scholarly journals Genetic analysis of self-associating immunoglobulin G rheumatoid factors from two rheumatoid synovia implicates an antigen-driven response.

1992 ◽  
Vol 175 (3) ◽  
pp. 831-842 ◽  
Author(s):  
T Olee ◽  
E W Lu ◽  
D F Huang ◽  
R W Soto-Gil ◽  
M Deftos ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heavy Chain ◽  
Immunoglobulin M ◽  
Natural Antibody ◽  
Antibody Repertoire ◽  
Rheumatoid Factors ◽  
Variable Regions ◽  
Genetic Origins ◽  
V Genes ◽  
Vh Gene

Although much has been learned about the molecular basis of immunoglobulin M (IgM) rheumatoid factors (RFs) in healthy individuals and in patients with mixed cryoglobulinemia and rheumatoid arthritis, little is known about the genetic origins of the potentially pathogenic IgG RFs in the inflamed rheumatoid synovia of patients. Recently, we generated from unmanipulated synovium B cells several hybridomas that secreted self-associating IgG RFs. To delineate the genetic origins of such potentially pathogenic RFs, we adapted the anchored polymerase chain reaction to rapidly clone and characterize the expressed Ig V genes for the L1 and the D1 IgG RFs. Then, we identified the germline counterparts of the expressed L1 IgG RF V genes. The results showed that the L1 heavy chain was encoded by a Vh gene that is expressed preferentially during early ontogenic development, and that is probably located within 240 kb upstream of the Jh locus. The overlap between this RF Vh gene and the restricted fetal antibody repertoire is reminiscent of the natural antibody-associated Vh genes, and suggests that at least part of the "potential pathogenic" IgG RFs in rheumatoid synovium may derive from the "physiological" natural antibody repertoire in a normal immune system. Indeed, the corresponding germline Vh gene for L1 encodes the heavy chain of an IgM RF found in a 19-wk-old fetal spleen. Furthermore, the comparisons of the expressed RF V genes and their germline counterparts reveal that the L1 heavy and light chain variable regions had, respectively, 16 and 7 somatic mutations, which resulted in eight and four amino acid changes. Strikingly, all eight mutations in the complementarity determining regions of the V gene-encoded regions were replacement changes, while only 6 of 11 mutations in the framework regions caused amino acid changes. Combined with L1's high binding affinity toward the Fc fragment, these results suggest strongly that the L1 IgG RF must have been driven by the Fc antigen.

scholarly journals Complete amino acid sequence of heavy chain variable regions derived from two monoclonal anti-p-azophenylarsonate antibodies of BALB/c mice expressing the major cross-reactive idiotype of the A/J strain.

1984 ◽  
Vol 160 (4) ◽  
pp. 1070-1086 ◽  
Author(s):  
K Meek ◽  
D Jeske ◽  
M Slaoui ◽  
O Leo ◽  
J Urbain ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heavy Chain ◽  
Gene Segment ◽  
Amino Acid Sequences ◽  
Entire Family ◽  
Antibody Diversity ◽  
Variable Regions ◽  
Amino Terminal ◽  
Variable Segment ◽  
Vh Gene

The primary structure of A/J anti-p-azophenylarsonate (anti-Ars) antibodies expressing the major A-strain cross-reactive idiotype (CRIA) has provided important insights into issues of antibody diversity and the molecular basis of idiotypy in this important model system. Until recently, this idiotype was thought to be rarely, if ever, expressed in BALB/c mice. Indeed, it has been reported that BALB/c mice lack the heavy chain variable segment (VH) gene that is utilized by the entire family of anti-Ars antibodies expressing the A/J CRI. Recently, however, it has been possible to elicit CRIA+, Ars binding antibodies in the BALB/c strain by immunizing first with anti-CRI and then with antigen. Such BALB/c, CRIA+ anti-Ars antibodies can be induced occasionally with antigen alone. VH region amino acid sequences are described for two CRIA+ hybridoma products derived from BALB/c mice. While remarkably similar to each other, their VH segments (1-98) differ from the VH segments of A/J CRIA+, anti-Ars antibodies in over 40 positions. Rather than the usual JH2 gene segment used by most A/J CRIA+ anti-Ars antibodies, one BALB/c CRIA+ hybridoma utilizes a JH1 gene segment, while the other uses a JH4. However, the D segments of both of the BALB/c antibodies are remarkably homologous to the D segments of several A/J CRIA+ antibodies sequenced previously, as are the amino terminal amino acid sequences of their light chains. These data imply that BALB/c mice express the A/J CRIA by producing antibodies with very similar, if not identical, light chain and heavy chain D segments, but in the context of different VH and JH gene segments than their A/J counterparts. The results document that molecules that share serologic specificities can have vastly different primary structures.

scholarly journals The amino acid sequences of the Fd fragments of two human γ 1 heavy chains

1970 ◽  
Vol 117 (4) ◽  
pp. 641-660 ◽  
Author(s):  
E. M. Press ◽  
N. M. Hogg
Keyword(s):  
Amino Acid ◽  
Aspartic Acid ◽  
Heavy Chain ◽  
Variable Region ◽  
Amino Acid Sequences ◽  
Light Chains ◽  
Aspartic Acid Residue ◽  
Variable Regions ◽  
Heavy Chain Variable Region ◽  
Heavy Chains

The amino acid sequences of the Fd fragments of two human pathological immunoglobulins of the immunoglobulin G1 class are reported. Comparison of the two sequences shows that the heavy-chain variable regions are similar in length to those of the light chains. The existence of heavy chain variable region subgroups is also deduced, from a comparison of these two sequences with those of another γ 1 chain, Eu, a μ chain, Ou, and the partial sequence of a fourth γ 1 chain, Ste. Carbohydrate has been found to be linked to an aspartic acid residue in the variable region of one of the γ 1 chains, Cor.

scholarly journals Amino acid sequence of a platelet-binding human anti-DNA monoclonal autoantibody

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 262-269 ◽  
Author(s):  
GW Lampman ◽  
B Furie ◽  
RS Schwartz ◽  
BD Stollar ◽  
BC Furie
Keyword(s):  
Amino Acid ◽  
Heavy Chain ◽  
Light Chain ◽  
Lupus Erythematosus ◽  
Amino Acid Sequences ◽  
Variable Regions ◽  
Germline Genes ◽  
Expression Product ◽  
Platelet Binding ◽  
Monoclonal Autoantibody

Abstract The complete amino acid sequences of the variable regions of the heavy and light chains of a human IgM monoclonal platelet-binding autoantibody have been determined. This antibody, HF2–1/17, produced by a human x human hybridoma prepared from lymphocytes of a patient with systemic lupus erythematosus and thrombocytopenia, is polyreactive with single-stranded DNA, synthetic polynucleotides, sulfated carbohydrates, and acidic glycolipids isolated from platelet membranes. The heavy chain is of the VHIII subgroup, and the light chain is of the VKI subgroup. The heavy chain is the expression product of the VH26 germline gene. The light chain bears significant homology to other immunoglobulins of known primary structure, including WEA, GAL, HAU, HK101, and DEE. These results suggest that HF2–1/17 may be an autoantibody derived with little or no modification from germline genes. A model of the antibody combining site suggests that arginine 24 and arginine 30 in the light chain (CDR1) interact with a surface defined by phosphate or sulfate groups of the antigen.

scholarly journals A conserved human germline V kappa gene directly encodes rheumatoid factor light chains.

1986 ◽  
Vol 164 (6) ◽  
pp. 2119-2124 ◽  
Author(s):  
V Radoux ◽  
P P Chen ◽  
J A Sorge ◽  
D A Carson
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Light Chain ◽  
Light Chains ◽  
Gene Repertoire ◽  
Rheumatoid Factors ◽  
Variable Regions ◽  
Normal People ◽  
Related Group ◽  
Full Length Gene

The full-length gene that encodes the light chain variable regions of an idiotypically related group of human IgM kappa rheumatoid factors (RFs) has been cloned and sequenced. The deduced amino acid sequence is identical to four separate RF proteins. These results prove that genes capable of encoding human anti-IgG autoantibody light chains without any somatic mutation are present in the kappa gene repertoire of normal people.

scholarly journals Complete amino acid sequences of variable regions of two human IgM rheumatoid factors, BOR and KAS of the Wa idiotypic family, reveal restricted use of heavy and light chain variable and joining region gene segments.

1987 ◽  
Vol 166 (2) ◽  
pp. 550-564 ◽  
Author(s):  
M M Newkirk ◽  
R A Mageed ◽  
R Jefferis ◽  
P P Chen ◽  
J D Capra
Keyword(s):  
Amino Acid ◽  
Gene Segment ◽  
Variable Region ◽  
Amino Acid Sequences ◽  
Light Chains ◽  
Rheumatoid Factors ◽  
Region Gene ◽  
Variable Regions ◽  
D Region ◽  
Restricted Use

Evidence derived from the complete amino acid sequences of the variable regions of both the heavy and light chains of two members (BOR and KAS) of the Wa idiotypic family of human rheumatoid factors suggests that not only are the light chains of these molecules derived from possibly one variable region gene segment, but the heavy chain variable regions are all derived from the VHI subgroup of human V region genes. These molecules exhibit a surprising conservation in the size of D region, and all use the JH4 gene element. This restriction in use of VL, VH, D, and JH suggests all of these elements may play a crucial role in either antigen binding and/or expression of the crossreactive idiotype.

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