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Genetics and pathogenesis of small-vessel vasculitis

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Abstract

Small-vessel vasculitides are uncommon autoimmune diseases characterised by inflammation and necrosis of arterioles, capillaries and venules, frequently described as various (previously eponymous) clinical syndromes. Some are associated with vessel wall immune complex deposition, whereas others are pauci-immune but paradoxically often associated with circulating anti-neutrophil cytoplasmic antibodies (ANCA). Most is known about the pathogenesis of the pauci-immune ANCA-associated syndromes, which are gradually becoming better understood with regard to their genetic predisposition and the critical pathways mediating disease initiation, as well as their particular phenotypic features. Through better understanding of key cellular and molecular players, we have been able to develop novel biomarkers and treatment strategies, which should translate to improved diagnostics, treatment protocols and, ultimately, better patient outcomes. These conditions are treatable but not yet curable, although it is clear that patients may follow different disease courses, which for some include restoration of their pre-morbid immune status.

Introduction

Small-vessel vasculitides, characterised by necrotising inflammation in arterioles, capillaries and venules, may be divided into two groups: those associated with immune complex deposition, such as IgA vasculitis (Henoch–Schonlein purpura), cryoglobulinaemia and anti-C1q vasculitis, or those that are pauci-immune, without significant immunoglobulin deposition, including granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg–Strauss Syndrome) or microscopic polyangiitis (MPA) (Fig. 1); the latter three conditions are frequently associated with circulating anti-neutrophil cytoplasmic antibody (ANCA) [1]. Investigation into the pathogenesis of small-vessel vasculitis is most advanced in ANCA-associated vasculitis (AAV), which forms the main focus of this chapter, while application of genetics and molecular biology analysis should provide some greater understanding of other immune complex conditions such as IgA vasculitis. One of the great successes in the vasculitis field has come from the two-way movement between laboratory science and clinical management, which has led to the testing of new therapies based on data from animal models, and the novel understanding of pathogenesis that has been derived from the use of modern therapies such as B cell-depleting agents. With such close links between the clinic and the laboratories, and with greater insights into key cellular and molecular players, there is hope that further refinement of therapy will allow the diseases that were once almost universally fatal, to not just be treatable but one day be curable.

Section snippets

Autoantibodies and ANCA antigens

Following the discovery of ANCA in patients with pauci-immune glomerulonephritis [2] and its subsequent close association with active GPA [3], the target antigens were identified as proteinase 3 (PR3) and myeloperoxidase (MPO). Tight correlations between PR3-ANCA expression and GPA are found but are less clear cut between MPO-ANCA and MPA [4]. Both antigens are expressed in neutrophils and monocytes within specialised granules and lysosomes, respectively, and are also found decorating

Genetics

Although familial cases of AAV are reported, they are uncommon [18]. However, like many other autoimmune diseases, both candidate gene approaches and genome-wide association studies (GWAS) have implicated certain genetic loci as susceptibility factors for disease. In AAV, two GWAS have demonstrated important associations between disease and the HLA gene locus on chromosome 6 in European and North American populations [10], [19]. Differences are found in the HLA association depending on the

Cellular immunity

All immune system cellular components have been implicated in AAV, with a breakdown of tolerance to one or other of the autoantigens. Circulating ANCA are class-switched immunoglobulins and require T cell for their production, and both MPO- and PR3-specific T cells have been identified in patients [25], [26]. In addition, both B and T cells are found infiltrating tissues and are critical components in granulomatous lesions found in GPA [27], [28], [29]. The balance between effector and

Complement

Clear evidence of complement involvement in disease pathogenesis has emerged from animal and more recently patient data in various populations. Using complement-deficient mice and models of anti-MPO-mediated vasculitis, a clear role for alternative pathway complement activation promoting disease, and specifically, a role for the C5a receptor (C5aR) as a central component in mediating these effects, was found [61], [62], [63]. This led to the development of therapeutic C5aR inhibition in

Summary

Small-vessel pauci-immune, ANCA-associated vasculitis develops in genetically susceptible individuals with numerous immune phenotype variants (compared to healthy individuals), which lead to a breakdown in tolerance to a specific and limited repertoire of leukocyte antigens, thereby resulting in particular clinical phenotypes. An intriguing question is whether or not we can re-establish immunological tolerance in those patients and revert back to a state of health, thereby preventing the

Conflicts of interest

No conflict of interest.

Funding statement

No funding received for this work.

References (68)

  • J.C. Jennette et al.

    2012 revised international Chapel Hill consensus Conference Nomenclature of vasculitides

    Arthritis Rheum

    (2013)
  • D.J. Davies et al.

    Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology?

    Br Med J

    (1982)
  • X. Bossuyt et al.

    Position paper: revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis

    Nat Rev Rheumatol

    (2017)
  • K. Kessenbrock et al.

    Netting neutrophils in autoimmune small-vessel vasculitis

    Nat Med

    (2009)
  • E.C. O'Brien et al.

    Intermediate monocytes in ANCA vasculitis: increased surface expression of ANCA autoantigens and IL-1beta secretion in response to anti-MPO antibodies

    Sci Rep

    (2015)
  • A. Schreiber et al.

    Membrane expression of proteinase 3 is genetically determined

    J Am Soc Nephrol

    (2003)
  • N. Thieblemont et al.

    Regulation of macrophage activation by proteins expressed on apoptotic neutrophils: subversion towards autoimmunity by proteinase 3

    Eur J Clin Invest

    (2018)
  • P.A. Lyons et al.

    Genetically distinct subsets within ANCA-associated vasculitis

    N Engl J Med

    (2012)
  • E. Csernok et al.

    Clinical and immunological features of drug-induced and infection-induced proteinase 3-antineutrophil cytoplasmic antibodies and myeloperoxidase-antineutrophil cytoplasmic antibodies and vasculitis

    Curr Opin Rheumatol

    (2010)
  • M.M. McGrath et al.

    Contaminated cocaine and antineutrophil cytoplasmic antibody-associated disease

    Clin J Am Soc Nephrol

    (2011)
  • A.J. Roth et al.

    Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis

    J Clin Invest

    (2013)
  • D.J. Bautz et al.

    Antibodies with dual reactivity to plasminogen and complementary PR3 in PR3-ANCA vasculitis

    J Am Soc Nephrol

    (2008)
  • T. Nagao et al.

    Direct activation of glomerular endothelial cells by anti-moesin activity of anti-myeloperoxidase antibody

    Nephrol Dial Transplant

    (2011)
  • R. Kain et al.

    Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis

    Nat Med

    (2008)
  • U. Eisenberger et al.

    ANCA-negative pauci-immune renal vasculitis: histology and outcome

    Nephrol Dial Transplant

    (2005)
  • A. Tanna et al.

    Familial granulomatosis with polyangiitis: three cases of this rare disorder in one Indoasian family carrying an identical HLA DPB1 allele

    BMJ Case Rep

    (2012)
  • P.A. Merkel et al.

    Identification of functional and expression Polymorphisms associated with risk for antineutrophil cytoplasmic autoantibody-associated vasculitis

    Arthritis Rheumatol

    (2017)
  • Y. Cao et al.

    DRB1*15 allele is a risk factor for PR3-ANCA disease in African Americans

    J Am Soc Nephrol

    (2011)
  • M. Hilhorst et al.

    HLA-DPB1 as a risk factor for relapse in antineutrophil cytoplasmic antibody-associated vasculitis: a cohort study

    Arthritis Rheumatol

    (2016)
  • G.A. Thun et al.

    Causal and synthetic associations of variants in the SERPIN gene cluster with alpha1-antitrypsin serum levels

    PLoS Genet

    (2013)
  • L. Ortiz-Fernandez et al.

    Cross-phenotype analysis of Immunochip data identifies KDM4C as a relevant locus for the development of systemic vasculitis

    Ann Rheum Dis

    (2018)
  • D.J. Ciavatta et al.

    Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis

    J Clin Invest

    (2010)
  • W.H. Abdulahad et al.

    T-helper cells as new players in ANCA-associated vasculitides

    Arthritis Res Ther

    (2011)
  • M.E. Griffith et al.

    T cell responses to myeloperoxidase (MPO) and proteinase 3 (PR3) in patients with systemic vasculitis

    Clin Exp Immunol

    (1996)
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