B cell-mediated pathogenesis of ANCA-mediated vasculitis

Abstract

B cells and their progeny that produce and release anti-neutrophil cytoplasmic autoantibodies (ANCA) are the primary cause for an aggressive form of necrotizing small vessel vasculitis. Cytoplasmic ANCA antigens are released at the surface and in the microenvironment of cytokine-primed neutrophils. Binding of ANCA to ANCA antigens activates neutrophils by both Fc receptor engagement and direct Fab'2 binding to antigen on the cell surface. ANCA-activated neutrophils release factors that induce alternative complement pathway activation, which establishes a potent inflammatory amplification loop that causes severe necrotizing vascular inflammation. The origin of the ANCA autoimmune response is unknown but appears to involve genetically determined HLA specificities that allow the autoimmune response to develop. One putative immunogenic mechanism begins with an immune response to a peptide that is complementary to the autoantigen and evolves through an anti-idiotypic network to produce autoantibodies to the autoantigen. Another putative immunogenic mechanism begins with an immune response to a microbe-derived molecular mimic of the autoantigen resulting in antibodies that cross-react with the autoantigen. Release of neutrophil extracellular traps, apoptosis, and increased granule protein expression of ANCA antigens may facilitate the initiation of an ANCA autoimmune response, augment established pathogenic ANCA production, or both. The ANCA B cell autoimmune response is facilitated by quantitatively and qualitatively impaired T cell and B cell suppression and by release from activated neutrophils of B cell-activating factors that enhance B cell proliferation and retard B cell apoptosis.

Figure 1

Indirect immunofluorescence microscopy showing the patterns of staining of cytospin preparations of alcohol-fixed normal human caused by ANCA. 1a: Cytoplasmic (C-ANCA) staining pattern caused by PR3-ANCA. 1b: Perinuclear (P-ANCA) staining caused by MPO-ANCA. (Second antibody is FITC-labeled rabbit anti-human IgG).

Figure 2

Direct immunofluorescence microscopy of glomerular capillaries demonstrating granular staining of capillary walls for IgG indicative of immune complex disease (2a), linear staining of glomerular basement membranes (GBM) for IgG indicative of anti-GBM disease (2b), and a paucity of staining of capillary walls for IgG in a patient with ANCA glomerulonephritis (2c). (FITC-labeled rabbit anti-human IgG)

Figure 3

Vascular inflammation is patients with ANCA disease. 1a: Leukocytoclastic angiitis affecting a venule in the renal medulla. Note the prominent karyorrhexis of neutrophils (leukocytoclasia). 2b: Segmental necrotizing glomerulonephritis with a focus of deeply eosinophilic fibrinoid material with an adjacent cellular reaction (crescent). 3c. Small artery with segmental fibrinoid necrosis in the upper right portion of the vessel wall with intramural and perivascular infiltration of neutrophils and mononuclear leukocytes. 4d: Pulmonary alveolar capillaritis with hemorrhage into the air spaces and numerous neutrophils within alveolar capillaries. (Hematoxylin and eosin stain)

Figure 4

Depiction of pathogenic events in ANCA vasculitis. 1) Normal unprimed neutrophils have ANCA antigens (e.g. MPO and PR3) sequestered within cytoplasmic granules. 2) Neutrophils that have been primed by cytokines release small amounts of ANCA antigens at the cell surface and in the microenvironment where they are targeted by ANCA. Fc receptor engagement by ANCA bound to ANCA antigens as well as Fab’2 binding to ANCA antigens on the cell surface activates neutrophils. 3) Activated neutrophils release factors that activate the alternative complement pathway with the generation of C5a. C5a is a potent chemoattractant for neutrophils and attracts more neutrophils to the nidus of inflammation, and C5a engages C5a receptor (CD88) resulting in additional priming of neutrophils for activation by ANCA. 4) A potent inflammatory amplification loop is established that drives severe necrotizing inflammation in vessel walls.

Figure 5

Diagram of the putative induction of an autoimmune response by an immune response to a peptide that is complementary to the autoantigen (e.g. autoantigen antisense peptide or mimic of the antisense peptide). An endogenous complementary peptide (e.g. 3′to 5′ antisense peptide or 5′ to 3′ sense peptide) or an exogenous peptide (e.g. a mimic of the antisense peptide brought in by a microbial organism) could be the target antigen #1 of an appropriate immune response resulting in the generation of B cells #1 that produce antibodies #1. The idiotopes of antibodies #1 are the target antigens #2.1 for antibodies #2 that are produced by B cells #2. Antibodies #2 act as both anti-idiotype antibodies for idiotope antigens #2.1 but also as autoantibodies against the autoantigen #2.2.

Figure 6

Diagram depicting the genesis, regulation and amplification of B cells that produce pathogenic ANCA. Beginning in the upper left, genetically determined HLA antigen binding sites present antigen that initiate T cell and B cell recognition of antigens that set in motion the evolution of a B cell response that results in B cells and plasma cells that produce pathogenic ANCA. This requires inefficient down regulation by T cells and B cells that normally would suppress a pathogenic autoimmune response. Neutrophil activation by ANCA may augment and sustain this autoimmune response by enhanced display of ANCA autoantigens on neutrophil extracellular traps and on apoptotic neutrophils, overexpression of ANCA antigens in neutrophils, and release of B cell activating factors. This sets up amplification loops (curved arrows) with ANCA production activating neutrophils and activated neutrophils in turn stimulating B cells to make more ANCA.