The I Binding Specificity of Human VH4-34 (VH4-21) Encoded Antibodies is Determined by Both VHFramework Region 1 and Complementarity Determining Region 3

Y, Li; Mb, Spellerberg; Stevenson, Freda K.; Jd, Capra; Kn, Potter

doi:10.1006/jmbi.1996.0110

Cited by 94 publications

(87 citation statements)

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“…This interpretation is consistent with studies of IgM 9G4 Abs showing that, conformationally, the HCDR3 lies in close proximity to the HP, may promote antidsDNA binding if positively charged, and may interfere with canonical 9G4 Ab I/i binding and 9G4-induced RBC agglutination (26,52,56). However, ours is the first demonstration, to our knowledge, of the reverse situation, in which the presence of the HP attenuates or even blocks binding to ANA, dsDNA, and APCB in Abs that otherwise possess the structural requirements for binding to this group of SLE Ags.…”

Section: Discussionsupporting

confidence: 88%

“…However, the influence of the HCDR3s is less understood in 9G4 Abs because the FR1 HP may be dominant in binding to the canonical I/i Ags, and, yet, at least for IgM cold-agglutinins, the HCDR3 can determine binding to other self-Ags while modulating anti-I reactivity (26,52,56). Accordingly, we hypothesized that the nature of the HCDR3 would preferentially influence HP-independent 9G4 autoreactivities (APCB, ANA, and dsDNA).…”

Section: The Vh4-34 Fr1 Hp Plays a Differential Role In Separate 9g4 mentioning

confidence: 99%

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Molecular Basis of 9G4 B Cell Autoreactivity in Human Systemic Lupus Erythematosus

Richardson

Chida

Adlowitz

et al. 2013

The Journal of Immunology

116

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9G4+ IgG Abs expand in systemic lupus erythematosus (SLE) in a disease-specific fashion and react with different lupus Ags including B cell Ags and apoptotic cells. Their shared use of VH4-34 represents a unique system to understand the molecular basis of lupus autoreactivity. In this study, a large panel of recombinant 9G4+ mAbs from single naive and memory cells was generated and tested against B cells, apoptotic cells, and other Ags. Mutagenesis eliminated the framework-1 hydrophobic patch (HP) responsible for the 9G4 idiotype. The expression of the HP in unselected VH4-34 cells was assessed by deep sequencing. We found that 9G4 Abs recognize several Ags following two distinct structural patterns. B cell binding is dependent on the HP, whereas anti-nuclear Abs, apoptotic cells, and dsDNA binding are HP independent and correlate with positively charged H chain third CDR. The majority of mutated VH4-34 memory cells retain the HP, thereby suggesting selection by Ags that require this germline structure. Our findings show that the germline-encoded HP is compulsory for the anti–B cell reactivity largely associated with 9G4 Abs in SLE but is not required for reactivity against apoptotic cells, dsDNA, chromatin, anti-nuclear Abs, or cardiolipin. Given that the lupus memory compartment contains a majority of HP+ VH4-34 cells but decreased B cell reactivity, additional HP-dependent Ags must participate in the selection of this compartment. This study represents the first analysis, to our knowledge, of VH-restricted autoreactive B cells specifically expanded in SLE and provides the foundation to understand the antigenic forces at play in this disease.

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Section: Discussionsupporting

confidence: 88%

Section: The Vh4-34 Fr1 Hp Plays a Differential Role In Separate 9g4 mentioning

confidence: 99%

Molecular Basis of 9G4 B Cell Autoreactivity in Human Systemic Lupus Erythematosus

Richardson

Chida

Adlowitz

et al. 2013

The Journal of Immunology

116

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“…In addition, all anti-I/i antibodies thus far studied were encoded by VH4-34, thereby indicating that the expression of this gene segment is mandatory for anti-I/i CA activity [36,37,38]. The ability of 9G4 antibodies to bind NAL reflects their ability to recognize this antigen in a superantigen-like fashion through residues encoded in the germline sequence of the first framework region and largely irrespective of the somatically generated third hypervariable region and of the associated light chain [33,39,40,41]. Indeed, it appears that most light chains (either κ or λ) are permissive of anti-I/i binding [40].…”

Section: G4 Antibodies In Health and Diseasementioning

confidence: 99%

Human innate B cells: a link between host defense and autoimmunity?

Milner

Anolik

Cappione

et al. 2005

Springer Semin Immun

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B cells play a variety of immunoregulatory roles through their antigen-presentation ability and through cytokine and chemokine production. Innate immune activation of B cells may play a beneficial role through the generation of natural cross-reactive antibodies, by maintaining B cell memory and by exercising immunomodulatory functions that may provide protection against autoimmunity. In this article, we review human B cell populations and their functional properties, with a particular focus on a population of inherently autoreactive B cells, which seem to play an important physiological role in innate immunity, but which, if selected into adaptive immune responses, appear to become pathogenic agents in systemic lupus erythematosus.

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“…The V 4-34 gene is also able to encode anti-DNA antibodies, and certain other antibodies [6,7]. One of the structural features of the gene product is that recognition of erythrocyte antigen appears to be via a framework sequence [8]. V 4-34 -encoded antibodies therefore can bind autoantigen via unconventional sites in a manner similar to binding of Staphylococcal protein A by V H 3-encoded antibodies [9].…”

Section: Introductionmentioning

confidence: 99%

Tracking of the V4–34 (VH4–21) gene in human tonsil reveals clonal isotype switch events and a highly variable degree of somatic hypermutation

Chapman

Mockridge

Hamblin

et al. 1996

Clinical and Experimental Immunology

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SUMMARYThe V 4-34 (V H 4-21) gene has been found to encode certain IgM autoantibodies, and is mandatory for pathological IgM anti-erythrocyte antibodies of I/i specificity. The gene is also commonly used by normal IgM-positive B lymphocytes, but its involvement in B cells which have undergone class switching to IgG or IgA is less clear. In order to track V 4-34 gene usage and class switching events during a normal immune response, we have probed RNA in a limited area of human tonsil. Results indicate that the V 4-34 gene undergoes class switching to IgG or IgA, with the progeny either remaining unmutated or containing large numbers of somatic mutations. Mutational patterns indicate possible 'hot spots', and some mutations appear deleterious. At the level of individual B cells, we have tracked a clonal isotype switch event from IgM to IgA, with each retaining close to germ-line configuration. In addition, we have followed a clonal switch from a mutated IgM to IgG, with no further accumulation of somatic mutations. These data indicate that the V 4-34 gene is involved in a maturing immune response, and that the routes to production of IgG or IgA antibodies are various.

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The I Binding Specificity of Human VH4-34 (VH4-21) Encoded Antibodies is Determined by Both VHFramework Region 1 and Complementarity Determining Region 3

Cited by 94 publications

References 0 publications

Molecular Basis of 9G4 B Cell Autoreactivity in Human Systemic Lupus Erythematosus

Molecular Basis of 9G4 B Cell Autoreactivity in Human Systemic Lupus Erythematosus

Human innate B cells: a link between host defense and autoimmunity?

Tracking of the V4–34 (VH4–21) gene in human tonsil reveals clonal isotype switch events and a highly variable degree of somatic hypermutation

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