Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis

INTRODUCTION — The antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). These vasculitides are complex, immune-mediated disorders in which tissue injury results from the interplay of an initiating inflammatory event and a highly specific immune response. Part of this response is directed against previously shielded epitopes of neutrophil granule proteins, leading to high-titer autoantibodies known as ANCA. The production of ANCA is one of the hallmarks of the ANCA-associated vasculitides. ANCA are directed against antigens present primarily within the granules of neutrophils and monocytes; these autoantibodies produce tissue damage via interactions with primed neutrophils and endothelial cells.

The pathogenesis of the ANCA-associated vasculitides and the evidence supporting a pathogenetic role for ANCA will be reviewed here. Other aspects of ANCA-associated vasculitis are discussed separately:

●(See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

●(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

●(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy".)

●(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease".)

●(See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of disease resistant to initial therapy".)

●(See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

RISK FACTORS AND POSSIBLE INITIATING EVENTS — The events leading to the initiation of ANCA-associated vasculitis are not well understood. Genetic factors, infectious agents, a variety of specific drugs, environmental exposures, and other factors may be responsible.

Genetic factors — Genome-wide association studies (GWAS) have identified a number of genes associated with susceptibility to ANCA-associated vasculitis. The first GWAS of a large cohort of patients with ANCA-associated vasculitis in Europe revealed associations between patients with proteinase 3 (PR3)-ANCA serotype and genes encoding alpha-1 antitrypsin (SERPINA1, the endogenous inhibitor of PR3), PR3 itself, and human leukocyte antigen (HLA)-DP [1]. Anti-myeloperoxidase (MPO)-ANCA was associated with HLA-DQ. An association between HLA-DPB1*0401 and PR3-ANCA-associated vasculitis was also identified in children [2].

In addition, the major histocompatibility complex (MHC) class II allele HLA-DRB1*15 appears to increase the risk of PR3-associated ANCA vasculitis among African Americans and also contributes to disease risk among White Americans [3], whereas HLA-B55 has been associated with ANCA-associated vasculitis in Asian but not in White patients [4]. A single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) has been associated with both ANCA disease and rheumatoid arthritis [5]. Other genetic variants reported to be associated with ANCA-associated vasculitis include CD226, CTLA4, FCGR2A, TLR9, RXRB, and STAT4 [4]; BACH2 among Scandinavian individuals with MPO-ANCA vasculitis [6]; and ATG7 among Chinese individuals with microscopic polyangiitis [7].

HLA-DPB1*0401 has been associated with an increased risk of relapse among patients with PR3-ANCA vasculitis, which appears to be driven by the HLA presentation of a specific epitope (PR3225-239) to autoreactive T cells [8]. In addition, variant carriers of a single nucleotide polymorphism, rs62132293, found upstream of the gene encoding PR3 (PRTN3) transcription start site, have been found to have elevated leucocyte PRTN3 gene expression compared with noncarriers, a younger age of onset of disease, and an increased risk of relapse compared with patients with MPO-ANCA vasculitis [9]. Together, these findings provide further support for the role of the PR3 antigen itself in the pathogenesis of PR3-ANCA vasculitis. Whether these genetic associations can be utilized clinically to stratify risk of relapse and tailor therapy requires further investigation and confirmation in prospective studies.  

Studies have also revealed an important role of epigenetic dysregulation in patients who are ANCA positive [10-13]. Patients with active disease appear to have hypomethylated and specific CpG sites when compared with patients who are in remission. In particular, there appears to be a DNA methylation site within PR3 that may be important during periods of active disease. In addition, there is increased autoantigen gene expression in leukocytes in patients with active disease when compared with those who are in remission [14]. There appears to be a positive correlation between expression of the MPO autoantigen and the degree of neutrophil activation [12].

The role of genetic factors in the pathogenesis of eosinophilic granulomatosis with polyangiitis (EGPA) is discussed separately. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Genetic factors'.)

Environmental factors

Infectious agents — Because the symptoms of granulomatosis with polyangiitis (GPA) at disease onset overlap substantially with those due to infectious processes, research efforts have focused upon the identification of pathogens that may precipitate GPA in individuals of the proper genetic background. Limited data demonstrating a higher rate of nasal carriage among patients with GPA have implicated Staphylococcus aureus as a possible inciting factor for relapse of GPA [15,16], an effect that may involve the staphylococcal toxic shock syndrome toxin 1 [17]. Functional antibodies directed against lysosome-associated membrane protein 2 (LAMP-2) in patients with ANCA-associated glomerulonephritis have been described and share complete homology with the bacterial adhesion molecule, FimH [18-20].

Drugs — A variety of drugs (hydralazine, minocycline, propylthiouracil, levamisole-adulterated cocaine, allopurinol, sofosbuvir, and rifampicin, as examples) have been reported to cause ANCA seroconversion, particularly thiol- and hydrazine-containing compounds. Whether these drugs actually cause a vasculitis is not always clear [21-23], but in some situations, a causal relationship is clear. The majority of these patients have MPO-ANCA; however, many of the patients with levamisole-adulterated, cocaine-associated disease have both MPO- and PR3-ANCA [22]. In addition to MPO-ANCA, patients with hydralazine-associated ANCA vasculitis typically also have anti-histone and anti-nuclear antibodies, and approximately one-third will also have dual ANCA positivity with anti-PR3 antibodies [24]. Hydralazine-associated ANCA is thought to be mediated by a reversal of epigenetic silencing of the MPO and PR3 encoding genes. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis'.)

Exposures — Given the frequency with which the first symptoms of GPA occur in the respiratory tract, exposure to noninfectious agents or toxins via the inhalational route is another possible inciting event. One such candidate is silica dust. The odds ratio of exposure to silica dust has been reported to be 4.4 times higher for patients with ANCA-associated vasculitis than in a comparison group of patients with kidney disease caused by lupus or other conditions [25]. Another case-control study reported a similarly increased risk of ANCA vasculitis associated with exposure to silica [26], and a meta-analysis of six case-control studies found a significant association of silica exposure with the development of disease [27]. Mercury and lead exposure have also been proposed as potential etiologic agents in the development of GPA [28].

However, exact relationships between such environmental exposures and vasculitis are complicated by difficulties in obtaining reliable measurements of exposures, the likelihood of recall bias among patients who are diagnosed with ANCA-associated vasculitis, and the choice of appropriate control groups. It is most likely that silica may serve at least as an adjuvant in patients with a predisposition to ANCA-associated vasculitis if it is not a primary trigger.

Cigarette smoking has also been associated with an increased risk of ANCA-associated vasculitis. In a large case-control study that included 473 patients with ANCA-associated vasculitis (65 percent were MPO-ANCA positive) and 1419 matched controls, smoking was associated with increased odds of having ANCA-associated vasculitis compared with nonsmoking (odds ratio 1.7, 95% CI 1.4-2.2) [29]. This association was particularly strong among patients who were MPO-ANCA positive, and there was a dose-response relationship between cumulative smoking time and risk of ANCA-associated vasculitis.

Other factors — Other factors that are associated with an increased risk for ANCA-associated vasculitis include the following:

●Alpha-1 antitrypsin (A1AT) deficiency – Because A1AT is the primary in vivo inhibitor of PR3, the observation that patients with A1AT deficiency are at increased risk for GPA suggests a potential pathogenic role in this disease for deficient PR3 clearance from sites of inflammation [30,31]. Decreased local concentrations of A1AT caused by genetic polymorphisms or alterations in the enzyme's functionality induced by inflammation may therefore lead to protease/antiprotease imbalance in the disease microenvironment. Although unproven, these events may be responsible for generating immunogenic forms of PR3 in these patients [31,32]. One study found increased plasma PR3 and A1AT levels in patients with active PR3- or MPO-ANCA vasculitis compared with healthy controls, with, on average, a 3.3-fold higher PR3:A1AT molar ratio [33]. A1AT was shown to prevent the binding of PR3 to the neutrophil surface receptor CD177, thereby reducing neutrophil activation by PR3-ANCA.

PATHOGENIC ROLE OF ANCA

Overview of ANCA — Approximately 90 percent of patients with granulomatosis with polyangiitis (GPA) have antineutrophil cytoplasmic autoantibodies (ANCA), although the percentage varies according to disease phenotype (patients with limited GPA are less likely to be ANCA positive). Approximately 70 percent of patients with microscopic polyangiitis (MPA) are ANCA positive. By contrast, only 30 to 40 percent of patients with eosinophilic granulomatosis with polyangiitis (EGPA) are ANCA positive.

The most commonly identified and evaluated autoantigens in GPA and MPA are proteinase 3 (PR3) and myeloperoxidase (MPO). ANCA directed against these antigens are known as MPO-ANCA and PR3-ANCA, respectively. GPA is primarily associated with PR3-ANCA, and MPA is primarily associated with MPO-ANCA; EGPA, when ANCA positive, is almost always associated with MPO-ANCA. Approximately one-third of patients with anti-glomerular basement membrane (GBM) disease have circulating ANCA, with MPO-ANCA accounting for approximately 70 percent of cases [34]. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Granulomatosis with polyangiitis' and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Microscopic polyangiitis' and "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Double-positive anti-GBM and ANCA-associated disease'.)

ANCA that target other antigens (eg, lactoferrin, cathepsin G, elastase, and bactericidal/permeability-increasing protein) are frequently observed in immune-mediated disorders not typically associated with vasculitis (eg, ulcerative colitis). These other ANCA are of uncertain clinical and pathological significance. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

Upon immunofluorescence testing of serum using a weak fixative such as ethanol-fixed neutrophils as the substrate, sera containing PR3-ANCA cause a cytoplasmic pattern of neutrophil staining (a "C-ANCA" pattern). By contrast, MPO migrates toward the nucleus, and sera containing MPO-ANCA lead to a perinuclear ("P-ANCA") pattern of staining. For unclear reasons, sera from patients with ANCA-associated vasculitis usually contain either PR3-ANCA or MPO-ANCA, although, occasionally, both may be present. This is most commonly found in drug-induced ANCA-associated vasculitis. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis'.)

The mechanisms by which ANCA arise and the role of these autoantibodies in causing disease remain unclear. One possibility is that these antibodies are epiphenomena (eg, the byproduct of more primary pathologic processes). However, in the majority of GPA cases and, particularly, in patients with generalized disease, ANCA appear, at minimum, to be involved directly in the widespread tissue damage that is the hallmark of this condition [35-37].

Mechanisms of ANCA production — The autoantibody response that produces ANCA is probably generated against newly exposed epitopes (ie, cryptic sites) of the target autoantigen. Following the production of ANCA, the antibody response may generalize to the rest of the molecule or to other components of a macromolecular protein complex via the process of epitope spreading. With ANCA-associated vasculitis, these neoepitopes may arise at the sites of initial tissue injury [38]. Roughly 10 percent of patients lack both MPO-ANCA and PR3-ANCA. A subset of such patients may harbor autoantibodies to other autoantigens; however, one study found that this subset of patients actually does have autoantibodies to MPO that are masked by its endogenous inhibitor, ceruloplasmin [39].

Epitope specificity appears to be of substantial importance in MPO-ANCA. Several studies have done epitope mapping, suggesting that there are critical epitopes that are important during disease activity that are different than those present in patients in remission or naturally occurring anti-MPO antibodies [39-41]. A specific portion of MPO that is largely hidden appears to be an important target. This MPO epitope-specific region is recognized by human leukocyte antigen (HLA), suggesting that MPO-ANCA patients respond to a restricted region of MPO to which B cells react [42].

In addition to the human epitope studies, a murine model has suggested that this same region is important in inducing MPO-ANCA autoantibodies in mice [43]. Nasal insufflation of this region of MPO in mice before immunization with MPO resulted in what appears to be the development of immune tolerance [44].

Antibodies are also generated against complementary peptides that are translated from the antisense RNA that encodes PR3 [45-47]. This has led to the hypothesis that the antigen that initiates the cascade of immunologic events in GPA and related vasculitides is not the autoantigen or mimic but the complementary protein of the autoantigen [46,48]. Antibodies to these complementary proteins elicit anti-idiotypic antibodies that may react with the autoantigen or with other unrelated antigens [47,48]. As an example of the latter, antibodies generated to peptides complementary to PR3 also react with plasminogen [47]. This hypothesis was tested and verified in mice with anti-GBM disease using a peptide complementary to the alpha-3 chain of type IV collagen [49].

Evidence for the pathogenicity of ANCA — Evidence for the pathogenetic role of ANCA comes from several clinical and preclinical studies:

●Animal models – Two murine models of ANCA-associated vasculitis reveal that adoptive transfer of autoantibody alone is sufficient to induce a necrotizing vasculitis that closely resembles human disease. Development of these models involved two types of genetically altered mice: the MPO knockout mouse and the recombinase-activating gene 2 (RAG-2)-deficient mouse. The latter species lacks both T and B cells.

These murine models provide in vivo evidence for the pathogenic potential of ANCA [50]:

•In the first model, MPO knockout mice were initially immunized with mouse MPO, resulting in the formation of anti-MPO splenocytes and anti-MPO antibodies within immunized mice. RAG-2-deficient mice were subsequently injected with either anti-MPO splenocytes or control splenocytes, which did not produce anti-MPO antibodies. RAG-2 mice that received anti-MPO splenocytes developed clinical features of ANCA-associated vasculitis, including crescentic glomerulonephritis and systemic necrotizing vasculitis. By comparison, RAG-2 mice that received non-MPO antibody-producing splenocytes displayed only a relatively mild immune complex glomerulonephritis.

•In the second disease model, RAG-2-deficient and wild-type mice were injected with anti-MPO or control immunoglobulins. Only mice receiving anti-MPO antibodies developed a pauci-immune glomerulonephritis.

Another murine model using MPO knockout mice also showed that transplant of MPO bone marrow to MPO-immunized mice resulted in necrotizing crescentic glomerulonephritis [51]. However, transfer of bone marrow that lacked a cysteine protease involved in the activation of enzymes that modulate inflammation appeared to protect mice from glomerulonephritis, suggesting that there is an important role for the activation of neutrophil serine proteases in anti-MPO antibody-induced glomerulonephritis. Of note, the proteasome inhibitor bortezomib post-bone marrow transplantation resulted in disease reduction [52].

A rat model of ANCA-associated vasculitis, induced by immunization with human MPO, demonstrated ANCA-mediated enhancement of interactions between leukocytes and the endothelium, thereby supporting the pathogenic role of ANCA [53].

The role of T cells has been substantiated by another animal model whereby mice were immunized with MPO and subsequently developed glomerulonephritis; however, this model also required the use of anti-GBM autoantibodies or lipopolysaccharide (LPS) to induce disease [54]. The murine T cell epitope identified in this model overlaps significantly with a major B cell epitope present in patients with active disease [39].

With respect to immunopathogenesis and tolerance, animal models comparing MPO-deficient mice and autoimmune regulator (Aire)-deficient mice have also shown that the transcription factor Aire promotes the expression of MPO in the thymus and depletion of regulatory T cells leads to more severe disease [55]. Mast cells are also important in this process, and cromolyn attenuated the vasculitis [56]. Other animal models have highlighted the importance of immunodominant T and B cell epitopes and explored the role of induction of nasal tolerance and injection of tolerogenic dendritic cells in attenuating disease [43,44,57].

●Human model – The first direct evidence in humans that ANCA are pathogenic was provided by a newborn in which the placental transmission of maternal anti-MPO autoantibodies resulted in the pulmonary-renal syndrome [58]. After treatment with glucocorticoids and supportive therapy, the syndrome completely resolved over time in conjunction with the eventual disappearance of maternal ANCA.

ANCA isotypes and the role of Fc receptors — In theory, the isotype of ANCA in a given individual may have pathophysiological importance. Most patients with ANCA-associated vasculitis, for example, produce isotype-switched immunoglobulin G (IgG) ANCA, implying a secondary immune response driven by T cells. However, studies regarding the relative importance of IgG subtypes and other types of ANCA (eg, immunoglobulin M [IgM], immunoglobulin A [IgA]) have been inconclusive and contradictory. At present, there is no conclusive evidence that particular ANCA isotypes influence the susceptibility to or clinical expression of ANCA-associated vasculitis.

The magnitude of enhanced neutrophil activation by ANCA may also be influenced by antibody specificity for different PR3 epitopes [28,59], IgG subclass, and the type of Fc-gamma receptors (Fc-gamma-Rs) engaged [60-64]. The Fc-gamma-RIIIB allele polymorphism NA1, which allows more efficient neutrophil activation by ANCA, is overrepresented in patients with severe forms of GPA [65,66].

ANCA antigens in kidney tissue — The emergence of ANCA-associated antigens in the kidney tissue of patients with glomerulonephritis may contribute to the underlying disease process. PR3, MPO, and elastase have been observed within the glomeruli, crescents, and tubular epithelial cells in kidney disorders associated with neutrophilic infiltrates but not in normal kidneys [67,68]. In one study, the extracellular (non-leukocyte associated) glomerular deposition of MPO was found to correlate with glomerular crescent formation and estimated glomerular filtration rate (eGFR) [69]. In a murine model of nephrotoxic nephritis, treatment with a direct MPO inhibitor (AZM198) reduced kidney injury (eg, glomerular thrombosis, proteinuria, and plasma creatinine) compared with vehicle alone but did not reduce glomerular neutrophil infiltration. These results suggested that the protective effect of MPO inhibition may be mediated by a reduction of neutrophil activation and extracellular MPO-mediated inflammation. However, this finding differs from that of a separate model in which reduction in the number of circulating neutrophils was protective, but the use of a direct MPO inhibitor was not [70]. (See 'Evidence for the pathogenicity of ANCA' above.)

In addition to enhancing the antineutrophil activity of ANCA, the proinflammatory activity of tumor necrosis factor (TNF) and other cytokines (such as interleukin [IL] 6) may also contribute directly to kidney injury [71,72]. Local TNF production by infiltrating mononuclear cells and intrinsic kidney cells has been demonstrated in active vasculitic lesions of the kidney in ANCA-positive patients [72]. The mechanism by which these cells become activated to release TNF is unclear.

PATHOGENESIS OF VASCULITIS

Neutrophil priming and activation — The effects of ANCA are determined by the state of neutrophil activation. Proteinase 3 (PR3) and myeloperoxidase (MPO), located in the cytosol, may be relatively inaccessible to antibody binding. However, neutrophils "primed" with tumor necrosis factor (TNF) as well as those undergoing apoptosis have enhanced expression of membrane-associated PR3 [36,73]. In some individuals, a higher proportion of nonactivated neutrophils may express membrane-associated PR3, which may be a risk factor for vasculitis or more severe manifestations of vasculitis [74]. Genes that encode both PR3 and MPO have been shown to be abnormally upregulated in the peripheral neutrophils of patients with ANCA-associated glomerulonephritis, possibly due to epigenetic silencing defects [10,75].

Once neutrophils have been activated by priming, ANCA are able to bind relevant membrane-bound antigens [76,77], causing abnormal constitutive activation via either the crosslinking of MPO or PR3 or the binding of Fc receptors [61,62,78,79]. ANCA binding to neutrophils can enhance neutrophil-endothelial cell interactions and subsequent microvascular injury, explaining a possible pathogenetic role for ANCA in systemic vasculitis [36,53].

The rate at which primed neutrophils degranulate and release chemoattractants and cytotoxic oxygen free-radical species into the local tissue environment is also increased by ANCA [67,80-86]. In addition, primed neutrophils can adhere to and damage vascular endothelial cells and attract additional neutrophils to the site of damage, thereby creating an autoamplifying loop specific to the microenvironment [73,84,85].

Patients with ANCA-associated vasculitis have increased numbers of primed neutrophils in kidney biopsy specimens as well as increased expression of neutrophil-specific genes, paralleling the activity of the disease [67,87]. In addition, persistent membrane expression of PR3 during periods of disease remission is associated with an increased risk of relapse in granulomatosis with polyangiitis (GPA) patients [85]. Enhanced generation of reactive oxygen species by circulating neutrophils in these patients compared with controls may also occur.

GPA patients in remission frequently experience disease flares following systemic bacterial or viral infections [36,71]. One potential explanation for this observation is that an infection or other inflammatory process can lead to suprathreshold neutrophil (and, perhaps, monocyte) priming in those individuals with circulating ANCA [88]. This process then sets off the amplifying cascade described above, which ultimately leads to vascular injury. The release of MPO, PR3, elastase, and other proteases from the activated neutrophils can also contribute directly to the local inflammatory process [71].

ANCA-associated activation may induce neutrophil actin polymerization, resulting in increased neutrophil rigidity [89]. Such activated neutrophils may become sequestered in small-sized vessels since they are unable to adapt morphologically to arterioles; this may help to explain the predilection for small blood vessels in ANCA-associated disease.

NET formation — As a killing strategy against invading pathogens, neutrophils release webs of decondensed chromatin called neutrophil extracellular traps (NETs) into the extracellular space [90]. NETs may also contribute to the pathogenesis of ANCA-associated vasculitis [91]. NETs containing PR3 and MPO autoantigens are released by ANCA-stimulated neutrophils and have been demonstrated in the kidneys of patients with ANCA-associated vasculitis [92]. In one study, in vitro NET formation by PR3-ANCA-stimulated neutrophils could be reduced by the addition of a direct MPO inhibitor [69]. Another study found that pharmacologic and genetic inhibition of cyclophilin D (CypD; a mitochondrial matrix protein that controls metabolism and reactive oxygen species production) suppressed ANCA-induced NET formation [93]. In mouse models of ANCA-associated vasculitis, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD-dependent neutrophil and endothelial necrosis.

Role of endothelial cells — In the early stages of ANCA-associated vasculitis, endothelial cells may recruit inflammatory cells and enhance their adhesion to sites of vascular injury. The subsequent release of PR3 and other neutrophil proteases may induce endothelial synthesis and secretion of interleukin (IL) 8, a potent neutrophil chemoattractant, thereby attracting additional neutrophils [94].

PR3 released by neutrophils may also enhance the adhesion of accumulating neutrophils and mononuclear cells to the endothelial surface via the induction of adhesion molecules, such as vascular cell adhesion molecule 1 (VCAM-1) [95,96]. The potential significance of adhesion via VCAM-1 is supported by the observation of enhanced in situ expression of this molecule in the affected glomerular tufts of patients with ANCA-associated vasculitis, particularly PR3-ANCA [97,98]. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)

Whether endothelial cells produce PR3 and display this molecule upon activation is controversial [99-104]. The contradictory results may be due, in part, to differences in experimental techniques.

The soluble endothelial protein C receptor binds activated neutrophils via interactions with PR3. This provides a link between neutrophil priming, vascular inflammation, and the coagulation cascade [105] and may explain, in part, the increased risk of venous thrombotic events in GPA [72].

There is also evidence for organ-specific antiendothelial cell antibodies (AECAs) [104]. The exact antigens and their role in disease development are unclear, but one possible target is the 60 kilodalton heat shock protein, which plays a role in protein assembly [106].

Activation of the alternative complement pathway — The alternative complement pathway may play a role in exacerbating and/or perpetuating anti-MPO-associated vasculitis [107]. Transgenic mice expressing human C5a receptor (C5aR) were protected from ANCA-associated vasculitis when given an oral small molecule antagonist of human C5aR called avacopan (also known as CCX168), indicating the importance of the alternative complement pathway in this model [108]. In humans, abnormal levels of C3a, C5a, and soluble C5b-9 have been identified in the plasma, kidneys, and urine of patients with either MPO- or PR3-ANCA-associated disease. Avacopan has been evaluated for the treatment of patients with ANCA-associated vasculitis; these data are discussed elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Avacopan'.)

Role of B cells — B cells also play an important role in ANCA-associated vasculitis [109]. In the early 1980s, studies with cyclophosphamide indicated that, among lymphocytes, its greater effect may be upon B cells rather than T cells [110]. Subsequently, it was shown that the number of activated B cells (but not the number of activated T cells) in circulation correlates with disease activity scores in ANCA-associated vasculitis [111]. In addition, large randomized trials have shown that anti-CD20 therapies (that deplete B cells) can induce remission in patients with GPA or microscopic polyangiitis (MPA). (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Induction therapy'.)

The rationale for why B cell depletion is effective in ANCA-associated vasculitis includes the complete removal or substantial reduction of ANCA production, diminution of the contribution of B cells to antigen presentation and cytokine production, and the inhibition of B cell/T cell crosstalk.

Role of T cells — Numerous studies have shown defects in both T regulatory (Treg) and B regulatory cells in patients with active ANCA-associated vasculitis [112]. In particular, while patients have an increased number of Treg cells, these cells appear to possess a diminished suppressive capacity, which may be associated with altered distribution of Treg subsets (increase in CD103⁺ and CCR7⁺ and decrease in CXCR3⁺ subsets) in patients with active ANCA-associated vasculitis compared with healthy controls [113].

Since ANCA-associated vasculitis is an antigen-driven process, the disease may heavily depend upon help from T cells. This hypothesis is supported by the finding that mononuclear cells have a significant role in this disorder [60,73,76,114-118]:

●Patients with active GPA have much higher levels of CD4+ T cell and monocytic activation than do patients in remission or healthy controls [114-116].

●Very high levels of the T helper (Th)1 cytokines TNF-alpha and interferon (IFN)-gamma are also observed in patients with active GPA. Monocytes from these patients release large quantities of IL-12, a major inducer of Th1 cytokines.

●Population-based studies of GPA patients reveal a diminished frequency of a major inhibitory cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) allele [60]. This may contribute to increased T cell activation in these patients.

These findings suggest that IL-10, a known antagonist of monocyte activation, may inhibit the Th1 pathway in this disease by impairing the production of IL-12. In one study, for example, IL-10 treatment of peripheral blood mononuclear cells from active GPA patients impaired the production of IFN-gamma in vitro [114].

Another finding that supports a likely role for cellular immunity in disease pathophysiology is the report of a study of five patients with very low cell surface expression of human leukocyte antigen (HLA) class I molecules (caused by impaired expression of the transporter associated with antigen presentation genes) and with clinical and pathologic findings that resembled GPA [118]. Close examination of the granulomatous lesions revealed a large percentage of activated natural killer cells, a subpopulation of non-major histocompatability complex (MHC)-restricted mononuclear cells. Similar findings suggesting a prominent role for the Th1 lymphocyte pathway and mononuclear cells have been observed in patients with giant cell arteritis.

SUMMARY

●Overview – The antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). These vasculitides are complex, immune-mediated disorders in which tissue injury results from the interplay of an initiating inflammatory event and a highly specific immune response. (See 'Introduction' above.)

●Risk factors – The risk factors and events leading to the initiation of ANCA-associated vasculitis are not well understood. Genetic factors, infectious agents, a variety of specific drugs, environmental exposures, and other factors may be responsible. (See 'Risk factors and possible initiating events' above.)

●Pathogenic role of ANCA – Approximately 90 percent of patients with GPA have ANCA, although the percentage varies according to disease phenotype (patients with limited GPA are less likely to be ANCA positive). Among patients with MPA or EGPA, the percentages of patients who are ANCA positive are approximately 70 and 50 percent, respectively. The most commonly identified and evaluated autoantigens in GPA and MPA are proteinase 3 (PR3) and myeloperoxidase (MPO). (See 'Pathogenic role of ANCA' above.)

The autoantibody response that produces ANCA is probably generated against newly exposed epitopes (ie, cryptic sites) of the target autoantigen. Following the production of ANCA, the antibody response may generalize to the rest of the molecule or to other components of a macromolecular protein complex via the process of epitope spreading. With ANCA-associated vasculitis, these neoepitopes may arise at the sites of initial tissue injury. (See 'Mechanisms of ANCA production' above.)

●Pathogenesis of vasculitis – The effects of ANCA are determined by the state of neutrophil activation. Once neutrophils have been activated by priming, ANCA are able to bind relevant membrane-bound antigens, causing abnormal constitutive activation via either the crosslinking of MPO or PR3 or the binding of Fc receptors. ANCA binding to neutrophils can enhance neutrophil-endothelial cell interactions and subsequent microvascular injury, explaining a possible pathogenetic role for ANCA in systemic vasculitis. (See 'Neutrophil priming and activation' above.)

In the early stages of ANCA-associated vasculitis, endothelial cells may recruit inflammatory cells and enhance their adhesion to sites of vascular injury. The subsequent release of PR3 and other neutrophil proteases may induce endothelial synthesis and secretion of interleukin (IL) 8, a potent neutrophil chemoattractant, thereby attracting additional neutrophils. Activation of the alternative complement pathway has also been implicated in exacerbating and perpetuating ANCA-associated vasculitis. (See 'Role of endothelial cells' above and 'Activation of the alternative complement pathway' above.)

B cells and T cells also appear to play an important role in ANCA-associated vasculitis. (See 'Role of B cells' above and 'Role of T cells' above.)

ACKNOWLEDGMENTS — UpToDate thanks John H Stone, MD, MPH, Stuart M Levine, MD, FACP, and William F Pendergraft III, MD, PhD, who contributed to earlier versions of this topic review.