**6. The role of Th17 cells in autoimmunity and glomerulonephritis**

The original description of Th1, IFNγ producing and Th2, IL-4 producing, T helper cells by Mosmann and Coffman [84] has been expanded to include a new subset of Th cells, the IL-17A producing Th17 cells.[79, 85-86] While the prototypic cytokine produced by Th17 cells is IL-17A, these cells produce numerous other cytokines, including the ubiquitous IL-6, TNF and IL-1β.[85] Two transcription factors are critical for the development of Th17 cells; STAT3 and Rorγt.[87-88] For the induction and maintenance Th17 cells, several cytokines are required, these include; IL-23,[89] IL-6, TGF-β,[90-93] while IL-21 is required for amplification of Th17 cells.[94-96]

Prior to the discovery of Th17 cells, autoimmunity was believed to be predominantly a Th1 mediated phenomenon. There were inconsistencies, however, in this paradigm, for example IFNγ-/- mice developed exaggerated organ inflammation and injury in experimental autoim‐ mune models.[97-98] Subsequently it was demonstrated that organ injury (in the most common autoimmune model, experimental autoimmune encephalomyelitis [EAE]) was unchanged in IL-12p35-/- mice (functionally Th1 deficient), while injury was significantly attenuated in IL-12p40-/- (functionally Th1 and Th17 deficient) and IL-12p19-/- (functionally Th17 deficient) mice.[99] Similarly IL-17A-/- mice were protected from EAE, [100] while increased IL-17 expression was seen in patients with multiple sclerosis, [101] a common autoimmune disease seen in clinical practice, which is the human equivalent of EAE. Further studies have implicated Th17 cells in several autoimmune diseases including rheumatoid arthritis,[102] consistent with this finding IL-17A-/- mice are protected from murine experi‐ mental arthritis.[103-104] IL-17A has been implicated in inflammatory bowel disease, both experimental[105] and clinical[106] as well as human inflammatory skin conditions.[107-108]

effect mediated through tryptophan.[121] Our current understanding of the role of Tregs in AAV is limited and further studies are required to improve our knowledge of their role in disease pathogenesis in order to facilitate treatments aimed at optimizing their therapeutic potential. It is well known that Th17 cells and Tregs require many of the same cytokines for growth and development and it has been postulated that they have an inverse relationship. Whilst this explanation may be simplistic it is attractive to hypothesise that both the initiation of disease and flares seen in AAV could be attributed to an imbalance in the Th17: Treg ratio; with Th17 overactivity promoting disease. This imbalance could be targeted in future treat‐

The Pathogenesis of Antineutrophil Cytoplasmic Antibody Renal Vasculitis

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

45

Neutrophils play a critical role in the pathogenesis of ANCA vasculitis. Not only are neutro‐ phils the primary effector cells in the kidney but neutrophils also contain the target autoantigens, MPO, PR3 (and LAMP-2) and hence are directly involved in the auto-immune process. We will discuss three different aspects of neutrophil involvement in disease, (a) The role of the Neutrophil in the development of Autoimmunity, (b) Neutrophil Activation by ANCAs and (c) Neutrophil Endothelial Interactions, which initiate glomerular injury.

It is well established that ANCAs bind to the autoantigens, MPO or PR3, located on the cell surface of the neutrophil. How and why these autoantigens translocate to the cell surface is poorly understood. We know that neutrophils die through apoptosis or necrosis and data suggests that neutrophil death through apoptosis can promote the loss of tolerance to MPO or PR3. After cell death neutrophils release granule constituents, including MPO and PR3, which translocate to the cell surface[122-123] where they serve as antigenic targets. This phenomenon was thought to occur exclusively after neutrophil death through apoptosis, which is possibly related to a slower mechanism of cell death, although the operational mechanisms of this

An additional pathway linking neutrophil cell death and autoimmunity has recently been proposed, involving a distinct method of neutrophil death involving neutrophil extracellular traps (NETs). Neutrophils extrude NETs which consist of chromatin structures and include anti-microbial peptides such as; MPO, PR3 elastin, cathepsin, and lactoferrin.[124] Dying neutrophils extrude NETs to kill invading pathogens in a process recently named NETosis. It is understood that neutrophils, through NETosis, contribute to the development of autoim‐ munity, a concept well established in SLE. In SLE, in response to chronic autoantibody stimulation neutrophils and their NETs activate plasmacytoid dendritic cells which secrete IFNα.[125-127] NETosis has been linked with glomerular injury in AAV, through the en‐ hancement of endothelial-leukocyte interaction,[71] however only recently have NETs been implicated in the development of ANCA autoimmunity. NETotic neutrophils interacted with

**8. Innate immune responses in ANCA associated vasculitis**

**8.1. Neutrophils, key effector cells, in ANCA associated vasculitis**

*8.1.1. The role of the neutrophil in the development of autoimmunity*

system require further clarification.

ment protocols.
