2Genetics and pathogenesis of small-vessel vasculitis
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.
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