Lupus nephritis: correlation of immunohistochemical expression of C4d, CD163-positive M2c-like macrophages and Foxp3-expressing regulatory T cells with disease activity and chronicity

Abstract

Background C4d, which is a serum complement cleavage product of the activated complement component C4, was found to be an accurate indicator of lupus activity compared to complement levels. Recently, macrophages have been considered to be pivotal members in the pathogenesis of lupus nephritis (LN). M2c-like macrophages have anti-inflammatory functions and promote fibrosis. Multiple studies have detected that LN is associated with an imbalance between the regulatory T cell (Treg) population and the inflammatory T helper subtypes. Methods We evaluated and scored the immunohistochemical expression of C4d, CD163-positive M2C-macrophages and Foxp3-expressing Tregs in 53 renal biopsies of LN. Their expression was scored and correlated with clinical and histological disease activity and chronicity. Results Class IV was the most prevalent class (50.9%), followed by class III (17%). PTC-C4d intensity score, CD163% of positive M2c macrophages and FOXP3% of positive Tregs were significantly correlated with chronicity index ( rs = 0.292, p = 0.034; rs = 0.407, p = 0.003; and rs = 0.296, p = 0.031, respectively). Also, FOXP3% of positive Tregs was significantly correlated with LN class ( rs = 0.31, p = 0.024). Conclusion C4d-PTC, CD163-positive M2c macrophages and FOXP3-positive Tregs are markers that significantly correlated with chronicity in LN. Further studies are needed to evaluate their prognostic value.

Complement C4d as a biomarker for systemic lupus erythematosus and lupus nephritis

“…[26][27][28] However, there are differences in the PTC C4d detection frequencies in LN patients. 16,20,26,27 Li et al 26 and Drachenber et al 16 recorded similar low frequencies of PTC C4d detection: 6.8% and 8.8%, respectively, by indirect immunofluorescence on frozen tissue sections. In contrast, studies by Gonzalo et al 27 and Allam et al 20 demonstrated that the frequency of PTC C4d detection was up to 86% and 77.3%, respectively, by immunohistochemistry on paraffin sections.…”

“…Similar findings have been reported in several studies. [18][19][20] For example, Batal et al 18 examined 53 renal biopsies from LN patients and found that glomerular C4d staining was positive in 49 of 53 cases (92.5%) and that the level of positivity was unrelated to either the renal pathological AI or the renal pathological chronicity index (CI) of renal biopsies. Other studies, however, noted differences.…”

Diagnostic, predictive and prognostic biomarkers in systemic lupus erythematosus: current insights

“…Urine VCAM-1 and ALCAM have been shown to determine the stage of chronic kidney disease (CKD) [55 ▪ ], whereas urine VCAM-1 was also correlated with NIH renal histology chronicity index scores in patients with LN [66,46 ▪ ]. Lastly, the percentage of CD163 + M2c-like macrophages in kidney biopsies also correlated with NIH chronicity index scores ( ρ = 0.41) [56 ▪ ].…”

“…Finally, another study reported associations of baseline urinary levels of monocyte chemoattractant protein 1 (MCP-1, also known as CCL2), a potent inducer of monocyte chemotaxis, and ceruloplasmin, an enzyme with copper-dependent oxidase activity, with response to rituximab therapy after 6-12 months from treatment commencement [86]. Finally, in a recent study of LN patients by Fava et al [53 ], early decreases in urinary concentrations of IL-16, CD163 and transforming growth factor beta 1 (TGF-b1) were seen in complete and partial responders but not in nonresponders after 12 months of induction therapy. ].…”

“…Table 2 summarises recent findings of biomarkers of disease activity and accumulated organ damage [8,12,13 ▪ ,16,24–28,29 ▪ ,30,31,32 ▪ ,33–45,46 ▪ ,47–52,53 ▪ –56 ▪ ,57]. Low complement component 3 (C3) [28] and C4 [28], and interferon (IFN)α [25] recently exhibited good performance as serum biomarkers of disease activity measured with Lupus Low Disease Activity State (LLDAS) [58] or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) [59].…”