While it is clear that ANCAs are involved with WG pathogenesis [81
], it is less certain if their presence or titer level corresponds with disease activity. Some reports suggest that ANCA titer at the end of aggressive therapy regimen relates to risk of relapse [82
]; however, another study reports no relationship between relapse and cANCA level [85
]. It would be useful to gauge the risk of relapse and necessary length of cyclophosphamide therapy, which is the first line pharmacologic treatment for WG, based on an immunological marker (i.e cANCA titer) given the adverse effects of the medication such as risk of bladder cancer, leukemia, and lymphoma [86
]. Due to the contradictory results of the above studies, perhaps a marker other than the IgG cANCA would be a more appropriate or adjunct marker of disease activity.
To date, both experimental studies and clinical diagnostic tools focus on the IgG isotype of ANCA as functionally important [81
]. This is understandable since IgG is the most common isotype in general, since IgG ANCA have been clinically related to WG disease activity [81
], and since genetic studies have implicated IgG FcRs with WG susceptibility and relapse [25
]. However, there may be a role in WG for other immunoglobulin (Ig) isotypes, and another isotype may serve as a marker for disease activity or risk of relapse.
Incubation with an IgM ANCA derived from a patient with severe vasculitis inhibits neutrophil adhesion and increases phagocytosis of apoptotic neutrophils by macrophages, which differ from the pro-inflammatory effects of IgG ANCA incubation [89
]. This study focused on an ANCA specific to MPO, which, while present at times, is not the most common ANCA target in WG. The IgM ANCA isotype has also been observed in a patient with pulmonary hemorrhage and acute renal failure [90
], symptoms commonly reported in WG. IgM ANCAs may be present and modulating disease severity in WG.
IgE ANCAs have not been reported in the experimental setting or in a case study isolated from a patient. While unlikely to impact WG pathogenesis, IgE ANCAs could play a role in another vasculitis such as Churg-Strauss syndrome that is known to have positive ANCA titers and high IgE levels. It is not clear if IgE ANCAs have been sought and not found or simply not investigated.
The most likely Ig isotype, other than IgG, to influence WG is IgA. As discussed above (and seen in the clinical vignette), mucosal manifestations are common among WG patients with nasal / oral inflammation and respiratory tract involvement being diagnostic markers of disease [4
]. Since IgA is the most prevalent antibody isotype at mucosal surfaces [91
] and since ANCAs are the most prevalent auto-antibodies involved in WG, it is probable that IgA ANCAs are present and impacting disease in WG patients. WG patients frequently manifest glomerular damage [4
], and IgA deposition is the most common cause of glomerulonephritis [92
] providing more circumstantial evidence for IgA ANCA involvement in WG.
IgA ANCAs have been observed in erythema elevatum diutinum [93
], which is a neutrophil-associated vasculitis of the skin. This identification establishes a precedent for IgA ANCA involvement in neutrophil-related and vasculitic diseases. Other conditions with observed IgA ANCAs include cutaneous vasculitis [94
], ulcerative colitis [95
], and Henoch-Schönlein purpura [96
]. It needs to be determined if IgA ANCAs can be detected in WG patients and if their presence mediates the disease process.
One possible avenue of investigation is the role of the FcR for IgA (FCAR
, CD89) in WG. If IgA ANCAs are present, this molecule would be central to any downstream effects. FCAR is a particularly interesting FcR since it has recently been shown to direct both pro-inflammatory and anti-inflammatory effects [97
] in an allele specific manner [99
]. The activating or inhibitory effects of IgA are due, at least in part, to differential stoichiometric binding of IgA with FCAR. When two FCAR molecules are complexed together on the cell surface, their close proximity creates a different Fc binding site for IgA that signals activation when engaged. When FCAR remains as a monomer on the cell suface, engagement of the traditional Fc binding site signals the cell to downregulate an immune response [97
]. In fact, the binding site of IgA to FCAR impacts immune evasion by Staphyloccus aureus
to allow chronic nasal carriage [100
], a risk factor for WG susceptibility [26
]. Supposing that IgA ANCAs are present in WG patients, such paradoxical regulation by FCAR could explain a role for ANCAs in the range of severity observed among WG patients [33
]. It needs to be determined if these other ANCA isotypes are present in WG patients and what, if any, impact they have on pathogenesis.