Membrane attack complex (mac) deposition in lupus nephritis is associated with hypertension and poor clinical response to treatment

Wang, Shudan; Wu, Ming; Chiriboga, Luis; Zeck, Briana; Belmont, H. Michael

doi:10.1016/j.semarthrit.2018.01.004

Cited by 22 publications

(30 citation statements)

References 31 publications

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“… 11 found that the majority (57%) of biopsies were negative for C9. In this study, activity and chronicity indices did not differ depending on the presence of C9; however, patients negative for C9 were more likely to respond to treatment 11 …”

Section: Discussionmentioning

confidence: 97%

“…Previous studies have demonstrated a high prevalence of MAC staining in LN and include peritubular MAC 7 ; colocalization of C3c and C5b-9 8 ; mesangial and mixed MAC staining distributions in class III and IV LN, respectively 9 ; and frequent presence of staining for both C5b-9 and mannose-binding lectin 10 . In contrast, C9 staining was demonstrable in only 43% of LN biopsies 11 . The kinetics of MAC staining in LN and its role in chronic LN are poorly characterized.…”

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confidence: 97%

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Glomerular membrane attack complex is not a reliable marker of ongoing C5 activation in lupus nephritis

Wilson

Medjeral-Thomas

Gilmore

et al. 2019

Kidney International

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Complement plays an important role in the pathogenesis of lupus nephritis (LN). With the emergence of therapeutic complement inhibition, there is a need to identify patients in whom complement-driven inflammation is a major cause of kidney injury in LN. Clinical and histopathological data were obtained retrospectively from 57 biopsies with class III, IV, and V LN. Biopsies were stained for complement components C9, C5b-9, C3c, and C3d and for the macrophage marker CD68. C9 and C5b-9 staining were highly correlated ( r = 0.92 in the capillary wall). C5b-9 staining was detected in the mesangium and/or capillary wall of both active and chronic proliferative LN in all but one biopsy and in the capillary wall of class V LN in all biopsies. C5b-9 staining intensity in the tubular basement membrane correlated with markers of tubulointerstitial damage, and more intense capillary wall C5b-9 staining was significantly associated with nonresponse to conventional treatment. Glomerular C5b-9 staining intensity did not differ between active and chronic disease; in contrast, C3c and CD68 staining were associated with active disease. Evaluation of serial biopsies and comparison of staining in active and chronic LN demonstrated that C5b-9 staining persisted for months to years. These results suggest that C5b-9 staining is almost always present in LN, resolves slowly, and is not a reliable marker of ongoing glomerular C5 activation. This limits the utility of C5b-9 staining to identify patients who are most likely to benefit from C5 inhibition.

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 97%

Glomerular membrane attack complex is not a reliable marker of ongoing C5 activation in lupus nephritis

Wilson

Medjeral-Thomas

Gilmore

et al. 2019

Kidney International

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“…In LTH, neutrophils undergo a NET-like cell death upon membrane attack complexes (MAC) formation. Clear documentation of complement activation, consumption and deposition in tissues exists for SLE [48][49][50] . Thus, it is likely that LTH could explain the observed co-localization of C9 and cit-LL37 in SLE-affected kidneys.…”

Section: Discussionmentioning

confidence: 99%

Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus

Lande

Palazzo

Gestermann

et al. 2020

Sci Rep

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LL37 exerts a dual pathogenic role in psoriasis. Bound to self-DNA/RNA, LL37 licenses autoreactivity by stimulating plasmacytoid dendritic cells-(pDCs)-Type I interferon (IFN-I) and acts as autoantigen for pathogenic Th17-cells. In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is target of pathogenic autoantibodies. However, whether LL37 activates T-cells in SLE and how the latter differ from psoriasis LL37-specific T-cells is unknown. Here we found that 45% SLE patients had circulating T-cells strongly responding to LL37, which correlate with anti-LL37 antibodies/disease activity. In contrast to psoriatic Th17-cells, these LL37-specific SLE T-cells displayed a T-follicular helper-(T fH)-like phenotype, with CXCR5/Bcl-6 and IL-21 expression, implicating a role in stimulation of pathogenic autoantibodies. Accordingly, SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro. Importantly, we identified abundant citrullinated LL37 (cit-LL37) in SLE tissues (skin and kidney) and observed very pronounced reactivity of LL37-specific SLE T-cells to cit-LL37, compared to native-LL37, which was much more occasional in psoriasis. Thus, in SLE, we identified LL37-specific T-cells with a distinct functional specialization and antigenic specificity. This suggests that autoantigenic specificity is independent from the nature of the autoantigen, but rather relies on the disease-specific milieu driving T-cell subset polarization and autoantigen modifications. Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a prevalence of about 20-50 cases per 100,000 in Northern Europe and USA 1 , characterized by immune-complex formation and deposition, which result in inflammation and tissue damage. In SLE, altered clearance of dying cells determines persistent exposure of autoantigens and activation of antigen-presenting cells (APCs), mainly via Toll-like receptors (TLR), thus favoring adaptive immune response licensing 1-3. SLE autoantibodies are preferentially directed against

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“…A study of 222 Chinese patients with active LN demonstrated that the alternative complement pathway may be important in the pathogenesis of LN and that factor Bb may be a biomarker for measuring disease activity [18]. Another study of 30 LN patients showed increased deposition of C9 in glomerular biopsy tissue in patients with worse disease compared to those with a more mild phenotype suggesting that the terminal complement complex (C5b-9) may be a suitable biomarker for LN disease activity [41].…”

Section: Discussionmentioning

confidence: 99%

A systematic review of the role of eculizumab in systemic lupus erythematosus-associated thrombotic microangiopathy

et al. 2020

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Background: Lupus nephritis (LN) is a severe consequence of systemic lupus erythematosus (SLE) that affects approximately 40% of patients. Pathogenic immune complexes that are characteristic of LN deposit in the kidney and activate immune mediated pathways including the complement system. Complete remission rates in LN are approximately 44% highlighting the need for new treatment strategies in these patients. Eculizumab is a fully humanised IgG2/IgG4 monoclonal antibody directed at C5 and thus prevents the formation of the terminal complement complex. Eculizumab is successfully used in atypical haemolytic uraemic syndrome (aHUS) and paroxysomal nocturnal haemoglobinuria (PNH) but it is not standardly used in LN. The aim of this project was to determine whether there is any role for eculizumab as adjunctive therapy in LN. Methods: Using a predefined search strategy on Ovid MEDLINE and EMBASE the literature was reviewed systematically to identify studies in which eculizumab had been used to treat patients with SLE. All patients were included that were treated with complement inhibitors. Favourable outcome in this study was defined as resolution of symptoms that led to treatment, discharge from hospital or recovery of renal function. Patients were excluded if there was no outcome data or if complement inhibition was unrelated to their SLE. Results: From 192 abstracts screened, 14 articles were identified, involving 30 patients. All SLE patients administered eculizumab were treated for thrombotic microangiopathy (TMA) secondary to LN diagnosed either histologically (66%) or as part of a diagnosis of aHUS (73%). 93% of patients had a favourable outcome in response to eculizumab treatment, of which 46% had a favourable outcome and successfully stopped treatment without relapse in symptoms during a median follow up of 7 months. Three patients (10%) reported adverse outcomes related to eculizumab therapy.

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Membrane attack complex (mac) deposition in lupus nephritis is associated with hypertension and poor clinical response to treatment

Cited by 22 publications

References 31 publications

Glomerular membrane attack complex is not a reliable marker of ongoing C5 activation in lupus nephritis

Glomerular membrane attack complex is not a reliable marker of ongoing C5 activation in lupus nephritis

Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus

A systematic review of the role of eculizumab in systemic lupus erythematosus-associated thrombotic microangiopathy

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