Elsevier

Journal of Autoimmunity

Volume 32, Issues 3–4, May–June 2009, Pages 189-194
Journal of Autoimmunity

MicroRNA in autoimmunity and autoimmune diseases

https://doi.org/10.1016/j.jaut.2009.02.012Get rights and content

Abstract

MicroRNAs (miRNAs) are small conserved non-coding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3′ untranslated region (UTR) of specific messenger RNAs (mRNAs) for degradation or translational repression. miRNA-mediated gene regulation is critical for normal cellular functions such as the cell cycle, differentiation, and apoptosis, and as much as one-third of human mRNAs may be miRNA targets. Emerging evidence has demonstrated that miRNAs play a vital role in the regulation of immunological functions and the prevention of autoimmunity. Here we review the many newly discovered roles of miRNA regulation in immune functions and in the development of autoimmunity and autoimmune disease. Specifically, we discuss the involvement of miRNA regulation in innate and adaptive immune responses, immune cell development, T regulatory cell stability and function, and differential miRNA expression in rheumatoid arthritis and systemic lupus erythematosus.

Introduction

MicroRNAs (miRNAs) are 20–22 nucleotide long non-coding RNA molecules that were first discovered in 1993 [1], [2]. Currently, the known function of miRNAs is the post-transcriptional regulation of certain subsets of messenger RNAs (mRNAs) by binding to their 3′ untranslated region (UTR) thus targeting them for degradation or translational repression [3].

The importance of miRNA regulation to cellular functions is becoming increasingly clear as new miRNA targets are revealed. Currently, miRNA is known to regulate cellular processes such as apoptosis, differentiation, cell cycle, and immune functions. To date, the miRNA sequence database, miRBase, includes over 8000 predicted miRNAs in numerous species of plants, animals, and viruses [4], [5]. For humans alone, miRBase lists over 800 predicted miRNAs, and other bioinformatics predictions indicate that as much as one-third of all mRNAs may be regulated by miRNA [6].

Section snippets

Biogenesis and maturation of miRNA

miRNAs are first transcribed from the genome by RNA polymerase II as primary miRNA (pri-miRNA) transcripts [7], [8]. In animals, miRNA maturation is then achieved by two main processing steps involving two ribonuclease III (RNase III) enzymes, Drosha and Dicer. First, Drosha and its partner protein DGCR8 (DiGeorge syndrome critical region 8) process the nuclear pri-miRNA into ∼70 nucleotide precursor miRNA (pre-miRNA) molecule [9], [10], [11], [12], [13]. The pre-miRNA is then exported from the

Cell biology and autoimmune targeting of the miRNA pathway

The key components of RISC are the argonaute (Ago) family of proteins. In mammals, there are four Ago proteins (Ago1–4), but only Ago2 is known to function in the miRNA and siRNA pathways. Ago2 has been shown to cleave mRNA targeted by miRNA or small interfering RNA (siRNA) and is known as the catalytic enzyme of RNA interference (RNAi) [22], [23]. In addition to Ago proteins, many other proteins are required for miRNA functioning including GW182 and Rck/p54, and these proteins all localize in

Role of miRNA in normal immune functions

Regulation of the immune system is vital to prevent many pathogenic disorders including autoimmune disease and cancers, and mammals have developed a complex system of checks and balances for immune regulation in order to maintain self tolerance while allowing immune responses to foreign pathogens, most of which are not fully understood. Recently, it has become evident that miRNAs play an important role in regulating immune response, as well as immune cell development. To date, a relatively

Role of miRNA in autoimmunity

Given that certain miRNA play critical roles in the regulation of immune response and immune cell development, it is not surprising that recent studies have revealed links between miRNA function and autoimmunity (Table 2). In 2007, the involvement of miRNA in a new pathway regulating autoimmunity was discovered in T lymphocytes in the sanroque mouse [54]. The sanroque mouse was originally selected from screening mutant mice derived from the chemical mutagen N-ethyl-N-nitrosourea (ENU), and has

Involvement of miRNA in autoimmune diseases

It is becoming increasingly clear from cell culture and animal studies that proper miRNA regulation is critical for the prevention of autoimmunity and normal immune functions. However, it is not yet well understood whether miRNA dysregulation could play a role in autoimmune disease pathogenesis in human patients. Several recent studies have uncovered possible roles for miRNA regulation in autoimmune diseases (Table 2), specifically rheumatoid arthritis (RA) and systemic lupus erythematosus

Acknowledgements

This work was supported in part by National Institute of Health grant AI47859 and the Andrew J. Semesco Foundation, Ocala FL. K.M.P. was supported by NIDCR oral biology training grant T32 DE007200.

References (67)

  • W. Tam

    Identification and characterization of human BIC, a gene on chromosome 21 that encodes a noncoding RNA

    Gene

    (2001)
  • D. Haasch et al.

    T cell activation induces a noncoding RNA transcript sensitive to inhibition by immunosuppressant drugs and encoded by the proto-oncogene, BIC

    Cell Immunol

    (2002)
  • E. Vigorito et al.

    MicroRNA-155 regulates the generation of immunoglobulin class-switched plasma cells

    Immunity

    (2007)
  • Q.J. Li et al.

    miR-181a is an intrinsic modulator of T cell sensitivity and selection

    Cell

    (2007)
  • F. Fazi et al.

    A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis

    Cell

    (2005)
  • T. Fukao et al.

    An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling

    Cell

    (2007)
  • C. Xiao et al.

    MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb

    Cell

    (2007)
  • J.S. Smolen et al.

    New therapies for treatment of rheumatoid arthritis

    Lancet

    (2007)
  • W. Filipowicz et al.

    Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?

    Nat Rev Genet

    (2008)
  • S. Griffiths-Jones

    The microRNA Registry

    Nucleic Acids Res

    (2004)
  • S. Griffiths-Jones

    miRBase: the microRNA sequence database

    Methods Mol Biol

    (2006)
  • X. Cai et al.

    Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs

    RNA

    (2004)
  • Y. Lee et al.

    MicroRNA genes are transcribed by RNA polymerase II

    EMBO J

    (2004)
  • A.M. Denli et al.

    Processing of primary microRNAs by the microprocessor complex

    Nature

    (2004)
  • R.I. Gregory et al.

    The microprocessor complex mediates the genesis of microRNAs

    Nature

    (2004)
  • J. Han et al.

    The Drosha-DGCR8 complex in primary microRNA processing

    Genes Dev

    (2004)
  • Y. Lee et al.

    The nuclear RNase III Drosha initiates microRNA processing

    Nature

    (2003)
  • E. Lund et al.

    Nuclear export of microRNA precursors

    Science

    (2004)
  • R. Yi et al.

    Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs

    Genes Dev

    (2003)
  • Y. Zeng et al.

    Structural requirements for pre-microRNA binding and nuclear export by Exportin 5

    Nucleic Acids Res

    (2004)
  • T. Du et al.

    microPrimer: the biogenesis and function of microRNA

    Development

    (2005)
  • J.G. Ruby et al.

    Intronic microRNA precursors that bypass Drosha processing

    Nature

    (2007)
  • J. Liu et al.

    Argonaute2 is the catalytic engine of mammalian RNAi

    Science

    (2004)
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