Insertion of N regions into heavy-chain genes is correlated with expression of terminal deoxytransferase in B cells

Desiderio, Stephen; Yancopouloš, George D.; Paskind, Michael; Thomas, Elise; Boss, Michael A.; Landau, Nathaniel R.; Alt, Frederick W.; Baltimore, David

doi:10.1038/311752a0

Cited by 499 publications

(238 citation statements)

References 33 publications

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“…These extra nucleotides may be the result of de novo N-additions or an unusual rearrangement resulting from the use of nucleotides from the non-coding germ-line 3 0 end of the V gene, 5 0 end of the J and P-additions [38]. Earlier studies of the incidence of N-addition had shown that the process is associated with the activity of the TdT enzyme, which was thought to be active only in pre-B cells before the production of functional heavy chains [44]. In human V genes, N-additions were mainly seen in abortive V -J rearrangements or in translocations involving the light locus, suggesting that TdT activity may occur in certain B cells at the stage of development when the rearranging machinery proceeds to the locus [45].…”

Section: Discussionmentioning

confidence: 99%

Analysis of Vκ genes in rheumatoid arthritis (RA) synovial B lymphocytes provides evidence for both polyclonal activation and antigen-driven selection

Moyes¹,

Brown²,

Scott³

et al. 1996

Clinical and Experimental Immunology

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SUMMARYTo define mechanisms of sustained activation of synovial B lymphocytes in RA, we studied hybridomas established from the local synovial B cell repertoire of two RA patients for V gene expression and for antigen-binding specificity. The analyses revealed that members of the main V families (I, II and III) were utilized at frequencies consistent with random V gene family use. Furthermore, although the hybridomas expressed genes frequently seen in response to other self-and exogenous antigens, only one V I-and two of three V III-expressing hybridomas exhibited reactivity with self-antigens. Nucleotide sequence analysis revealed that all hybridomas, with the exception of rheumatoid factor (RF)-producing hybridomas, expressed V genes highly related to known germ-line genes (99 . 3-100% homology) and that diversity was generated by deletions and random nucleotide insertions at the V -J junction. Examination of the few nucleotide changes seen within the V genes revealed a predominance of silent to replacement changes. Moreover, most of these changes can be attributable either to allotypic variations or to limited random nucleotide replacements independent of antigen selection. In contrast, one IgG-RF (B4D8) exhibited predominantly replacement nucleotide changes in the complementaritydetermining regions, suggestive of antigen-driven selection. The random expression of immunoglobulin variable region genes with no, or little, evidence of mutation in the synovial B lymphocyte repertoire, including natural polyreactive antibodies, alongside mutated IgG-RF, suggest that both polyclonal activation and antigen-driven responses occur in RA synovia.

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Section: Discussionmentioning

confidence: 99%

Analysis of Vκ genes in rheumatoid arthritis (RA) synovial B lymphocytes provides evidence for both polyclonal activation and antigen-driven selection

Moyes¹,

Brown²,

Scott³

et al. 1996

Clinical and Experimental Immunology

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“…It is not possible to tell whether such breaks are single or double stranded. Although TdT is able e¤ciently to tail single-stranded DNA in vitro (Sambrook et al 1989) and can probably tail a nicked template (Grawunder & Lieber 1997), its only known in vivo action is the tailing of double-strand breaks during V(D)J recombination (Alt & Baltimore 1982;Desiderio et al 1984;Landau et al 1987). In vitro studies suggest that this action on doublestrand breaks is less e¤cient if the break is £ush or has a recessed 3'-end (Bollum 1974).…”

Section: Dna Breaks In Hypermutation and Isotype Switchingmentioning

confidence: 99%

In vivoandin vitrostudies of immunoglobulin gene somatic hypermutation

Sale

Bemark

Williams

et al. 2001

Phil. Trans. R. Soc. Lond. B

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Following antigen encounter, two distinct processes modify immunoglobulin genes. The variable region is diversi¢ed by somatic hypermutation while the constant region may be changed by class-switch recombination. Although both genetic events can occur concurrently within germinal centre B cells, there are examples of each occurring independently of the other. Here we compare the contributions of classswitch recombination and somatic hypermutation to the diversi¢cation of the serum immunoglobulin repertoire and review evidence that suggests that, despite clear di¡erences, the two processes may share some aspects of their mechanism in common.

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“…This conundrum was elegantly answered many years ago by an expansion of the primary Ab repertoire through genetic recombination of VDJ gene segments and by resultant combinatorial diversity arising from rearranged heterodimers of light and heavy chains (1). Recent high-throughput sequencing data in zebra fish and humans have provided further insights into the extent of the expressed Ab repertoire, as envisaged by Tonegawa et al (2,3) However, quantitative assessment, even after considering other possible mechanisms, proves this diversity to be inadequate for recognition of infinite Ags (4).…”

mentioning

confidence: 99%

Structural Elucidation of the Mechanistic Basis of Degeneracy in the Primary Humoral Response

Khan

Salunke

2012

The Journal of Immunology

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The mechanistic basis for efficient combating of the infinite range of foreign Ags by the limited repertoire of naive Abs expressed on primary B cell surfaces during their first encounter was addressed through elegantly designed crystallographic analyses. Resolution of the discrepancy arising from the limited number of possible germline Ab receptors on primary B cells for recognizing the unlimited pool of possible Ags has been attempted by invoking the degenerate recognition potential of the germline Abs. Structural analyses of germline mAb BBE6.12H3 in an Ag-free state, as well as bound to four different peptide Ags, established the correlation of its degenerate specificity with conformational versatility of the paratope. Six distinct paratope topologies observed for a single germline mAb provided a quantitative description of the primary Ag recognition repertoire at the tertiary structural level. Each of the four different peptide Ags was bound specifically to a distinct conformation of the paratope, which was also different from that of the Ag-free states of the same germline mAb. A minimal conserved motif in the pristine Ag-combining site essential for multispecificity and Ag binding-mediated change in the elbow angle of Fab was also discernible. It is proposed that the generation of a primary Ab repertoire involves large, yet finite, germline Ab clones, each capable of adopting discrete conformations, which in turn exhibit diverse binding modes.

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Insertion of N regions into heavy-chain genes is correlated with expression of terminal deoxytransferase in B cells

Cited by 499 publications

References 33 publications

Analysis of Vκ genes in rheumatoid arthritis (RA) synovial B lymphocytes provides evidence for both polyclonal activation and antigen-driven selection

Analysis of Vκ genes in rheumatoid arthritis (RA) synovial B lymphocytes provides evidence for both polyclonal activation and antigen-driven selection

In vivoandin vitrostudies of immunoglobulin gene somatic hypermutation

Structural Elucidation of the Mechanistic Basis of Degeneracy in the Primary Humoral Response

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