AID dysregulation in lupus-prone MRL/Fas lpr/lpr mice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgH loci translocations

Modulation by HoxC4

Clayton A. White, J. Seth Hawkins, Egest J. Pone, Elliot S. Yu, Ahmed Al-Qahtani, Thach Mai, Hong Zan, Paolo Casali

Research output: Contribution to journalArticle

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Abstract

Immunoglobulin gene somatic hypermutation (SHM) and class switch DNA recombination (CSR) play important roles in the generation of autoantibodies in systemic lupus erythematosus. Systemic lupus is characterized by the production of an array of pathogenic high-affinity mutated and class-switched, mainly IgG, antibodies to a variety of self-antigens, including nuclear components, such as dsDNA, histones, and chromatin. We previously found that MRL/Fas lpr/lpr mice, which develop a systemic autoimmune syndrome sharing many features with human lupus, display greatly upregulated CSR, particularly to IgG2a, in B cells of the spleen, lymph nodes, and Peyer's patches. In MRL/Fas lpr/lpr mice, the significant upregulation of CSR is associated with increased expression of activation-induced cytidine deaminase (AID), which is critical for CSR and SHM. We also found that HoxC4 directly activates the promoter of the AID gene to induce AID expression, CSR and SHM. Here, we show that in both lupus patients and lupus-prone MRL/Fas lpr/lpr mice, the expression of HoxC4 and AID is significantly upregulated. To further analyze the role of HoxC4 in lupus, we generated HoxC4 -/- MRL/Fas lpr/lpr mice. In these mice, HoxC4-deficiency resulted in reduced AID expression, impaired CSR, and decreased serum anti-dsDNA IgG, particularly IgG2a, autoantibodies, which were associated with a reduction in IgG deposition in kidney glomeruli. In addition, consistent with our previous findings in MRL/Fas lpr/lpr mice that upregulated AID expression is associated with extensive DNA lesions, comprising deletions and insertions in the IgH locus, we found that c-Myc to IgH (c-Myc/IgH) translocations occur frequently in B cells of MRL/Fas lpr/lpr mice. The frequency of such translocations was significantly reduced in HoxC4 -/- MRL/Fas lpr/lpr mice. These findings suggest that in lupus B cells, upregulation of HoxC4 plays a major role in dysregulation of AID expression, thereby increasing CSR and autoantibody production and promoting c-Myc/IgH translocations.

Original languageEnglish (US)
Pages (from-to)585-598
Number of pages14
JournalAutoimmunity
Volume44
Issue number8
DOIs
StatePublished - Dec 2011

Fingerprint

Genetic Recombination
DNA
Autoantibodies
B-Lymphocytes
Immunoglobulin Somatic Hypermutation
Up-Regulation
Immunoglobulin G
Kidney Glomerulus
Peyer's Patches
Immunoglobulin Genes
AICDA (activation-induced cytidine deaminase)
Autoantigens
Systemic Lupus Erythematosus
Histones
Chromatin
Spleen
Lymph Nodes
Antibodies
Serum
Genes

Keywords

  • Activation-induced cytidine deaminase (AID)
  • B-cell lymphoma
  • C-Myc/IgH translocation
  • Class switch DNA recombination (CSR)
  • HoxC4
  • Systemic lupus erythematosus (SLE)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

AID dysregulation in lupus-prone MRL/Fas lpr/lpr mice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgH loci translocations : Modulation by HoxC4. / White, Clayton A.; Seth Hawkins, J.; Pone, Egest J.; Yu, Elliot S.; Al-Qahtani, Ahmed; Mai, Thach; Zan, Hong; Casali, Paolo.

In: Autoimmunity, Vol. 44, No. 8, 12.2011, p. 585-598.

Research output: Contribution to journalArticle

White, Clayton A. ; Seth Hawkins, J. ; Pone, Egest J. ; Yu, Elliot S. ; Al-Qahtani, Ahmed ; Mai, Thach ; Zan, Hong ; Casali, Paolo. / AID dysregulation in lupus-prone MRL/Fas lpr/lpr mice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgH loci translocations : Modulation by HoxC4. In: Autoimmunity. 2011 ; Vol. 44, No. 8. pp. 585-598.
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abstract = "Immunoglobulin gene somatic hypermutation (SHM) and class switch DNA recombination (CSR) play important roles in the generation of autoantibodies in systemic lupus erythematosus. Systemic lupus is characterized by the production of an array of pathogenic high-affinity mutated and class-switched, mainly IgG, antibodies to a variety of self-antigens, including nuclear components, such as dsDNA, histones, and chromatin. We previously found that MRL/Fas lpr/lpr mice, which develop a systemic autoimmune syndrome sharing many features with human lupus, display greatly upregulated CSR, particularly to IgG2a, in B cells of the spleen, lymph nodes, and Peyer's patches. In MRL/Fas lpr/lpr mice, the significant upregulation of CSR is associated with increased expression of activation-induced cytidine deaminase (AID), which is critical for CSR and SHM. We also found that HoxC4 directly activates the promoter of the AID gene to induce AID expression, CSR and SHM. Here, we show that in both lupus patients and lupus-prone MRL/Fas lpr/lpr mice, the expression of HoxC4 and AID is significantly upregulated. To further analyze the role of HoxC4 in lupus, we generated HoxC4 -/- MRL/Fas lpr/lpr mice. In these mice, HoxC4-deficiency resulted in reduced AID expression, impaired CSR, and decreased serum anti-dsDNA IgG, particularly IgG2a, autoantibodies, which were associated with a reduction in IgG deposition in kidney glomeruli. In addition, consistent with our previous findings in MRL/Fas lpr/lpr mice that upregulated AID expression is associated with extensive DNA lesions, comprising deletions and insertions in the IgH locus, we found that c-Myc to IgH (c-Myc/IgH) translocations occur frequently in B cells of MRL/Fas lpr/lpr mice. The frequency of such translocations was significantly reduced in HoxC4 -/- MRL/Fas lpr/lpr mice. These findings suggest that in lupus B cells, upregulation of HoxC4 plays a major role in dysregulation of AID expression, thereby increasing CSR and autoantibody production and promoting c-Myc/IgH translocations.",
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AU - White, Clayton A.

AU - Seth Hawkins, J.

AU - Pone, Egest J.

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AU - Al-Qahtani, Ahmed

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AU - Zan, Hong

AU - Casali, Paolo

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