Structure of Antibodies with Shared Idiotypy: The Complete Sequence of the Heavy Chain Variable Regions of Two Immunoglobulin M Anti-Gamma Globulins

Capra, J. Donald; Kehoe, J. Michael

doi:10.1073/pnas.71.10.4032

Cited by 105 publications

(45 citation statements)

References 40 publications

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“…B-CLL is not associated with HCV infection (25), but the antigeninduced expansion of clonotypic B cells may be similar. Over twenty-five years ago, our laboratory showed that the similarity among heavy chain complementaritydetermining regions (CDRs) 2 and 3 in the mixed cryoglobulin rheumatoid factors Pom and Lay (26,27) was perhaps an early hint of similar results to those reported by Ghiotto et al in this issue (16). EMC now is thought to arise from CD5 -immunocytomas that are considered marginal zone lymphomas.…”

Section: Clonotypic Igs Are Seen In Other Disease Processessupporting

confidence: 68%

Ig V region restrictions in human chronic lymphocytic leukemia suggest some cases have a common origin

Kolar¹,

Capra²

2004

J. Clin. Invest.

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The factors that contribute to the development of B cell chronic lymphocytic leukemia (B-CLL) are unknown, and the groups of individuals at the greatest risk for developing this common leukemia are not well defined. Molecular features are important for classifying cases of B-CLL, and it is now apparent that similarities among Ig rearrangements between patients may give important clues to the origin of this disease

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Section: Clonotypic Igs Are Seen In Other Disease Processessupporting

confidence: 68%

Ig V region restrictions in human chronic lymphocytic leukemia suggest some cases have a common origin

Kolar¹,

Capra²

2004

J. Clin. Invest.

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“…The structural basis of human autoantibodies has been the subject of intensive investigation for more than four decades (41,61). Initial studies of rheumatoid factor paraproteins provided critical insights into the structural basis of idiotypes and Ab diversity while also hinting at a role for somatic hypermutation first recognized by seminal studies of mouse L chains (62).…”

Section: Discussionmentioning

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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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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“…The presence of methionine residues at positions 34 and 83 of the heavy chain variable region in all mouse phosphorylcholine-binding proteins has facilitated their sequence determination by the procedures employed for M603 (17). These proteins provide a unique opportunity to evaluate primary structural differences among a group of antibodies demonstrating activity for the same chemically defined hapten.…”

Section: Discussionmentioning

confidence: 99%

Size differences among immunoglobulin heavy chains from phosphorylcholine-binding proteins.

Rudikoff¹,

Potter²

1976

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

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The entire sequences of the heavy chain variable regions of M167 and TEPC 15 (phosphorylcholine-binding myeloma proteins of BALB/c origin) have been determined. These sequences are compared with the phosphorylcholinebinding protein M603. T15 differs from M603 at four positions, all of which are located in antigen-binding complementarity regions. M167, in addition to having differences in the complementarity regions, also has five substitutions in the conserved framework portion of the variable region when compared to T15 and M603. Each of the three proteins has a different length in the third complementarity region. It is unlikely that complementarity regions of different lengths associated with similar framework regions could be generated by proposed mechanisms of somatic mutation which are generally limited to point mutations. It appears more likely that these products are directly encoded by different structural germ line genes.

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Structure of Antibodies with Shared Idiotypy: The Complete Sequence of the Heavy Chain Variable Regions of Two Immunoglobulin M Anti-Gamma Globulins

Cited by 105 publications

References 40 publications

Ig V region restrictions in human chronic lymphocytic leukemia suggest some cases have a common origin

Ig V region restrictions in human chronic lymphocytic leukemia suggest some cases have a common origin

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

Size differences among immunoglobulin heavy chains from phosphorylcholine-binding proteins.

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