Page 110 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

86 Alan D. Salama and Mark A. Little

Keywords: Vasculitis, ANCA, Animal, Models

Introduction

Anti-neutrophil cytoplasm antibodies (ANCA) are associated with diseases characterized
by relapsing necrotising vasculitis of small calibre blood vessels, frequently involving the
kidneys and lungs respectively leading to pauci-immune glomerulonephritis and pulmonary
capillaritis.

Many organs may be affected and, as a result, the conditions cause significant morbidity
and mortality. The precise disease triggers are not known, but clinical associations with
infection have been reported, with experimental data implicating altered responses to
microorganisms as potentially important initiators of autoimmune responses.

ANCA are directed towards two autoantigen, proteinase 3 (PR3) and myeloperoxidase
(MPO), found in neutrophil granules and monocyte lysosomes that are involved in innate
immune responses to infection, while the clinical significance of other proposed ANCA
targets, including lysosome associated membrane protein (LAMP)-2 [1] and moesin [2]
remain to be completely characterised. The ANCA-associated vasculitides (AAV) are more
common in older age and although they can be treated with immunosuppressive therapies, the
disease relapses in up to 50% of treated patients and with re-treatment there is the increased
likelihood of treatment related adverse events.

Animal models of experimental autoimmune vasculitis (EAV) have been developed to
dissect the pathological basis of disease, to understand the role of ANCA in the
etiopathogenesis of AAV, and to replicate the clinical features. The use of murine models has
been favoured because they allow the use of genetically altered animals so that key molecules
and pathways involved in pathogenicity can be investigated.

The most novel insight gained from such an approach was the discovery the importance
of the alternate complement pathway employing passive anti-MPO antibody transfer in C5
and factor B deficient animals [3], a finding that later prompted a therapeutic trial targeting
complement C5a receptor as adjunctive therapy in patients with AAV and renal disease.

Development of adequate models has taken considerable time, with many attempts and
refinements over the years. There remain major deficiencies in modelling granulomatous
PR3-AAV, relapsing disease overlap syndromes and non-pulmonary-renal involvement such
as cardiac, neurological and gastrointestinal disease.

Moreover, the impact of age and immune senescence, infectious triggers, and latent viral
infections on disease susceptibility and initiation need further exploration. The inability to
model PR3-AAV in mice is in part due to differences between human and rodent neutrophil
PR3 expression.

These important omissions and differences should lend some caution to translating the
findings from one animal model to all forms of human AAV. PR3-and MPO-AAV may have
certain common features, such as the occurrence of pauci-immune glomerulonephritis and
pulmonary capillaritis, but they also display many diverse characteristics that translate into
important differences in disease phenotype and outcome.

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