The pathogenesis of systemic lupus erythematosus—an update

https://doi.org/10.1016/j.coi.2012.10.004Get rights and content

Systemic lupus erythematosus (SLE, lupus) is characterized by a global loss of self-tolerance with activation of autoreactive T and B cells leading to production of pathogenic autoantibodies and tissue injury. Innate immune mechanisms are necessary for the aberrant adaptive immune responses in SLE. Recent advances in basic and clinical biology have shed new light on disease mechanisms in lupus, with this review discussing the recent studies that offer valuable insights into disease-specific therapeutic targets.

Highlights

► Innate effectors are critical for the lupus phenotype. ► Aberrant adaptive immune responses promote disease progression in SLE. ► Dissection of pathogenic events in SLE offers new therapeutic targets in SLE.

Introduction

Systemic lupus erythematosus (SLE, or lupus) is a systemic autoimmune disease with multi-organ inflammation. SLE is characterized by production of pathogenic autoantibodies directed against nucleic acids and their binding proteins, reflecting a global loss of self-tolerance (reviewed in [1]). The loss of tolerance with subsequent immune dysregulation is a consequence of genetic factors, in the setting of environmental triggers and stochastic events, with recent studies implicating over 30 genetic loci in disease pathogenesis (for recent reviews, see [2, 3, 4, 5]).

Aberrant innate immune responses play a significant role in the pathogenesis of SLE, contributing both to tissue injury via release of inflammatory cytokines as well as to aberrant activation of autoreactive T and B cells, with the latter leading to pathogenic autoantibody production and resultant end-organ injury (reviewed in [6]) (Figure 1). Autoantigenic nucleic acids and their binding proteins are required for self-antigen specific activation of autoreactive lymphocytes. Autoantigens complexed with their cognate autoantibodies also directly contribute to activation of innate immune cells via Fc receptor (FcR)-mediated uptake of complexes (or in the case of autoreactive B cells, initial engagement of the B cell antigen receptor by autoantigens per se), with the nucleic acid component of these complexes upon endosomal trafficking engaging intracellular Toll-like receptors (TLRs) with subsequent innate and B cell activation.

This review will focus upon recently dissected biologic events that provide insight into disease pathogenesis in three major areas, dysregulation of innate and adaptive immune responses in SLE, and the role of autoantibodies in triggering end-organ injury (Figure 1). We will necessarily, in the interest of space, focus upon studies that offer new paradigmatic insights into pathogenic events.

Section snippets

Innate immunity in SLE

Dendritic cells (DCs) play a central role in adaptive immunity by activating B and T cells, with the presumption that they are similarly required for the activation of autoreactive T and B cells. But their precise involvement in autoimmunity, and the effects of their selective subsets in autoreactive lymphocyte activation, is less clearly understood. A recent study addressed this question by adapting a DC-depletion model (CD11c-diptheria toxin A; CD11c-DTA) to the widely used MRL.Faslpr mouse

Adaptive Immunity in SLE

Given the roles of autoantibodies and B cells in disease pathogenesis [14, 34], a number of studies have been devoted to analysis of the function of autoreactive B and T cells in SLE (for reviews, see [35, 36]). B cell tolerance is defective at several levels in SLE, including both abnormalities in central and peripheral selection responsible for removal of self-reactive immature B cells [37, 38, 39]. Aberrant tolerance, combined with enhanced BCR [40], TLR [41], and BAFF receptor signaling

Autoantibodies as initiators of tissue injury in SLE

The kidney is a primary site of tissue injury in murine and human lupus. Nephritis results from glomerular deposition of immune complexes of autoantibodies and autoantigens, with engagement of FcRs on immune cells along with complement fixation [62]. These effector mechanisms initiate infiltration and activation of tissue-infiltrating macrophages that promote the inflammatory response with resultant tissue injury [63, 64]. The contributions of autoantibody isotypes to tissue injury in the

Conclusions

The pathogenic mechanisms that lead to the clinical lupus phenotype are becoming clear, with genetic predisposition in the setting of environmental and/or stochastic triggers leading to innate immune system activation associated with pathological T-B cell collaboration and subsequent inflammation and tissue injury. These interactions are critical to understand, as their interruption is important therapeutically, as demonstrated by clinical studies in patients. Since there have been, and will

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • •• of outstanding interest

Acknowledgements

This work was supported partly by NIH grants AR40072, AR44076, AI075157, and AR053495, and by the Alliance for Lupus Research. S. Kim was supported by a Research Scientist Development Award from the American College of Rheumatology Research and Education Foundation.

References (81)

  • A. Bergtold et al.

    FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis

    J Immunol

    (2006)
  • M.J. Shlomchik et al.

    From T to B and back again: positive feedback in systemic autoimmune disease

    Nat Rev Immunol

    (2001)
  • Y. Deng et al.

    Genetic susceptibility to systemic lupus erythematosus in the genomic era

    Nat Rev Rheumatol

    (2010)
  • K.E. Taylor et al.

    Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes

    PLoS Genet

    (2011)
  • J.E. Craft

    Dissecting the immune cell mayhem that drives lupus pathogenesis

    Sci Transl Med

    (2011)
  • J. William et al.

    Evolution of autoantibody responses via somatic hypermutation outside of germinal centers

    Science

    (2002)
  • B.F. Hoyer et al.

    Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice

    J Exp Med

    (2004)
  • E.A. Leadbetter et al.

    Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors

    Nature

    (2002)
  • R.A. Herlands et al.

    T cell-independent and toll-like receptor-dependent antigen-driven activation of autoreactive B cells

    Immunity

    (2008)
  • A. Mathian et al.

    Interferon-alpha induces unabated production of short-lived plasma cells in pre-autoimmune lupus-prone (NZBxNZW)F1 mice but not in BALB/c mice

    Eur J Immunol

    (2011)
  • M.J. Shlomchik

    Sites and stages of autoreactive B cell activation and regulation

    Immunity

    (2008)
  • C.P. Chappell et al.

    Extrafollicular B cell activation by marginal zone dendritic cells drives T cell-dependent antibody responses

    J Exp Med

    (2012)
  • P. Blanco et al.

    Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus

    Science

    (2001)
  • L. Ronnblom et al.

    The natural interferon-alpha producing cells in systemic lupus erythematosus

    Hum Immunol

    (2002)
  • T.B. Niewold et al.

    IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus

    Ann Rheum Dis

    (2012)
  • T.B. Niewold

    Interferon alpha as a primary pathogenic factor in human lupus

    J Interferon Cytokine Res

    (2011)
  • M.S. Lo et al.

    Treatment of systemic lupus erythematosus: new advances in targeted therapy

    Ann N Y Acad Sci

    (2012)
  • J.T. Merrill et al.

    Safety profile and clinical activity of sifalimumab, a fully human anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study

    Ann Rheum Dis

    (2011)
  • McBride JM, Jiang J, Abbas AR, Morimoto A, Li J, Maciuca R, Townsend M, Wallace DJ, Kennedy WP, Drappa J: Safety and...
  • A. Mathian et al.

    Active immunisation of human interferon alpha transgenic mice with a human interferon alpha Kinoid induces antibodies that neutralise interferon alpha in sera from patients with systemic lupus erythematosus

    Ann Rheum Dis

    (2011)
  • M.J. Kaplan

    Neutrophils in the pathogenesis and manifestations of SLE

    Nat Rev Rheumatol

    (2011)
  • E. Villanueva et al.

    Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus

    J Immunol

    (2011)
  • V. Brinkmann et al.

    Neutrophil extracellular traps kill bacteria

    Science

    (2004)
  • R. Lande et al.

    Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus

    Sci Transl Med

    (2011)
  • G.S. Garcia-Romo et al.

    Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus

    Sci Transl Med

    (2011)
  • F.J. Barrat et al.

    Development of TLR inhibitors for the treatment of autoimmune diseases

    Immunol Rev

    (2008)
  • K. De Bosscher et al.

    The interplay between the glucocorticoid receptor and nuclear factor-κB or activator protein-1: molecular mechanisms for gene repression

    Endocr Rev

    (2003)
  • C. Guiducci et al.

    TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus

    Nature

    (2010)
  • O.T. Chan et al.

    The central and multiple roles of B cells in lupus pathogenesis

    Immunol Rev

    (1999)
  • J.C. Crispin et al.

    T cells as therapeutic targets in SLE

    Nat Rev Rheumatol

    (2010)
  • Cited by (242)

    • Lupus nephritis, an update

      2023, Revista Colombiana de Reumatologia
    • Pediatric rheumatic diseases

      2023, Encyclopedia of Child and Adolescent Health, First Edition
    View all citing articles on Scopus
    *

    These authors contributed equally.

    View full text