with SCH94.03 reduced by 2- to 3-fold the number of CD4(+) and CD8(+) cells infiltrating the CNS of SJL/J mice chronically infected with TMEV, in the absence of global lymphocyte depletion. Associated with the decreased inflammation was a 2- to 3-fold increase in virus antigen expression without a significant increase in viral RNA or virus titers. Treatment with SCH94.03 also suppressed the humoral immune response to a T cell-dependent antigen in chronically infected mice. Immunohistochemical staining showed that SCH94.03 labeled MHC class II-positive dendritic cells in peripheral lymphoid organs. These results are consistent with the proposed immunomodulatory function of Natural autoantibodies and suggest that one mechanism whereby SCH94.03 promotes CNS remyelination in chronically infected SJL/J mice is through inhibition of a pathogenic immune response.

  • a monoclonal Autoantibody that promotes central nervous system remyelination in a model of multiple sclerosis is a Natural Autoantibody encoded by germline immunoglobulin genes
    Journal of Immunology, 1995
    Co-Authors: David J Miller, Moses Rodriguez
    Abstract:

    Antibodies directed against self-Ags are frequently considered detrimental, and have been shown to play a pathogenic role in certain autoimmune diseases. However, the presence of autoreactive Abs in normal individuals suggests that some autoantibodies could participate in normal physiology. Our previous studies demonstrated that monoclonal autoantibodies SCH94.03 and SCH94.32, generated from the splenocytes of uninfected SJL/J mice injected with normal homogenized spinal cord, promote central nervous system remyelination when passively transferred into syngeneic mice chronically infected with Theiler's murine encephalomyelitis virus, an established experimental model of multiple sclerosis. In this study we show that these two monoclonal autoantibodies are identical, and have phenotypic characteristics of Natural autoantibodies. By using a solid phase assay system, SCH94.03 and SCH94.32 showed reactivity toward several protein Ags and chemical haptens, with prominent reactivity toward spectrin, (4-hydroxy-3-nitrophenyl)acetyl, and fluorescein. Sequence analysis showed that both SCH94.03 and SCH94.32 were encoded by identical germline Ig light chain V kappa 10/J kappa 1 and heavy chain V23/DFL16.1/JH2 genes, with no definitive somatic mutations. These results indicate that a Natural Autoantibody participates in a beneficial physiologic response to central nervous system injury.

Richard R Hardy - One of the best experts on this subject based on the ideXlab platform.

  • Autoreactive B-1 B Cells: Constraints on Natural Autoantibody B Cell Antigen Receptors
    2015
    Co-Authors: Ben Rowleya, Lingjuan Tang, Susan A Shinton, Kyoko Hayakawa, Richard R Hardy
    Abstract:

    B-1 B-cells constitute a distinctive population cells that are enriched for self-reactive B cell receptors (BCRs). These BCRs are encoded by a restricted set of heavy and light chains, including heavy chains that lack nontemplated nucleotide additions at the V-D and D-j joining regions. One prototype Natural Autoantibody produced by B-1 B cells binds to a cryptic determinant exposed on senescent red blood cells that includes the phosphatidylcholine (PtC) moiety. The VH11Vκ9 BCR that accounts for a large fraction of the anti-PtC specificity is underrepresented in other B-cell populations, including newly-formed B cells in bone marrow, and the transitional B cells, follicular B cells, and marginal zone B cells in spleen. Previous work has shown that VH11 heavy chains pair ineffectively with surrogate light chain (SLC) and so do not promote development in bone marrow, but instead allow fetal liver maturation because of a fetal preferences for weaker pre-BCR signaling. Such inefficient SLC pairing constitutes one constraint on maturation of B cells containing VH11 rearrangements that biases their generation to fetal development. Here, we examine another possible bottleneck to the B1 cell repertoire: light chain pairing with VH11 heavy chain, finding very significant preferences

  • Natural anti intestinal goblet cell Autoantibody production from marginal zone b cells
    Journal of Immunology, 2015
    Co-Authors: Daiju Ichikawa, Susan A Shinton, Richard R Hardy, Masanao Asano, Joni Brilldashoff, Anthony M Formica, Anna Velcich, Kyoko Hayakawa
    Abstract:

    Expression of a germline VH3609/D/JH2 IgH in mice results in the generation of B1 B cells with anti-thymocyte/Thy-1 glycoprotein autoreactivity by coexpression of Vk21-5/Jk2 L chain leading to production of serum IgM Natural Autoantibody. In these same mice, the marginal zone (MZ) B cell subset in spleen shows biased usage of a set of Ig L chains different from B1 B cells, with 30% having an identical Vk19-17/Jk1 L chain rearrangement. This VH3609/Vk19-17 IgM is reactive with intestinal goblet cell granules, binding to the intact large polymatrix form of mucin 2 glycoprotein secreted by goblet cells. Analysis of a μκ B cell AgR (BCR) transgenic (Tg) mouse with this anti–goblet cell/mucin2 autoreactive (AGcA) specificity demonstrates that immature B cells expressing the Tg BCR become MZ B cells in spleen by T cell–independent BCR signaling. These Tg B cells produce AGcA as the predominant serum IgM, but without enteropathy. Without the transgene, AGcA autoreactivity is low but detectable in the serum of BALB/c and C.B17 mice, and this Autoantibody is specifically produced by the MZ B cell subset. Thus, our findings reveal that AGcA is a Natural Autoantibody associated with MZ B cells.

  • autoreactive b 1 b cells constraints on Natural Autoantibody b cell antigen receptors
    Journal of Autoimmunity, 2007
    Co-Authors: Ben Rowley, Lingjuan Tang, Susan A Shinton, Kyoko Hayakawa, Richard R Hardy
    Abstract:

    B-1 B-cells constitute a distinctive population of cells that are enriched for self-reactive B cell receptors (BCRs). These BCRs are encoded by a restricted set of heavy and light chains, including heavy chains that lack nontemplated nucleotide additions at the V-D and D-J joining regions. One prototype Natural Autoantibody produced by B-1 B cells binds to a cryptic determinant exposed on senescent red blood cells that includes the phosphatidylcholine (PtC) moiety. The V(H)11Vkappa9 BCR, which accounts for a large fraction of the anti-PtC specificity, is underrepresented in other B-cell populations, including newly formed B cells in bone marrow, and the transitional B cells, follicular B cells, and marginal zone B cells in spleen. Previous work has shown that V(H)11 heavy chains pair ineffectively with surrogate light chain (SLC) and so do not promote development in bone marrow, but instead allow fetal liver maturation because of a fetal preference for weaker pre-BCR signaling. Such inefficient SLC pairing constitutes one constraint on the maturation of B cells containing V(H)11 rearrangements that biases their generation to fetal development. Here, we examine another possible bottleneck to the B1 cell repertoire: light chain pairing with V(H)11 heavy chain, finding very significant preferences.

  • b 1 b cells development selection Natural Autoantibody and leukemia
    Current Opinion in Immunology, 2006
    Co-Authors: Richard R Hardy
    Abstract:

    B-1 (CD5+) B cells constitute a phenotypic and functionally distinct population of B cells in mouse that show enriched expression of autoreactive B-cell antigen receptors and that produce several types of Natural autoantibodies. Recently, there has been much progress in this field of research. Evidence has appeared for the existence of distinctive B-cell precursors that preferentially generate B-1 B cells, and the crucial requirement for strong B-cell antigen receptor signaling in the maturation of B-1 B cells has been established. Other work focuses on a phenotypically similar population that lacks CD5, termed ‘B-1b’, which shows similarities and differences from most CD5+ B cells in both development and function. The relationship of normal B-1 cells with B-cell lymphomas and leukemias continues to be a subject of interest and debate.

  • selection during development of vh11 b cells a model for Natural Autoantibody producing cd5 b cells
    Immunological Reviews, 2004
    Co-Authors: Richard R Hardy, Chiju Wei, Kyoko Hayakawa
    Abstract:

    Natural autoantibodies constitute a large portion of serum immunoglobulin M (IgM) and bridge the adaptive and innate immune systems, serving as a rapid response to common pathogens. Many arise from a distinctive subset of B cells, termed B-1, that express CDS. Here, we describe our studies with a representative CD5 + B-cell-derived Natural Autoantibody, the V H 11V κ 9 B-cell receptor (BCR) that binds a determinant on senescent erythrocytes. This specificity represents 5-10% of the CD5 + B-cell subset, with a large portion accounted for by two novel BCRs, V H 11V κ 9 and V H 12V κ 4. We have found that the development of B-lineage cells with a V H 11 rearrangement is surprisingly restricted at several crucial bottlenecks: (i) one of the most common V H 11 rearrangements generates a heavy-chain protein that only inefficiently assembles a pre-BCR, key for recombinase-activating gene downregulation/allelic exclusion and pre-B-clonal expansion; (ii) cells containing V H 11-μ chains lacking N-addition are favored for progression to the B-cell stage, eliminating most bone marrow V H 11 rearrangements; and (iii) only a subset of V κ -light chains combine with V H 11 heavy chain to foster progression to the mature B-cell stage. Together, these constrain V H 11 generation to fetal development and may favor production of B cells with the prototype V H 11V κ 9 BCR.

Toshikazu Shirai - One of the best experts on this subject based on the ideXlab platform.

  • genetic association between Natural Autoantibody responses to histones and dna in murine lupus
    Autoimmunity, 1992
    Co-Authors: Katsutoshi Tokushige, Kohji Kinoshita, Sachiko Hirose, Toshikazu Shirai
    Abstract:

    Genetic regulation of the spontaneous anti-histone antibody production in systemic lupus erythematosus (SLE) was studied using the H-2-congenic and T cell receptor beta chain gene complex (TCR beta)-congenic NZB and NZW strains and their crosses. We found that the original, parental H-2d/d NZB mice produced significantly higher titers of serum IgM class anti-histone antibodies than did the congenic H-2d/z or H-2z/z NZB mice. However, none of these three NZB strains produced IgG antibodies. The NZW strain of any H-2 haplotype did not produce IgM and IgG anti-histone antibodies. The IgG anti-histone antibodies were produced only by H-2d/z heterozygous NZB x NZW F1, but not by homozygous H-2z/z or H-2d/d NZB x NZW F1 mice. In studies using (NZB x NZW) F1 x NZB backcross mice, only the progeny having both H-2d/z and NZW-type TCR beta genotypes produced high amounts of IgG antibodies. There was a tight linkage between the NZW-type TCR beta and the production of IgG anti-histone antibodies in TCR beta-congenic NZB x NZW F1 mice. All these findings were in keeping with our preceding observations on the genetic regulation of anti-DNA antibodies in these mice and suggest that certain common mechanisms such as super-antigen-mediated or common idiotope-mediated regulations may underlie the production of these two distinct autoantibodies in NZB x NZW F1 mice.

  • an early activation antigen of murine t cells recognized by monoclonal Natural Autoantibody nta204 and the expression on t cells from aged nzb x nzw f1 mice with overt autoimmune disease
    Autoimmunity, 1992
    Co-Authors: Genjiroh Ueda, Sachiko Hirose, Toshikazu Shirai
    Abstract:

    A monoclonal Natural thymocytotoxic Autoantibody NTA204 established from an autoimmune-prone NZB mouse reacted with the majority of thymocytes, all peripheral B cells, granulocytes and bone marrow myeloid cells, but not with peripheral resting T cells of normal mice. In aged NZB/W F1 mice with overt autoimmune disease, the population of NTA204+ CD4+ CD25- T cells was remarkably increased. The NTA204 antigen could be induced on splenic T cells from normal healthy mice as early as 3 hr after the initiation of culture with stimulant Con A, and was expressed on the vast majority in the 48-hr culture. The expression preceded that of other T cell activation antigens tested, CD25 and CD45R. Cell cycle analysis suggested that NTA204 is expressed at an early phase of G1A. T cells, particularly CD8+ T cells, in the allogeneic mixed lymphocyte culture (MLC) could be divided into two populations, NTA204+ and NTA204-. By immunohistochemical analysis, 30% of NTA204+ CD8+, but few NT204- CD8+ T cells were intensely positive for large cytoplasmic granules of perforin, an important cytolytic mediator of cytotoxic T cells. Thus the increased population of NTA204+ T cells in aged NZB/W F1 mice appear to be activated T cells and might be at least partly involved in the pathogenesis of disease in these mice. Immunoblotting analysis of Con A-activated splenic T cells showed that NTA204 molecules have a molecular mass of 49 Kd.

Kyoko Hayakawa - One of the best experts on this subject based on the ideXlab platform.

  • Autoreactive B-1 B Cells: Constraints on Natural Autoantibody B Cell Antigen Receptors
    2015
    Co-Authors: Ben Rowleya, Lingjuan Tang, Susan A Shinton, Kyoko Hayakawa, Richard R Hardy
    Abstract:

    B-1 B-cells constitute a distinctive population cells that are enriched for self-reactive B cell receptors (BCRs). These BCRs are encoded by a restricted set of heavy and light chains, including heavy chains that lack nontemplated nucleotide additions at the V-D and D-j joining regions. One prototype Natural Autoantibody produced by B-1 B cells binds to a cryptic determinant exposed on senescent red blood cells that includes the phosphatidylcholine (PtC) moiety. The VH11Vκ9 BCR that accounts for a large fraction of the anti-PtC specificity is underrepresented in other B-cell populations, including newly-formed B cells in bone marrow, and the transitional B cells, follicular B cells, and marginal zone B cells in spleen. Previous work has shown that VH11 heavy chains pair ineffectively with surrogate light chain (SLC) and so do not promote development in bone marrow, but instead allow fetal liver maturation because of a fetal preferences for weaker pre-BCR signaling. Such inefficient SLC pairing constitutes one constraint on maturation of B cells containing VH11 rearrangements that biases their generation to fetal development. Here, we examine another possible bottleneck to the B1 cell repertoire: light chain pairing with VH11 heavy chain, finding very significant preferences

  • Natural anti intestinal goblet cell Autoantibody production from marginal zone b cells
    Journal of Immunology, 2015
    Co-Authors: Daiju Ichikawa, Susan A Shinton, Richard R Hardy, Masanao Asano, Joni Brilldashoff, Anthony M Formica, Anna Velcich, Kyoko Hayakawa
    Abstract:

    Expression of a germline VH3609/D/JH2 IgH in mice results in the generation of B1 B cells with anti-thymocyte/Thy-1 glycoprotein autoreactivity by coexpression of Vk21-5/Jk2 L chain leading to production of serum IgM Natural Autoantibody. In these same mice, the marginal zone (MZ) B cell subset in spleen shows biased usage of a set of Ig L chains different from B1 B cells, with 30% having an identical Vk19-17/Jk1 L chain rearrangement. This VH3609/Vk19-17 IgM is reactive with intestinal goblet cell granules, binding to the intact large polymatrix form of mucin 2 glycoprotein secreted by goblet cells. Analysis of a μκ B cell AgR (BCR) transgenic (Tg) mouse with this anti–goblet cell/mucin2 autoreactive (AGcA) specificity demonstrates that immature B cells expressing the Tg BCR become MZ B cells in spleen by T cell–independent BCR signaling. These Tg B cells produce AGcA as the predominant serum IgM, but without enteropathy. Without the transgene, AGcA autoreactivity is low but detectable in the serum of BALB/c and C.B17 mice, and this Autoantibody is specifically produced by the MZ B cell subset. Thus, our findings reveal that AGcA is a Natural Autoantibody associated with MZ B cells.

  • autoreactive b 1 b cells constraints on Natural Autoantibody b cell antigen receptors
    Journal of Autoimmunity, 2007
    Co-Authors: Ben Rowley, Lingjuan Tang, Susan A Shinton, Kyoko Hayakawa, Richard R Hardy
    Abstract:

    B-1 B-cells constitute a distinctive population of cells that are enriched for self-reactive B cell receptors (BCRs). These BCRs are encoded by a restricted set of heavy and light chains, including heavy chains that lack nontemplated nucleotide additions at the V-D and D-J joining regions. One prototype Natural Autoantibody produced by B-1 B cells binds to a cryptic determinant exposed on senescent red blood cells that includes the phosphatidylcholine (PtC) moiety. The V(H)11Vkappa9 BCR, which accounts for a large fraction of the anti-PtC specificity, is underrepresented in other B-cell populations, including newly formed B cells in bone marrow, and the transitional B cells, follicular B cells, and marginal zone B cells in spleen. Previous work has shown that V(H)11 heavy chains pair ineffectively with surrogate light chain (SLC) and so do not promote development in bone marrow, but instead allow fetal liver maturation because of a fetal preference for weaker pre-BCR signaling. Such inefficient SLC pairing constitutes one constraint on the maturation of B cells containing V(H)11 rearrangements that biases their generation to fetal development. Here, we examine another possible bottleneck to the B1 cell repertoire: light chain pairing with V(H)11 heavy chain, finding very significant preferences.

  • selection during development of vh11 b cells a model for Natural Autoantibody producing cd5 b cells
    Immunological Reviews, 2004
    Co-Authors: Richard R Hardy, Chiju Wei, Kyoko Hayakawa
    Abstract:

    Natural autoantibodies constitute a large portion of serum immunoglobulin M (IgM) and bridge the adaptive and innate immune systems, serving as a rapid response to common pathogens. Many arise from a distinctive subset of B cells, termed B-1, that express CDS. Here, we describe our studies with a representative CD5 + B-cell-derived Natural Autoantibody, the V H 11V κ 9 B-cell receptor (BCR) that binds a determinant on senescent erythrocytes. This specificity represents 5-10% of the CD5 + B-cell subset, with a large portion accounted for by two novel BCRs, V H 11V κ 9 and V H 12V κ 4. We have found that the development of B-lineage cells with a V H 11 rearrangement is surprisingly restricted at several crucial bottlenecks: (i) one of the most common V H 11 rearrangements generates a heavy-chain protein that only inefficiently assembles a pre-BCR, key for recombinase-activating gene downregulation/allelic exclusion and pre-B-clonal expansion; (ii) cells containing V H 11-μ chains lacking N-addition are favored for progression to the B-cell stage, eliminating most bone marrow V H 11 rearrangements; and (iii) only a subset of V κ -light chains combine with V H 11 heavy chain to foster progression to the mature B-cell stage. Together, these constrain V H 11 generation to fetal development and may favor production of B cells with the prototype V H 11V κ 9 BCR.