Histone deacetylase inhibitors upregulate B cell microRNAs that silence AID and Blimp-1 expression for epigenetic modulation of antibody and autoantibody responses.
Class-switch DNA recombination (CSR) and somatic hypermutation (SHM), which require activation-induced cytidine deaminase (AID), and plasma cell differentiation, which requires B lymphocyte-induced maturation protein-1 (Blimp-1), are critical for the generation of class-switched and hypermutated (mature) Ab and autoantibody responses. We show that histone deacetylase inhibitors valproic acid and butyrate dampened AICDA/Aicda (AID) and PRDM1/Prdm1 (Blimp-1) mRNAs by upregulating miR-155, miR-181b, and miR-361 to silence AICDA/Aicda, and miR-23b, miR-30a, and miR-125b to silence PRDM1/Prdm1, in human and mouse B cells. This led to downregulation of AID, Blimp-1, and X-box binding protein 1, thereby inhibiting CSR, SHM, and plasma cell differentiation without altering B cell viability or proliferation. The selectivity of histone deacetylase inhibitor-mediated silencing of AICDA/Aicda and PRDM1/Prdm1 was emphasized by unchanged expression of HoxC4 and Irf4 (important inducers/modulators of AICDA/Aicda), Rev1 and Ung (central elements for CSR/SHM), and Bcl6, Bach2, or Pax5 (repressors of PRDM1/Prdm1 expression), as well as unchanged expression of miR-19a/b, miR-20a, and miR-25, which are not known to regulate AICDA/Aicda or PRDM1/Prdm1. Through these B cell-intrinsic epigenetic mechanisms, valproic acid blunted class-switched and hypermutated T-dependent and T-independent Ab responses in C57BL/6 mice. In addition, it decreased class-switched and hypermutated autoantibodies, ameliorated disease, and extended survival in lupus MRL/Fas(lpr/lpr) mice. Our findings outline epigenetic mechanisms that modulate expression of an enzyme (AID) and transcription factors (Blimp-1 and X-box binding protein 1) that are critical to the B cell differentiation processes that underpin Ab and autoantibody responses. They also provide therapeutic proof-of-principle in autoantibody-mediated autoimmunity.
Department of Microbiology and Immunology, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and Institute for Immunology, University of California, Irvine, CA 92697.
Clayton A
CA
White
Institute for Immunology, University of California, Irvine, CA 92697.
Egest J
EJ
Pone
Department of Microbiology and Immunology, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and Institute for Immunology, University of California, Irvine, CA 92697.
Tonika
T
Lam
Department of Microbiology and Immunology, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and Institute for Immunology, University of California, Irvine, CA 92697.
Connie
C
Tat
Institute for Immunology, University of California, Irvine, CA 92697.
Ken L
KL
Hayama
Department of Microbiology and Immunology, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and Institute for Immunology, University of California, Irvine, CA 92697.
Guideng
G
Li
Department of Microbiology and Immunology, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and Institute for Immunology, University of California, Irvine, CA 92697.
Hong
H
Zan
Department of Microbiology and Immunology, University of Texas School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and Institute for Immunology, University of California, Irvine, CA 92697 pcasali@uthscsa.edu.
Paolo
P
Casali
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000378:metabolism; D000917:Antibody Formation; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003564:Cytidine Deaminase / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D035683:MicroRNAs / Q000235:genetics*; D010950:Plasma Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins / Q000235:genetics*; D027041:Somatic Hypermutation, Immunoglobulin / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000906:Antibodies; D001323:Autoantibodies; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D035683:MicroRNAs; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase