Molecular characterization of the J558 family of heavy chain variable region gene segments

Rathbun, Gary; Otani, Fabrízia Sayuri; Milner, Eric C. B.; Capra, J D; Tucker, P W

doi:10.1016/0022-2836(88)90272-0

Cited by 38 publications

(22 citation statements)

References 41 publications

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“…Although five hybridomas expressed J558 V H family genes, they were encoded by distinct V H germline segments (7,(26)(27)(28)32). The sixth hybridoma, 11C6-E3, expressed a VGAM3.8 V H family gene and was encoded by the BALB/c VFM1 germline gene (30).…”

Section: Resultsmentioning

confidence: 99%

T-Cell-Dependent Antibody Response to the Dominant Epitope of Streptococcal Polysaccharide,N-Acetyl-Glucosamine, Is Cross-Reactive with Cardiac Myosin

Malkiel¹,

Liao²,

Cunningham

et al. 2000

Infect Immun

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Autoantibodies against myosin are associated with myocarditis and rheumatic heart disease. In this study, the antigenic cross-reactivity of myosin and N-acetyl-glucosamine (GlcNAc), the dominant epitope of Group A streptococcal polysaccharide, was examined. Six antimyosin monoclonal antibodies (MAbs) derived from mice with cardiac myosin-induced myocarditis were characterized. All MAbs cross-reacted with GlcNAc, mimicking a subset of MAbs derived from rheumatic carditis patients that bind both myosin and streptococcal polysaccharide. Variable (V) region gene usage was diverse, with five of six MAb heavy-chain V regions encoded by distinct members of the J558 family and the sixth encoded by a member of the VGAM3.8 family. Light-chain V-region segments were derived from the Vk1, Vk4/5, Vk10, and Vk21 families. These antimyosin, anti-GlcNac MAbs demonstrated several T-cell-dependent features: they were predominantly immunoglobulin G, were encoded by V-region genes expressed late in development, and displayed somatic mutation. A direct correlation between the extent of somatic mutation and the affinity for myosin was observed. Affinity for GlcNAc also increased with the frequency of mutation, demonstrating that affinity maturation can occur simultaneously for both self antigen and foreign antigen. Based on these observations, we immunized mice with GlcNAc coupled to bovine serum albumin and demonstrated that a T-cell-dependent response to GlcNAc leads to antimyosin reactivity. We speculate that the pathogenic antibody response in rheumatic carditis may reflect the conversion of a T-cell-independent response to GlcNAc to a T-cell-dependent cross-reactive response to GlcNAc and myosin.

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Section: Resultsmentioning

confidence: 99%

T-Cell-Dependent Antibody Response to the Dominant Epitope of Streptococcal Polysaccharide,N-Acetyl-Glucosamine, Is Cross-Reactive with Cardiac Myosin

Malkiel¹,

Liao²,

Cunningham

et al. 2000

Infect Immun

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“…The procedures used to engineer and express Ig-OVA are similar to those described for Ig-PLP1 (20). In brief, the 91A 3 V H gene (24) was subcloned into the EcoRI site of the pUC19 plasmid and used as template DNA in PCR mutagenesis reactions to generate 91A 3 V H fragments carrying OVA 323-339 nucleotide sequence in place of the D segment within complementarity determining region 3 region. The resulting 91A 3 V H -OVA fragment was then analyzed by nucleotide sequencing to ensure that the D segment was deleted and a nucleotide sequence that will encode full OVA peptide was inserted instead.…”

Section: Ig Chimerasmentioning

confidence: 99%

“…However, to test for the organ-specific T cell regulation, an Ig chimera expressing the OVA peptide for which the DO11.10 T cells are specific was needed. Thus, the nucleotide sequence coding for OVA peptide was inserted within the 91A 3 V H gene (24), and sequencing analysis indicated that the D segment of complementarity determining region 3 region was deleted, and a nucleotide sequence coding for the full OVA 323-339 peptide was inserted instead (Fig. 1, top).…”

Section: Presentation Of Ova Peptide On Igsmentioning

confidence: 99%

Neonatal Immunity Develops in a Transgenic TCR Transfer Model and Reveals a Requirement for Elevated Cell Input to Achieve Organ-Specific Responses

Legge

Min

et al. 2001

The Journal of Immunology

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In recent years, it has become clear that neonatal exposure to Ag induces rather than ablates T cell immunity. Moreover, rechallenge with the Ag at adult age can trigger secondary responses that are distinct in the lymph node vs the spleen. The question addressed in this report is whether organ-specific secondary responses occur as a result of the diversity of the T cell repertoire or could they arise with homogeneous TCR-transgenic T cells. To test this premise, we used the OVA-specific DO11.10 TCR-transgenic T cells and established a neonatal T cell transfer system suitable for these investigations. In this system, neonatal T cells transferred from 1-day-old DO11.10/SCID mice into newborn (1-day-old) BALB/c mice migrate to the host’s spleen and maintain stable frequency. The newborn BALB/c hosts were then given Ig-OVA, an Ig molecule carrying the OVA peptide, and challenged with the OVA peptide in CFA at the age of 7 wk; then their secondary responses were analyzed. The findings show that the lymph node T cells were deviated and produced IL-4 instead of IFN-γ and the splenic T cells, although unable to proliferate or produce IFN-γ, secreted a significant level of IL-2. Supply of exogenous IL-12 during Ag stimulation restores both proliferation and IFN-γ production by the splenic T cells. This restorable form of splenic unresponsiveness referred to as IFN-γ-dependent anergy required a transfer of a high number of neonatal DO11.10/SCID T cells to develop. Thus, the frequency of neonatal T cell precursors rather than repertoire diversity exerts control on the development of organ-specific neonatal immunity.

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“…Mainly conventional B cells (B2) contribute to the production of these autoantibodies, which are primarily encoded by genes from the J558 family (19). The J558 family is the largest and most-5' VH gene family ofthe murine Igh-b locus (20). Based on nucleotide homology, the J558 genes were initially grouped into six subfamilies (20), which were later expanded to eight (21).…”

mentioning

confidence: 99%

“…The J558 family is the largest and most-5' VH gene family ofthe murine Igh-b locus (20). Based on nucleotide homology, the J558 genes were initially grouped into six subfamilies (20), which were later expanded to eight (21). It is not known whether the genes encoding these antibodies are dispersed over the entire J558 gene family cluster or derived from a single subfamily.…”

mentioning

confidence: 99%

Molecular characterization of J558 genes encoding tight-skin mouse autoantibodies: identical heavy-chain variable genes code for antibodies with different specificities.

Kasturi

Yio²,

Bona³

1994

Proc. Natl. Acad. Sci. U.S.A.

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Tight-skin mouse, a mutant strain with a single gene defect, develops cutaneous hyperplasia and specific autoantibodies, like humans affected by scleroderma. The autoantibodies produced in the tight-skin mouse are encoded primarily by heavy-chain variable (Vu) genes from the J558 family. To understand the genetic basis of production of autoantibodies, we have analyzed the structure of J558 genes encoding these autoantibodies. The results showed that J558 genes encoding these antibodies were not derived from a selected germ-line gene(s) or a single subfamily but were derived from genes belonging to diverse J558 subfamilies. However, two prototype VH genes representing two new subfamilies were found to be repeatedly expressed in their germline form in eight independent clones. Autoantibodies with distinct specificities appear to be generated by pairing of similar/identical VH genes with different V,, genes derived from the same or different families. Fourteen of 18 autoantibodies shared a conserved heptapeptide sequence motif, YNEKFKG, in the second complementarity-determining region of heavy chains. Usage of germ-line genes from diverse J558 sub s bearing a common motif to encode autoantibodies suggests a regulatory role for this motif. Thus, selection and expansion of the autoreactive B-cell repertoire in the tight-skin mouse appear to be VH-gene mediated. The frequency of N nucleotide addition at diversity-joining (D-JH) junctions was lower, whereas the frequency of usage of the DFL16 segment was higher. Finally, in contrast to normal and other autoimmune mouse strains, the frequencies of D-D fusions and D inversions were higher in tight-skin mouse total immunoglobulin as well as autoantibody repertoires.Antibody diversity is generated by somatic recombination of diverse germ-line gene segments coding for heavy and light chains of immunoglobulins. In addition, somatic mutation, insertion or deletion of nucleotides at V(D)J junctions, D-D fusion, D inversion, and gene conversion that occur during the recombination process contribute to antibody diversity (1)(2)(3)(4)

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Molecular characterization of the J558 family of heavy chain variable region gene segments

Cited by 38 publications

References 41 publications

T-Cell-Dependent Antibody Response to the Dominant Epitope of Streptococcal Polysaccharide,N-Acetyl-Glucosamine, Is Cross-Reactive with Cardiac Myosin

T-Cell-Dependent Antibody Response to the Dominant Epitope of Streptococcal Polysaccharide,N-Acetyl-Glucosamine, Is Cross-Reactive with Cardiac Myosin

Neonatal Immunity Develops in a Transgenic TCR Transfer Model and Reveals a Requirement for Elevated Cell Input to Achieve Organ-Specific Responses

Molecular characterization of J558 genes encoding tight-skin mouse autoantibodies: identical heavy-chain variable genes code for antibodies with different specificities.

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