CD80 and CD86 are members of immunoglobulin (Ig) superfamily with their extracellular regions consisting of two Ig-like domains, an NH2-terminal Ig variable-like domain (IgV) followed by a constant-like domain (IgC). Despite having only ~25 % sequence homology, CD80 and CD86 have similar receptor-binding properties [2]. Usually, CD80 is expressed on the activated B cells and APC such as monocytes, macrophages, and dendritic cells. Both molecules bind CTLA-4 and CD28 with much higher affinity with CTLA-4 [1].

There are several other co-stimulatory pathways. Inducible T cell co-stimulator (ICOS) on the T cell binds ICOS ligand on the APC, and programmed cell death protein-1 (PD-1) on the T cells binds programmed death-ligand 1 (PD-L1) or programmed death-ligand 2 (PD-L2) on APC. Thus, co-stimulatory pathway regulates the activation of T cells and prevents excess inflammation or autoreactive immune responses [3].

The expression of CD80 in the non-hematopoietic cells is relatively rare. In human keratinocytes, CD80 expression was upregulated by allergens or irritants [4]. Microglia in the brain and epidermal Langerhans cells also express CD80 on activation [5, 6].

Although the detailed difference between the role of CD80 and CD86 is not well elucidated, the role of CD80 has been postulated as a cause of proteinuric conditions, especially in MCNS [7–9].

The regulatory mechanisms of CD80 have been mostly investigated in the immune cells. Various immune stimuli such as anti-CD40 antibody, interferon (IFN)-γ, interleukin-2 (IL-2), IL-4, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) and the binding of Toll-like receptor (TLR) with its ligands induce CD80 expression [10]. Meanwhile, IL-10 and CTLA-4 negatively regulate the expression of CD80 [5, 10, 11].

Regulatory T cells expressing forkhead box P3 (Foxp3) have an anti-inflammatory role by their enriched expression of CTLA-4 and by releasing anti-inflammatory cytokines such as IL-10 and transforming growth factor β (TGF-β) [12]. CTLA-4 competes with CD28 and preferentially binds with CD80/CD86, thus preventing T cell activation [12]. Besides, CTLA-4 suppresses the expression of CD80/CD86 in dendritic cells [13] and in B cells which leads to altered T cell-B cell interaction [14], CTLA-4 also has the ability to reduce CD80 in the opposing cells by trans-endocytosis [15]. CTLA-4 is expressed on the T cell; besides, soluble form (sCTLA-4) exists in the serum and has the ability to bind CD80/CD86 [11]. The expression of CTLA-4 becomes upregulated in the activated T cells; therefore, it is assumed that CTLA-4 helps the termination of the inflammation.

The role of CD80 in the proteinuric conditions was first described by Reiser et al. in 2004 [8]. α3β1-Integrin is thought to be largely responsible for the attachment of podocyte foot process to the glomerular basement membrane. α3β1-Integrin-deficient mice are unable to maintain normal podocyte structure [16]. The search for the changes in the α3 integrin-deficient podocytes unexpectedly led to the discovery of CD80 expression in the podocytes [17]. They demonstrated that CD80 can be induced in podocytes and transient proteinuria was observed concomitantly. In vivo administration of lipopolysaccharides (LPS) or puromycin aminonucleoside (PAN), genetic α3 integrin deficiency, and lupus nephritis in mice as well as in human were associated with increased CD80 expression in podocytes. Furthermore, CD80 expression in human lupus nephritis was associated with its severity. Interestingly, proteinuria was not induced in the CD80 knockout mice by LPS, but it was induced in the SCID mice which are immunodeficient lacking B cells and T cells, showing that CD80 is a key step, and this is independent of T cells and B cells. In vitro study using conditionally immortalized podocytes demonstrated that podocytes express CD14 and TLR4; both of them are the receptors which recognize LPS as ligands. Also, they described that LPS induced podocyte actin reorganization which is regarded as a change corresponding to the foot process effacement [8].

Then, Garin et al. suggested the role of urinary CD80 in MCNS for the first time in 2009 [7]. They showed that urinary CD80 levels are increased in MCNS in relapse compared with those observed in remission and control subjects. In patients with other glomerular diseases such as membranous nephropathy, lupus nephritis, IgA nephropathy, and focal segmental glomerulosclerosis (FSGS), urinary CD80 was not significantly increased compared with control subjects. They also showed that soluble CTLA-4 levels in the serum which usually regulate CD80 were not significantly altered, but the CD80/CTLA-4 ratio was increased in MCNS during relapse, with levels returning to normal range in remission. The serial measurements of urinary CD80 in recurrence and remission in the eight patients with MCNS revealed elevated levels of CD80 in recurrence and marked reduction in 1 month after remission.

In 2010, they showed that urinary CD80 is a useful biomarker to distinguish MCNS and FSGS [9]. Immunofluorescent staining showed that CD80 expression in the podocytes was positive in MCNS in relapse but not in remission nor in FSGS. Western blot of CD80 protein revealed that the molecular size of urinary CD80 was 53 kD, demonstrating its membrane-associated form. Soluble CD80 usually seen in the serum is 23 kD; therefore, it was suggested that urinary CD80 derives from podocytes.

The host defense against microbial pathogens consists of innate immunity and acquired immunity. Innate immunity serves as the first-line defense which recognizes pathogen-associated molecular patterns (PAMPs). TLR is one of the pattern recognition receptor families that play a key role in innate immunity [18]. TLRs are expressed in various cell types, most abundantly in APC. Recognition of microbial pathogens by TLR results in downstream inflammatory responses such as activation of nuclear factor kappa B (NFκB) and production of type I interferon and inflammatory cytokines via activation of several adapter proteins such as myeloid differentiation primary response gene 88 (MyD88) and Toll/interleukin-1 receptor-domain-containing adapter-inducing interferon-β (TRIF). Of note, recognition of microbial pathogens by TLR enhances the expression of CD80/CD86 which is a critical step to the development of antigen-specific acquired immunity.

Recent advances of research revealed that TLRs recognize internal ligands as well as microbial pathogens which lead to various pathological conditions, such as ischemic acute kidney injury, organ transplant rejection, and various glomerulonephritis [19]. Among the 11 human and 13 mouse TLR receptors, TLR4 recognizes LPS, also known as endotoxin, which is a component of outer membrane of gram-negative bacteria, and TLR3 recognizes double-stranded RNA which is produced by most viruses during their replication [18].

The link between MCNS and atopic disorders has been suggested for a long time. The frequency is generally 30–40 %, and elevated IgE levels are sometimes seen even in the absence of allergic symptoms [29]. Usually, allergic tendency was associated with type 2 helper T cell activation, and increased IL-4 and IL-13 trigger the class switch of B cells for production of IgE [29]. The direct link between the allergy and MCNS has not proven, and it seems that allergy is not indispensable for MCNS; however, the recurrence sometimes occurs right after exposure to allergens such as pollens, mold, poison oak, bee stings, and vaccinations, suggesting causal relationship in some cases. The elevated levels of IL-13 in the serum have been suggested in MCNS [30, 31], although the data vary among reports. Importantly, Lai et al. demonstrated that overexpression of IL-13 in rat induced MCNS-like nephrotic syndrome [32]. They produced the IL-13 overexpression model in Wistar rats through transfection of a mammalian expression vector cloned with the rat IL-13 gene into the quadriceps by in vivo electroporation. The IL-13-transfected rats showed significant albuminuria, hypoalbuminemia, and hypercholesterolemia when compared with control rats. No significant histologic changes were seen in glomeruli by periodic acid-Schiff stain. However, electron microscopy showed foot process fusion up to 80 % of podocytes. Glomerular gene expression was significantly upregulated for CD80, IL-4 receptor-α, and IL-13 receptor-α2 but downregulated for nephrin, podocin, and dystroglycan. The strength of this study was that their model has close similarity to human MCNS compared with other proteinuric models which only induce transient proteinuria. They demonstrated that podocytes express IL-13 receptor and IL-13 induces CD80 in podocytes for the first time. Whereas there are possible problems because this model has not been reproduced in mice, probably, genetic background is crucial for the induction of nephrotic syndrome by IL-13. Besides, the levels of IL-13 in the patients with MCNS did not correlate with disease status [29, 33].

The etiology of idiopathic nephrotic syndrome is still far from being fully elucidated, although recent advances in the podocyte biology have provided us the novel views of nephrotic syndrome as podocytopathies [46].

In MCNS, massive foot process effacement which is a reversible phenotype change of podocytes, namely, actin reorganization, occurs, and the number of podocyte per glomerulus does not change. Corticosteroid reverses this condition. Although there are several other candidates as a cause of MCNS, evidence for the role of elevated urinary CD80 induction in the patients with MCNS is now reported from different research groups [7, 47], suggesting a certain role, at least to some extent. Insufficient regulatory system presumably due to the impaired regulatory T cell function leads to prolonged CD80 expression, although it requires more evidences [29, 34, 35]. Of note, in the very rare cases of renal transplantations, MCNS could relapse when a patient with MCNS received a kidney [48]. On the other hand, when a patient with MCNS donates kidneys, there was no recurrence of proteinuria [49]. Thus, MCNS cannot be solely explained by podocyte disorder, but the circulating factors are suggested.

Recent view of podocytopathy revealed that detachment or death of podocytes leads to glomerulosclerosis in FSGS [46]. It is a heterogeneous disease [50]. In addition to the circulating factors which have been suggested, genetic defects in the important component of podocytes lead to FSGS in some familial or sporadic cases. The “primary FSGS” in a narrow sense is presumably attributed by the circulating factors. In these cases, plasmapheresis is often effective and posttransplant recurrence rates are high, and recurrences sometimes occur very quickly, supporting the idea that circulating factors exist, whereas in the cases with gene mutations, posttransplant recurrences occur less [51].

It is suggested that the levels of soluble urokinase-type plasminogen activator receptor (suPAR) in the serum are elevated in primary FSGS, and it serves as a possible biomarker [52]. Although there are some conflicting data and heated debate, it is based on the scientific explanation that suPAR increases glomerular permeability and activates alphaV beta3　integrin on podocytes causing foot process detachment of glomerular basement membrane [52]. Ling et al. performed the measurement of urinary CD80 in MCNS in relapse, remission, FSGS, and control subjects. They demonstrated that urinary CD80 was significantly higher in the patient with recurrent MCNS compared with other groups. Here, four out of 27 FSGS patients had values near or exceeding the cutoff value, and histological findings in these patients were three cases of tip lesions and one case of not otherwise specified (NOS). Tip lesions could be observed in MCNS patient with heavy proteinuria, and no one had the collapsing type, which has the worst prognosis [47]. In the patients with MCNS and FSGS, Cara-Fuentes et al. measured urinary suPAR, suPAR in the serum, and urinary CD80 simultaneously. They confirmed the elevated urinary CD80 in MCNS and elevated suPAR in the serum in FSGS. The levels of suPAR in the urine were just correlated with urinary protein both in MCNS and FSGS [53].

Recently, Cara-Fuentes et al. reported a case of nephrotic syndrome with NPHS2 mutation which usually causes FSGS [54]. The patient was a 5-year-old Caucasian boy, and the findings in the biopsy were mild mesangial expansion and cellularity which could be early signs of FSGS, at the same time not inconsistent with MCNS with robust proteinuria. In this case, the expression of CD80 in the podocytes was shown by immunofluorescent staining, and increased urinary CD80 was also demonstrated by western blotting. At the same time, mildly elevated suPAR in the urine and serum was observed. Theoretically, if we consider MCNS and FSGS as different disease entities, the hybrid cases are possible. Or we can interpret these data that urinary CD80 is consistent with the initial idea that Reiser et al. showed that genetic defect leads to CD80 induction in the podocytes [8].

The future studies will further elucidate the diagnostic value of urinary CD80 and suPAR in the serum. It would be of great clinical value if the combinations of these parameters are helpful to distinguish MCNS, primary FSGS, and FSGS with gene mutations.

Previously, CD4+ T cell subset was regarded as type 1 helper T cell (Th1)/Th2 binary system. Th1 cells produce IFN-γ and are involved in cell-mediated immunity. Th2 cells produce IL-4 and IL-13 and contribute to humoral immunity and are involved in allergic tendency. Since MCNS is frequently accompanied with allergies, it was postulated as Th2 disease [29]. The recent advances in the immunology expanded Th1/Th2 paradigm to include Th17 and regulatory T cells (Treg) [12]. Indeed, Liu et al. showed that there are Th17/Treg imbalances in MCNS [55]. It is very intriguing that in the very rare cases of congenital T cell immune disorder, several cases of MCNS are reported in immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome which is caused by mutation of Foxp3, the key transcription factor of Treg [56], and hyper IgE syndrome which is caused by mutations of signal transducer and activator of transcription (STAT) 3, the indispensable factor for the Th17 cell differentiation [57]. GATA-3, STAT-5, and IL-13 mRNA levels are increased in the PBMC from patients with MCNS in relapse [58]. Allergy as well could be interpreted as an imbalance of CD4+ T cells. In contrast to the genetic mutations in the podocyte components in FSGS, various types of T cell imbalances are observed in the patients with MCNS. These T cell disorders may be related to the impaired regulatory mechanism to terminate CD80 expression via insufficient function of CTLA-4 or other mechanisms, although the proof for the direct relationship between CD80 and these T cell imbalances is lacking.