Establishment and Functional Implications of B‐cell Connectivity

Holmberg, Dan; Andersson, Åsa; Carlsson, Leif; Forsgren, Sture

doi:10.1111/j.1600-065x.1989.tb00028.x

Cited by 60 publications

(35 citation statements)

References 54 publications

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“…Fetal diversity was also reported to reflect limited diversification of the CDR3 region during early ontogeny. This was related to a relative paucity of N region additions (7,29), a high frequency of homology-directed recombination (17), and generation of shorter CDR3 domains during the fetal life (30). It has been suggested that the restricted diversity of the fetal Ig repertoire predisposes to the generation of multireactive, low affinity self-reactive Abs at this stage of development (31).…”

Section: Discussionmentioning

confidence: 99%

The VλJλ Repertoire in Human Fetal Spleen: Evidence for Positive Selection and Extensive Receptor Editing

Lee

Monson

Lipsky

2000

The Journal of Immunology

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VλJλ rearrangements obtained from genomic DNA of individual IgM+ B cells from human fetal spleen were analyzed. A nonrandom pattern of λ gene rearrangements that differed from the adult Vλ repertoire was found. The Vλ distal genes 8A and 4B were absent from the nonproductive fetal repertoire, whereas 2E and 3L were overrepresented and 1B was underrepresented in the productive fetal repertoire. Positive selection of the Vλ gene, 2E, along with Vλ rearrangements employing homologous VλJλ joins were observed in the fetal, but not in the adult Vλ repertoire. Overrepresentation of Jλ distal cluster C genes rearranging to the Vλ distal J segment, Jλ7, in both productive and nonproductive fetal repertoires suggested that receptor editing/replacement was more active in the fetus than in adults. Numerous identical VλJλ junctions were observed in both the productive and nonproductive repertoire of the fetus and adult, but were significantly more frequent in the productive repertoire of the fetus, suggesting expansion of B cells expressing particular λ-light chains in both stages of development, with more profound expansion in the fetal repertoire. Notably, B cells expressing identical λ-light chains expressed diverse heavy chains. These data demonstrate that three mechanisms strongly influence the shaping of the human fetal λ-chain repertoire that are less evident in the adult: positive selection, receptor editing, and expansion of B cells expressing specific λ-light chains. These events imply that the expressed fetal repertoire is shaped by exposure to self Ags.

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Section: Discussionmentioning

confidence: 99%

The VλJλ Repertoire in Human Fetal Spleen: Evidence for Positive Selection and Extensive Receptor Editing

Lee

Monson

Lipsky

2000

The Journal of Immunology

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“…This recurrent use of certain genetic elements in different autoantibodies suggests that human autoreactive immunoglobulins are encoded by a restricted set of V region genes. Furthermore, this observation provides a genetic explanation for the high degree of idiotypic cross-reactivity (or connectivity) observed in the autoantibody repertoire [26].…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of the variable region genes encoding a monospecific human natural anti-DNA antibody

Daley

Misener

Olee

et al. 1993

Clinical and Experimental Immunology

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SUMMARYRecent evidence suggests that natural autoantibodies may ptay an integral rote in the development of the normal immune repertoire. To explore the genetic origins of these antibodies, we have isolated and sequenced the variable (V) region genes encoding both the heavy (H) and light (L) chains of a natural anti-DNA antibody, Kim It.4. The genes appear to be derived from the VH4.t8 (subgroup VntV), JH5, Hum t LI (subgroup VAt) and JA3 germline genes. The origin of the H chain diversity gene is more obscure, being potentially derived from one or more of several germline genes, arranged in either the forward or reverse orientations. Both the Kim 11.4 VH and VL genes share significant degrees of similarity with those utilized in other autoantibodies, indicating that at least some degree of V restriction may exist in human autoreactive B cells. The pattern of nucleotide differences between the Kiml 1.4 VH and VL genes and their putative germline counterparts suggests that the Kiml 1.4 genes may have undergone somatic mutation and arisen as a result of antigen selection.

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“…One might wonder why an anti-Id response would suppress rather than stimulate an Id Ab response. A possible explanation could be due to the well known observation that anti-Id Ab given during the fetal or neonatal period often enhances production of the corresponding Id Ab while injection of anti-Id Ab during adulthood almost always inhibits Id Ab production (Holmberg et al, 1989). Consequently as these vaccines are further developed, special attention should be given to a recipient's age.…”

Section: Discussionmentioning

confidence: 99%

Possible therapeutic vaccines for canine myasthenia gravis: Implications for the human disease and associated fatigue

Galin¹,

Chrisman²,

Cook³

et al. 2007

Brain, Behavior, and Immunity

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Myasthenia gravis (MG) is caused by T-cell dependent antibodies reactive with acetylcholine receptors. These autoreactive antibodies cause muscle weakness by interfering with neuromuscular transmission via removal of acetylcholine receptors from the neuromuscular junction as well as changing the architecture of the junction itself. Consequently, muscle fatigue is a debilitating aspect of MG often leading to more general feelings of tiredness not directly due to muscle weakness. We have previously described two peptides that are mimetics of antigen receptors on certain autoreactive T and B cells that are involved in MG. When used as vaccines in the rat model of MG, these peptides prevented and ameliorated disease and muscle fatigue by blunting acetylcholine receptor antibody responses. Such disease protection resulted from vaccine-induced anergizing antibodies against acetylcholine receptor-specific T and B-cell antigen receptors. The present study prospectively evaluated the efficacy of these two vaccines in spontaneous acquired MG in pet dogs. When compared to historical controls that were prospectively studied, the vaccines increased the proportion of remitted dogs from 17% to 75%. In comparison to retrospectively studied historical controls that spontaneously remitted from MG, the vaccines accelerated the rate of decline in acetylcholine receptor antibody titers which resulted in a 3-fold decrease in the mean time to remission. These results are suggestive of a new type of targeted therapy that can drive autoimmune responses into long-term remission and possibly afford a means of determining whether correction of a physical cause of muscle weakness also corrects the perception of chronic, generalized fatigue.

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Establishment and Functional Implications of B‐cell Connectivity

Cited by 60 publications

References 54 publications

The VλJλ Repertoire in Human Fetal Spleen: Evidence for Positive Selection and Extensive Receptor Editing

The VλJλ Repertoire in Human Fetal Spleen: Evidence for Positive Selection and Extensive Receptor Editing

Genetic analysis of the variable region genes encoding a monospecific human natural anti-DNA antibody

Possible therapeutic vaccines for canine myasthenia gravis: Implications for the human disease and associated fatigue

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