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Light chain usage in anti-double-stranded DNA B cell subsets: role in cell fate determination.

Spatz L, Saenko V, Iliev A, Jones L, Geskin L, Diamond B - J. Exp. Med. (1997)

Bottom Line: Studies to date suggest that low avidity interactions between B cells and autoantigen lead to B cell silencing, whereas high avidity interactions lead to deletion.A major implication of this observation is that dsDNA may not be the self antigen responsible for cell fate determinations of anti-dsDNA B cells.Light chain usage may determine antigenic cross-reactivity, and cross-reactive antigens may regulate B cells that also bind dsDNA.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

ABSTRACT
Two major mechanisms for the regulation of autoreactive B cells that arise in the bone marrow are functional silencing (anergy) and deletion. Studies to date suggest that low avidity interactions between B cells and autoantigen lead to B cell silencing, whereas high avidity interactions lead to deletion. Anti-double stranded (ds) DNA antibodies represent a pathogenic autospecificity in Systemic Lupus Erythematosus (SLE). An understanding of their regulation is critical to an understanding of SLE. We now demonstrate in a transgenic model in which mice express the heavy chain of a potentially pathogenic anti-DNA antibody that antibody affinity for dsDNA does not alone determine the fate of anti-dsDNA B cells. B cells making antibodies with similar affinities for dsDNA are regulated differently, depending on light chain usage. A major implication of this observation is that dsDNA may not be the self antigen responsible for cell fate determinations of anti-dsDNA B cells. Light chain usage may determine antigenic cross-reactivity, and cross-reactive antigens may regulate B cells that also bind dsDNA.

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Nucleotide and amino acid sequences of Vk1 light chains from  autoimmune transgenic hybridomas. Light chain nucleotide and amino  acid sequences from hybridomas from autoimmune NZB/W F1 transgenic mice are compared to their most homologous Vk1 germline genes.  (A) Vk1-A, (B) Vk1-B, and (C) Vk1-C (38, 41). CDR regions are underlined and are according to Kabat et al. (40). Dashes indicate identity of  nucleotides to the germline sequence. Silent base changes are designated  by lowercase letters. Nucleotide changes leading to amino acid replacements in the V region are indicated by uppercase letters. Those leading to  amino acid replacements in the J regions are indicated in bold. Amino acid replacements are indicated above the nucleotide sequence. Amino acid replacements from the germline J are indicated in bold. The BW prefix precedes all numeric designations of light chains derived from NZB/W F1 mice.
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Figure 3: Nucleotide and amino acid sequences of Vk1 light chains from autoimmune transgenic hybridomas. Light chain nucleotide and amino acid sequences from hybridomas from autoimmune NZB/W F1 transgenic mice are compared to their most homologous Vk1 germline genes. (A) Vk1-A, (B) Vk1-B, and (C) Vk1-C (38, 41). CDR regions are underlined and are according to Kabat et al. (40). Dashes indicate identity of nucleotides to the germline sequence. Silent base changes are designated by lowercase letters. Nucleotide changes leading to amino acid replacements in the V region are indicated by uppercase letters. Those leading to amino acid replacements in the J regions are indicated in bold. Amino acid replacements are indicated above the nucleotide sequence. Amino acid replacements from the germline J are indicated in bold. The BW prefix precedes all numeric designations of light chains derived from NZB/W F1 mice.

Mentions: Transgene expressing anti-dsDNA hybridomas from R4A-γ2b transgenic NZB/W F1 mice could be obtained from non-LPS activated B cells as well as from LPS activated splenocytes, confirming activation in vivo of antidsDNA B cells in the autoimmune mice. In contrast to the dominant Vk1 usage seen in nonautoimmune mice, only 5 of 16 autoimmune derived anti-dsDNA hybridomas use a Vk1 gene (Table 1). 12 cell lines were obtained from LPSstimulated splenocytes, of which only 4 (33%) use Vk1 genes. Only 1 of 4 cell lines obtained from unstimulated NZB/W F1 splenocytes (25%) uses a Vk1 light chain. Therefore, there is little difference in the frequency of Vk1 expression in hybridomas from LPS-stimulated and unstimulated splenocytes. Vk1 genes from NZB/W F1 hybridomas display no somatic mutation in three (BW19G10, BW21D11, and BW10D9) of the five Vk1 genes sequenced (Fig. 3). The base change observed at the junction of Vk and Jk in Bw19G10 and BW21D11 is likely the result of imprecise joining during Vk-Jk rearrangement.


Light chain usage in anti-double-stranded DNA B cell subsets: role in cell fate determination.

Spatz L, Saenko V, Iliev A, Jones L, Geskin L, Diamond B - J. Exp. Med. (1997)

Nucleotide and amino acid sequences of Vk1 light chains from  autoimmune transgenic hybridomas. Light chain nucleotide and amino  acid sequences from hybridomas from autoimmune NZB/W F1 transgenic mice are compared to their most homologous Vk1 germline genes.  (A) Vk1-A, (B) Vk1-B, and (C) Vk1-C (38, 41). CDR regions are underlined and are according to Kabat et al. (40). Dashes indicate identity of  nucleotides to the germline sequence. Silent base changes are designated  by lowercase letters. Nucleotide changes leading to amino acid replacements in the V region are indicated by uppercase letters. Those leading to  amino acid replacements in the J regions are indicated in bold. Amino acid replacements are indicated above the nucleotide sequence. Amino acid replacements from the germline J are indicated in bold. The BW prefix precedes all numeric designations of light chains derived from NZB/W F1 mice.
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Related In: Results  -  Collection

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Figure 3: Nucleotide and amino acid sequences of Vk1 light chains from autoimmune transgenic hybridomas. Light chain nucleotide and amino acid sequences from hybridomas from autoimmune NZB/W F1 transgenic mice are compared to their most homologous Vk1 germline genes. (A) Vk1-A, (B) Vk1-B, and (C) Vk1-C (38, 41). CDR regions are underlined and are according to Kabat et al. (40). Dashes indicate identity of nucleotides to the germline sequence. Silent base changes are designated by lowercase letters. Nucleotide changes leading to amino acid replacements in the V region are indicated by uppercase letters. Those leading to amino acid replacements in the J regions are indicated in bold. Amino acid replacements are indicated above the nucleotide sequence. Amino acid replacements from the germline J are indicated in bold. The BW prefix precedes all numeric designations of light chains derived from NZB/W F1 mice.
Mentions: Transgene expressing anti-dsDNA hybridomas from R4A-γ2b transgenic NZB/W F1 mice could be obtained from non-LPS activated B cells as well as from LPS activated splenocytes, confirming activation in vivo of antidsDNA B cells in the autoimmune mice. In contrast to the dominant Vk1 usage seen in nonautoimmune mice, only 5 of 16 autoimmune derived anti-dsDNA hybridomas use a Vk1 gene (Table 1). 12 cell lines were obtained from LPSstimulated splenocytes, of which only 4 (33%) use Vk1 genes. Only 1 of 4 cell lines obtained from unstimulated NZB/W F1 splenocytes (25%) uses a Vk1 light chain. Therefore, there is little difference in the frequency of Vk1 expression in hybridomas from LPS-stimulated and unstimulated splenocytes. Vk1 genes from NZB/W F1 hybridomas display no somatic mutation in three (BW19G10, BW21D11, and BW10D9) of the five Vk1 genes sequenced (Fig. 3). The base change observed at the junction of Vk and Jk in Bw19G10 and BW21D11 is likely the result of imprecise joining during Vk-Jk rearrangement.

Bottom Line: Studies to date suggest that low avidity interactions between B cells and autoantigen lead to B cell silencing, whereas high avidity interactions lead to deletion.A major implication of this observation is that dsDNA may not be the self antigen responsible for cell fate determinations of anti-dsDNA B cells.Light chain usage may determine antigenic cross-reactivity, and cross-reactive antigens may regulate B cells that also bind dsDNA.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

ABSTRACT
Two major mechanisms for the regulation of autoreactive B cells that arise in the bone marrow are functional silencing (anergy) and deletion. Studies to date suggest that low avidity interactions between B cells and autoantigen lead to B cell silencing, whereas high avidity interactions lead to deletion. Anti-double stranded (ds) DNA antibodies represent a pathogenic autospecificity in Systemic Lupus Erythematosus (SLE). An understanding of their regulation is critical to an understanding of SLE. We now demonstrate in a transgenic model in which mice express the heavy chain of a potentially pathogenic anti-DNA antibody that antibody affinity for dsDNA does not alone determine the fate of anti-dsDNA B cells. B cells making antibodies with similar affinities for dsDNA are regulated differently, depending on light chain usage. A major implication of this observation is that dsDNA may not be the self antigen responsible for cell fate determinations of anti-dsDNA B cells. Light chain usage may determine antigenic cross-reactivity, and cross-reactive antigens may regulate B cells that also bind dsDNA.

Show MeSH
Related in: MedlinePlus