Organisation of lymphocytic infiltrates in <scp>ANCA</scp>‐associated glomerulonephritis

Brix, Silke R.; Noriega, Mercedes; Herden, Elisabeth M; Goldmann, Birgit; Langbehn, Ulrike; Busch, Martin; Jabs, Wolfram J.; Steinmetz, Oliver M.; Panzer, Ulf; Huber, Tobias B.; Stahl, Rolf A.K.; Wiech, Thorsten

doi:10.1111/his.13487

Cited by 18 publications

(13 citation statements)

References 45 publications

(104 reference statements)

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“…Also, FHR1 concentrations in AAV patients without immunosuppressive therapy showed increased IL-1β concentrations. These results confirm the pro-inflammatory function of FHR1 in AAV, which is characterized by forms of necrosis and inflammation, including NLRP3 activation, elevated IL-1β serum concentrations 29 , and local accumulation of immune cells 46, 47 .…”

Section: Discussionsupporting

confidence: 79%

Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies

et al. 2019

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Persistent inflammation is a hallmark of many human diseases, including anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and atherosclerosis. Here, we describe a dominant trigger of inflammation: human serum factor H-related protein FHR1. In vitro, this protein selectively binds to necrotic cells via its N-terminus; in addition, it binds near necrotic glomerular sites of AAV patients and necrotic areas in atherosclerotic plaques. FHR1, but not factor H, FHR2 or FHR3 strongly induces inflammasome NLRP3 in blood-derived human monocytes, which subsequently secrete IL-1β, TNFα, IL-18 and IL-6. FHR1 triggers the phospholipase C-pathway via the G-protein coupled receptor EMR2 independent of complement. Moreover, FHR1 concentrations of AAV patients negatively correlate with glomerular filtration rates and associate with the levels of inflammation and progressive disease. These data highlight an unexpected role for FHR1 during sterile inflammation, may explain why FHR1-deficiency protects against certain diseases, and identifies potential targets for treatment of auto-inflammatory diseases.

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Section: Discussionsupporting

confidence: 79%

Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies

et al. 2019

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“…Still, less interstitial inflammation in females was observed, further supporting that sex may affect AAV manifestations and outcomes. While only limited data are available, distinct inflammatory lesions have previously been shown to affect the long-term renal outcomes in ANCA GN ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Sex Differences at Disease Manifestation in ANCA-Associated Glomerulonephritis

et al. 2021

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Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis affecting multiple organ systems, including the kidney. Besides investigations focusing on renal outcomes, sex differences associated with distinct clinical and histopathological findings in ANCA glomerulonephritis (GN) have not been systematically investigated. Therefore, we here aimed to systematically analyze sex differences in patients with AAV and biopsy-proven ANCA GN. We provide a comprehensive analysis of 53 kidney biopsies with ANCA GN retrospectively included between 2015 and 2020 and identified specific sex differences in ANCA GN concerning laboratory parameters and systematic scoring of renal histopathology glomerular and tubulointerstitial lesions, and extrarenal manifestations of AAV. We did not observe any correlation between sex and short-term clinical AAV course or disease severity by comparing general AAV parameters. AAV manifestations in females occurred at an older age with more joint involvement. Regarding histopathological findings, we, again, observed no sex difference among ANCA GN classification, but a significant correlation between females and distinct histopathological findings with less tubulointerstitial inflammation and vasculitis of peritubular capillaries. Finally, we here identified fewer associations between clusters of clinical, laboratory parameters, and histopathological findings in females as compared to males. These findings are of great relevance and further improve our understanding of sex differences in the pathogenesis of ANCA GN. While future studies about specific sex differences and conclusions in these clusters are crucial, our observations further support that sex differences are relevant, affect distinct parameters, and influence clinical, laboratory parameters, and histopathological findings in AAV, particularly ANCA GN.

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“…Although B cell and plasma cell infiltration in lesions of GPA patients has been demonstrated before (34), to our knowledge, we are the first to describe plasma cell infiltration into the inflamed kidney in GPA. A recent article by Brix et al described B cell infiltrates in kidney biopsies from active ANCA-associated glomerulonephritis patients and also found an association of ectopic lymphoid structures with end stage renal disease during follow-up (35). Identification of CD27 + CD38 hi B cells by immunohistochemistry is technically challenging, since double staining of the cell membrane is difficult to evaluate.…”

Section: Discussionmentioning

confidence: 99%

CD27+CD38hi B Cell Frequency During Remission Predicts Relapsing Disease in Granulomatosis With Polyangiitis Patients

et al. 2019

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Background: Granulomatosis with polyangiitis (GPA) patients are prone to disease relapses. We aimed to determine whether GPA patients at risk for relapse can be identified by differences in B cell subset frequencies.Methods: Eighty-five GPA patients were monitored for a median period of 3.1 years (range: 0.1–6.3). Circulating B cell subset frequencies were analyzed by flow cytometry determining the expression of CD19, CD38, and CD27. B cell subset frequencies at the time of inclusion of future-relapsing (F-R) and non-relapsing (N-R) patients were compared and related to relapse-free survival. Additionally, CD27+CD38hi B cells were assessed in urine and kidney biopsies from active anti-neutrophil cytoplasmic autoantibody-associated vasculitides (AAV) patients with renal involvement.Results: Within 1.6 years, 30% of patients experienced a relapse. The CD27+CD38hi B cell frequency at the time of inclusion was increased in F-R (median: 2.39%) compared to N-R patients (median: 1.03%; p = 0.0025) and a trend was found compared with the HCs (median: 1.33%; p = 0.08). This increased CD27+CD38hi B cell frequency at inclusion was correlated to decreased relapse-free survival in GPA patients. In addition, 74.7% of patients with an increased CD27+CD38hi B cell frequency (≥2.39%) relapsed during follow-up compared to 19.7% of patients with a CD27+CD38hi B cell frequency of <2.39%. No correlations were found between CD27+CD38hi B cells and ANCA levels. CD27+CD38hi B cell frequencies were increased in urine compared to the circulation, and were also detected in kidney biopsies, which may indicate CD27+CD38hi B cell migration during active disease.Conclusions: Our data suggests that having an increased frequency of circulating CD27+CD38hi B cells during remission is related to a higher relapse risk in GPA patients, and therefore might be a potential marker to identify those GPA patients at risk for relapse.

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Organisation of lymphocytic infiltrates in ANCA‐associated glomerulonephritis

Cited by 18 publications

References 45 publications

Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies

Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies

Comprehensive Analysis of Sex Differences at Disease Manifestation in ANCA-Associated Glomerulonephritis

CD27+CD38hi B Cell Frequency During Remission Predicts Relapsing Disease in Granulomatosis With Polyangiitis Patients

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