Review
Figure 6 The role of neutrophil extracellular traps in immune mediated kidney disease. NETosis plays a critical role in most autoimmune kidney diseases and are involved in many processes perpetuating inflammation, eventually leading to a humoral immune response, further the deposition of immune deposits and complexes, which then leads to the onset of glomerulonephritis.
glomerular injury and with clinical features and outcome. In LN, membranous or class V LN has better prognosis compared with the class III and IV despite more severe proteinuria, 53 while in IgAV, the deposition of the terminal complement complex colo- calised with IgA is associated with decreased kidney function and nephrotic syndrome, 54 which resulted in a significant increase in prescription of immunosuppression in this cohort. Nephritogenicity in anti-GBM disease is characterised by production of pathogenic antibodies against constituents of the basement membrane, comprising the non-collagenous domain of α 3 chain of type IV collagen. Alongside linear IgG deposition on GBM, patients with anti-GBM typically present with cellular crescents present in most glomeruli, which directly predicts overall renal survival. 23 Our understanding of kidney histology change over time is limited to ‘atypical’ anti-GBM disease, but a transition from acute lesions to chronic damage (presence of global glomerulosclerosis) needs to be expected in cases with severe kidney disease. The inflammatory response seen in many diseases with immune deposits will eventually lead to chronic lesions with global glomerulosclerosis and interstitial fibrosis (IF) as charac- teristic features of common final pathways of kidney damage, if the respective processes are not terminated early. 26 55 Repeat kidney biopsy (either protocol biopsies or as per indication) indi- cated that the number of globally sclerosed glomeruli and the proportion of patients with severe IF/tubular atrophy (IF/TA) increased in ANCA-GN with evidence of active disease despite immunosuppressive treatment. 56 This indicates that despite treatment and clinical remission, sub-clinical inflammation and disease progression may still progress unnoticed. In line, protocol biopsies in LN indicate an increase of the Chronicity Index (CI), IF/TA and glomerulosclerosis over time. Higher percentage of glomerulosclerosis and IF/TA, and higher CI are associated with CKD progression. 57 A possible explanation, especially in patients that lack response to therapy, is that persistent glomer- ular overexpression of interferon and JAK/STAT signalling is found in transcriptome analyses in non-responding patients in comparison to those achieving remission. 58 Single cell RNA sequencing revealed local activation of B cells, an interferon response of most cells, and a crucial role of chemokine receptors in LN. More importantly, these transcripts in urine and kidney
20 weeks. A potential explanation for this role of megsin is the inhibitory effect of megsin on plasmin activity. The plasminogen activator/plasmin cascade plays an important role in degrading matrix components, and this might be disturbed by the presence of megsin–plasmin complexes. 43 The evolvement of crescent formation in the context of MPGN requires alterations of the complement system, as only double-knockout factor H mice developed crescents. 44 Comple- ment alternative pathway anaphylatoxin C5a plays an essential role in neutrophil influx in a cryoglobulin-induced glomerulone- phritis model and has shown a crucial involvement in the patho- genesis of several autoimmune diseases including AAV. 45 46 The absence of C5 in an ICGN model resulted in reduced crescent formation and deposition of immune complexes. 47 The comple- ment system plays a pivotal role in perpetuating inflammatory responses. In C3-deficient mice a pronounced accumulation of immune complexes and a progressive decline in kidney function was reported after injection of anti-GBM antibodies. 48 Lower C3 levels in circulation of patients with AAV are associated not only with reduced patient and kidney survival, but also indicates a proportion of patients at risk to develop CKD. 49 50 Addition- ally, C3 deposits in the kidney are associated with worse renal and patient survival. 51 Importantly, the presence of immune complexes in glom- eruli alone is not sufficient to induce severe nephritis in a LN mouse model. 52 Rather, there is a delicate interplay between inflammatory immune responses and inhibitory pathways, but once an imbalance in favour of inflammation occurs, kidney injury evolves. In addition, tissue damage caused by immune complexes is dependent on the biochemical and biologic prop- erties of the antigen and antibody and the relative concentration of the antigen and antibody in the circulation and tissues. Thus, the sole presence of immune deposits/complexes might not be capable to induce related tissue lesions, but rather the concom- itant induction of inflammatory pathways involving the innate and adaptive immune system leads to tissue injury. PRESENCE OF IMMUNE DEPOSITS/COMPLEXES AND PROGNOSTICATION/THERAPEUTIC RESPONSE The presence, location and type of immune deposits in the kidney is directly associated with the pattern and severity of
Kronbichler A, et al . Ann Rheum Dis 2023; 82 :585–593. doi:10.1136/annrheumdis-2022-222495
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