**The Pathogenesis of Antineutrophil Cytoplasmic Antibody Renal Vasculitis**

Sharon Lee Ford, Stephen Roger Holdsworth and Shaun Andrew Summers

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54637

### **1. Introduction**

The vasculitides comprise a heterogeneous group of diseases characterized by inflammation and destruction of blood vessels. Vessels of any size can be involved which explains the diverse spectrum of clinical diseases attributed to vasculitis. While the immunological basis of disease for vasculitis was recognized over thirty years ago,[1] a standardized classification system was only adopted nearly twenty years later. The initial classification system proposed by the American College of Rheumatology attempted to classify vasculitis according to standardized criteria.[2] The subsequent system described by the Chapel Hill Conference on the Nomen‐ clature of Systemic Vasculitis[3] introduced a system which coupled contemporary commonly used disease names and the size of vessel(s) involved.

#### **1.1. Small vessel vasculitis**

Necrotizing arteritis is common to many forms of vasculitis, but involvement of vessels smaller than arteries is unique to small vessel vasculitis.[4] A clinical report of 'Vasculitis' originated from the mid-nineteenth century[5] and clinical descriptions of these diseases were published in the 1930s,[6] however it was not until the 1950s that Wegener's Granulo‐ matosis, Churg Strauss Syndrome and Microscopic polyangiitis were identified as unique clinical entities.[7] In the 1980s it was appreciated that the small vessel vasculitides repre‐ sented a clinically distinct form of disease.[8] These small vessel vasculitides will be the pri‐ mary focus of this chapter.

© 2013 Ford et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


toimmune small vessel vasculitis. Subsequent work by a Dutch group helped establish the correlation between ANCAs and the three clinical syndromes; Wegener's granuloma‐ tosis, microscopic polyangiits and Churg-Strauss syndrome.[13] More recently these syn‐ dromes have been renamed to generate nomenclature free from the use of eponyms. [14-16] The new nomenclature proposed and adopted into the literature and clinical prac‐ tice in 2011 is as follows; Microscopic Polyangiitis (MPA), Granulomatosis with polyangii‐ tis, (GPA), formally known as Wegener's, Allergic Granulomatosis and Angiitis (AGA) formally known as Churg Strauss Disease and Renal Limited Vasculitis (RLV).[14] This

The Pathogenesis of Antineutrophil Cytoplasmic Antibody Renal Vasculitis

http://dx.doi.org/10.5772/54637

35

In this chapter, we will concentrate on renal injury resulting from AAV which has formed the basis for clinical and experimental studies. For both MPA and GPA target autoantigens have been identified which are constituents of neutrophils. For MPA, myeloperoxidase (MPO) is usually the target autoantigen, while antibodies to proteinase 3 (PR3) are usually detectable in patients with clinical features of GPA. In both clinical and experimental AAV (GPA or MPA) two separate key steps are required for the development of glomerulonephritis and renal injury. The first critical step involves the development of systemic autoimmunity to the target antigen, MPO or PR3. The second step involves antigen specific nephritogenic immune

The development of autoimmunity is a complex process, multifactorial in origin, which involves the loss of tolerance and enhanced cellular and humoral activity.[17] In AAV, disease is defined and characterized by antibodies detected against MPO or PR3. While antibodies form the diagnostic hallmark of disease, cellular immunity is critical and is required for the development of humoral immunity and the subsequent generation of B cells and production of ANCAs. A role for cellular immunity has been defined in both clinical and experimental ANCA vasculitis. In addition to adaptive immune cells, innate immune cells contribute to the generation of autoimmunity with evidence for involvement of different cell types in this

**2.3. The initiation and progression of rapidly progressive glomerulonephritis and renal**

Enhanced cellular autoimmunity and innate cells stimulate B cells resulting in the production of antigen specific ANCAs. These auto-antibodies bind to and activate circulating neutrophils. These activated neutrophils are recruited to glomerular capillaries,[18] where they degranulate and initiate renal injury. Degranulating neutrophils release their noxious constituents and also deposit MPO [19] and probably PR3 in the glomerulus. Later, CD4+ T cells recognise the autoantigen (MPO/PR3) in the glomerulus and attract additional immune effector cells; this results in severe renal injury. In both clinical and experimental settings cellular nephritogenic immunity, humoral immunity and innate immune cells are critical for the development of rapidly progressive glomerulonephritis.[20-24] Our current treatment regimes were designed

new terminology will be adopted for the remainder of this chapter.

**2.2. The development of systemic autoimmunity in MPA and GPA**

responses driving glomerular injury and renal disease.

to target these cells, or combinations of them.

disease process.

**injury in AAV**

**Table 1.** The Chapel Hill Conference on the Nomenclature of Systemic Vasculitis
