Plasma cells within granulomatous inflammation display signs pointing to autoreactivity and destruction in granulomatosis with polyangiitis

Abstract

IntroductionPlasma cells residing in inflamed tissues produce antibodies in chronic inflammatory and systemic autoimmune diseases. This study examined if plasma cells, located within inflamed nasal tissue in granulomatosis with polyangiitis (GPA), express features potentially associated with the autoimmune and destructive character of this disease.MethodsIg gene mutation patterns of individual tissue-derived plasma cells from GPA (n = 5) were analyzed, by using laser-assisted microdissection followed by semi-nested polymerase chain reaction (PCR). Signs of B-lymphocyte maturation (ectopic lymphoid structures, ELS) and survival (a proliferation-inducing ligand, APRIL; B-cell maturation antigen, BCMA; transmembrane-activator and calcium modulator and cyclophilin interactor, TACI; receptor activator of nuclear factor κB ligand, RANKL) were examined in nasal tissues or serum, respectively, by using immunohistochemistry/fluorescence and enzyme-linked immunosorbent assay, ELISA.ResultsPlasma-cell derived Ig genes (light- and heavy-chain pairs, n = 4; heavy chains, n = 33) resembled mutation patterns seen in other autoimmune diseases, predominantly displaying selection against replacement mutations within the framework region of Ig genes (10 of 15), which is responsible for structural integrity. Ectopic lymphoid structures were similar between GPA and a disease control (that is, unspecific chronic rhinosinusitis. However, histomorphologic features distinguishing GPA from rhinosinusitis (that is, neutrophilic microabscess and granuloma) expressed considerable amounts of membrane-associated and secreted APRIL, respectively. The latter was co-localized with CD138 and found in close proximity to cells expressing IgG, TACI, and BCMA. Interestingly, plasma cells strongly expressed receptor activator of nuclear factor κB ligand (RANKL), apart from fibroblast-like cells.ConclusionsPlasma cells within granulomatous inflammation appear to display features that might be required for autoreactivity and, possibly, RANKL-mediated destruction in GPA.

Implication of B lymphocytes in the pathogenesis of ANCA-associated vasculitides

“…CXCL13, a B-cell specific chemokine, was detected in TLS, and CXCR5, the CXCL5 receptor, was expressed by infiltrating B lymphocytes [49]. Similar results were found regarding CCL21, expressed by perivascular stromal cells, and CCR7, expressed by B and T lymphocytes infiltrating ectopic lymphoid structure [49].…”

“…Similar results were found regarding CCL21, expressed by perivascular stromal cells, and CCR7, expressed by B and T lymphocytes infiltrating ectopic lymphoid structure [49]. Zhao et al [50] also investigated the expression of CCR10 at the surface of circulating and tissue infiltrating B-cells.…”

Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis

“…pDCs are located within close proximity to macrophages and apoptotic neutrophils expressing PR3 within granulomatous inflammation. In addition to granulomatous inflammation featuring neutrophils, macrophages, and T lymphocytes (including Tregs) in close proximity (37), IFN-α + CD123 + cells representing pDCs were also identified ( Figure 8A). Some IFN-α + CD123 + cells were located at the edge of neutrophilic microabscesses in lung tissue PR3 to polarize CD4 + T cells in vivo, mice were injected with apoptotic cells i.v.…”

Pathogenetic and Clinical Aspects of Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitides

“…Histopathological classification for extravascular granulomatous lesions in GPA has been proposed ( 31 ). Ectopic lymphatic structures have been found in both extravascular granulomatous lesions and glomerulonephritis ( 32 , 33 ). In EGPA, extravascular and vascular lesions are characterized by eosinophilic infiltration ( 24 , 25 ).…”