MicroRNAs in lupus

Abstract

Systemic lupus erythematosus is a prototypic autoimmune disease characterized by the production of an array of pathogenic autoantibodies, including high-affinity anti-dsDNA IgG antibodies, which play an important role in disease development and progression. Lupus preferentially affects women during their reproductive years. The pathogenesis of lupus is contributed by both genetic factors and epigenetic modifications that arise from exposure to the environment. Epigenetic marks, including DNA methylation, histone post-translational modifications and microRNAs (miRNAs), interact with genetic programs to regulate immune responses. Epigenetic modifications influence gene expression and modulate B cell functions, such as class-switch DNA recombination, somatic hypermutation and plasma cell differentiation, thereby informing the antibody response. Epigenetic dysregulation can result in aberrant antibody responses to exogenous antigens or self-antigens, such as chromatin, histones and dsDNA in lupus. miRNAs play key roles in the post-transcriptional regulation of most gene-regulatory pathways and regulate both the innate and adaptive immune responses. In mice, dysregulation of miRNAs leads to aberrant immune responses and development of systemic autoimmunity. Altered miRNA expression has been reported in human autoimmune diseases, including lupus. The dysregulation of miRNAs in lupus could be the result of multiple environmental factors, such as sex hormones and viral or bacterial infection. Modulation of miRNA is a potential therapeutic strategy for lupus.

Keywords: Activation-induced cytidine deaminase; autoantibody; autoimmunity; class-switch DNA recombination; epigenetics; microRNA; somatic hypermutation; systemic lupus erythematosus.

Figure 1. miRNA biogenesis and function

Mature miRNAs are generated from endogenous hairpin-shaped transcripts and derived from the processing of long primary miRNA transcripts (pri-miRNA) by a Drosha/DGCR8 microprocessor in the nucleus to produce precursor miRNAs (pre-miRNAs). Alternatively, in a noncanonical miRNA biogenesis pathway, “mirtrons,” a new class of miRNA precursors bypasses Drosha processing and are spliced by the spliceosome to yield branched pre-mitrons, which then go through lariat-mediated debranching to generate pre-miRNAs. After being exported from the nucleus into the cytoplasm by Exportin-5, pre-miRNAs are processed by the RNAIII enzyme Dicer, yielding imperfectly matched miRNA/miRNA* duplexes which are loaded into the Argonaute (Ago) protein to generate the RNA-induced silencing complex (RISC). The guided strand of the miRNA/miRNA* duplex remains in the RISC as a mature miRNA, and the complementary strand (the passenger strand miRNA*) is degraded. Once loaded onto RISC, the mature miRNA will interact with the 3′ UTR of its target mRNA to silence the mRNA strand, thereby, dampening gene expression.

Figure 2. miRNA in immune and autoimmune responses

Select miRNAs specifically regulate genes that are critical at different stages of peripheral B cell differentiation. miRNAs play an important role in gene regulation through direct targeting of the 3′ UTR transcripts of those genes, thereby regulating sequential B cell differentiation stages. Naïve mature B cells in peripheral lymphoid organs are activated by primary stimuli to undergo SHM and CSR (e.g., to IgG, depicted) and to differentiate into plasma cells or memory B cells. Several miRNAs (miR-17-92, miR-34a, miR-125, and miR-150) are involved in the pro-B to pre-B cell transition and regulate the generation of B cells in the bone marrow during the early stages of development. Other miRNAs, miR-181b and miR-155 target AID, while miR-125b, miR-9, and miR-30 target Blimp-1 and Irf4, which mediate plasma cell differentiation. Upregulation (red arrow) or downregulation (black arrow) of miRNAs results in alterations in the expression of these key genes. E2f-1, E2 promoter binding factor-1; AID, activation-induced cytidine deaminase; Blimp-1, B lymphocyte-induced maturation protein-1; HDAC, histone deacetylase; Irf4, interferon regulatory factor 4; NuRD, nucleosome remodeling and histone deacetylase; Pax-5, Paired box protein-5; Spi-B, spleen focus-forming virus integration site; CIITA, major histocompatibility complex class II transactivator.

Figure 3. Modulation of miRNA in lupus

Genetic, environmental and hormonal factors all contribute to miRNA dysregulation in lupus. For example, miR-146a contributes to lupus pathogenesis by repressing the function of type I IFN and TLR signaling, through downregulating target genes Traf6/Irak1, and Tlr7 or Tlr9 and inflammatory cytokine expression. miR-181 impairs CSR in activated B cells by targeting AID, whereas miR-23b, miR-30a, miR-125a regulate autoantibody production by repressing Blimp-1 expression and plasma cell differentiation. In lupus, miR-21, miR-148 and miR-126, which target Dnmt1, are all upregulated suggesting that hypomethylation in lupus is mediated by those miRNAs. Conversely, histone modifications and DNA methylation also affect miRNAs in lupus T cells.