Background

Idiopathic nephrotic syndrome (INS) is one of the most common glomerular diseases, which is characterized by massive proteinuria associated with hypoalbuminemia and varying degrees of edema. Minimal Change Nephrotic Syndrome (MCNS) is the most common histological disorder observed in children.1,2 In 1974, Shalhoub proposed that elevated T cell-derived permeability factors and dysfunction may contribute to INS3,4,5 and since then, T cells have been recognized as the major cells involved in the pathogenesis of INS. However, recently, B cell-depleting agents have also been confirmed as the effective treatment for MCNS.6,7 With the in-depth investigation of the B cell functional subsets, an increasing number of studies have suggested the involvement of B cells in the pathogenesis of INS.8,9 Classically, B cells were recognized as positive modulators of inflammation and immune responses by releasing antibodies and activating T cells through antigen presentation. Similar to T cells, B cells may also secrete cytokines and participate in pathogenesis through negative immune regulation. Podocytes are demonstrated to play a pivotal role in maintaining normal glomerular function. The occurrence of podocyte disease may be related to abnormal B cell dysfunction, which may ultimately lead to foot process fusion and proteinuria.10,11 In this review, we aimed to systematically focus on the possible roles of B cells in the pathogenesis of INS, which were highlighted and identified in some advanced studies.

Development, differentiation, and functions of B-lymphocytes

B-lymphocytes constitute a heterogeneous population of different subsets of cells having specific phenotypes and functions. In cell biology, the development and differentiation of B cells may be considered a paradigm for many other developmental processes. The hematopoietic stem cells (HSCs) first differentiate into common lymphocyte precursors (CLPs) through multipotent precursor cells (MPPs), which then develop into immature B cells through progenitor B (Pro-B) and precursor B (Pre-B) cells. In the bone marrow, the establishment of immature B cells is driven by signals generated from a functional B cell receptor (BCR), which deletes autoreactive B cells through receptors, editing death and apoptosis as well as cell elimination.12 The surviving cells migrating from bone marrow to the periphery are called transitional B cells (CD19+CD24highCD38high). These cells undergo the transformation process from T1 B cells (CD23–IgMhighCD62L–) to T2 B cells (CD23+IgMintermediateCD62L+) differentiating into naive/mature B cells (CD19+CD27–IgD+).13,14 The proportional relationship between transitional B cells and mature B cells indicated that the former cells also underwent a phase similar to the negative selection of immature B cells. Hence, the developmental stage of transitional B cells determined the survival fate of self-reactive B cells. Once the naive B cells are activated, few cells stay in situ and differentiate into short-lived plasma cells, probably secreting the antibody IgM to play a transient defensive role.15 Activated naive B cells form the germinal center (GC) of the lymph nodes through migration and proliferation while GC B cells undergo antibody affinity maturation, immunoglobulin (Ig) class switch, or other series processes and differentiate into short-lived plasma cells that produce serum IgG, IgA, and IgE. The GC is left behind, exerting an immune effect, while another part of plasma cells migrates back to the bone marrow, surviving for a long time. These cells are called long-lived plasma cells,16,17 which can maintain high-efficiency antibody production. GC B cells can also differentiate into memory B cells performing immune memory functions.18,19,20 CD27 molecules are surface markers of memory B cells, which can be divided into multiple subgroups according to their class switch occurrence, including IgM+ memory B cells (CD27+IgD–IgM+), non-class switch memory B cells (CD27+IgD+IgM+), and class-switching memory B cells (CD27+IgD–IgM–)21,22 (Fig. 1).

Fig. 1: Different stages of B cells in the bone marrow and peripheral tissues.
figure 1

The development of most B cells begins with HSCs, but the final differentiation is completed in the spleen. In the bone marrow, hematopoietic stem cells (HSCs) pass through the stages of multipotent precursor cells (MPPs), common lymphoid progenitors (CLPs), progenitor B (Pro-B) cells, precursor B (Pre-B) cells, and immature B cells, and then migrate to the periphery along with the bloodstream to transform into transitional B cells. The T2 subtype of transitional B cells eventually differentiates into mature B cells in the spleen. The activated mature B cells activate, proliferate, and differentiate into the germinal center (GC) B cells in the GC of lymph nodes. With the help of helper T (Th) cells and the stimulation of antigens, GC B cells eventually develop into plasma cells and memory B cells, exerting an immune response effect.

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Therapeutic effect of Rituximab implies the role of B lymphocytes in INS

Recent studies have performed a systematic summary and analysis of the outcomes of RTX treatment in SDNS/frequently relapsing nephrotic syndrome (FRNS) patients and confirmed the therapeutic effect of Rituximab. Their results showed an effective reduction in the relapse rate and adverse events, enhancing long-term remission by RTX consolidation therapy.23,24,25 RTX is a human-mouse chimeric anti-CD20 monoclonal antibody. It acts on CD20+B cells and induces their apoptosis through antibody-dependent cytotoxicity, complement activation pathways, and direct promotion.26 CD20 is a membrane protein antigen expressing on the surface of B lymphocytes, except for long-lived plasma cells, so the production of some autoantibodies is not interfered by RTX treatment.27 We speculated that the mechanism of action of RTX in treating INS was a B cell-dependent mechanism since the RTX depleted almost all B cell functional subsets in peripheral blood.28 B cells may participate in the pathogenesis of INS in alternative ways, including the secretion of some soluble factors and antibodies. Some researchers also proposed that RTX exerted an effect by blocking the interaction between B and T cells or indirectly or directly regulating homeostasis and functions of T cell subsets.29,30,31 Previous studies have reported that RTX may deplete certain T cells and natural killer cells (NK cells) expressing low levels of CD20. However, whether this effect was involved in the therapeutic effect of RTX has not been elucidated yet.32 Recently, some studies confirmed the direct protective effect of RTX on podocytes. RTX prevents the actin cytoskeleton of podocytes in patients from being destroyed using sphingomyelin phosphodiesterase acid-like-3b (SMPDL-3b) protein, which reduces the apoptosis of podocytes and alleviates proteinuria.33,34

Additionally, RTX may also exert therapeutic effects by modifying immunity through Toll-like receptors (TLR). In 2015, Jamin et al. reported an increase in the TLR3 expression in B cells of INS patients in remission and TLR8 expression in CD4+ T and B cells. Although the TLR3 and TLR8 expressions were normal, an increase was observed in the expression of IFN-α and IL-6 after the RTX treatment. Also, the DNA load of Epstein-Barr Virus (EBV) in patients with relapse and remission was higher than that in healthy controls. The TLR family could recognize different components of pathogen-associated molecular patterns (PAMPs) of bacteria and viruses, through which it exerted anti-infectious effects by initiating innate immunity and also promoting B cell differentiation and development along with the production of immunoglobulins and cytokines via the independent roles of T cells.35 Several INS patients in relapses were often accompanied by EBV infection. EBV can establish a latent, lifelong infection in memory B cells. A latent EBV infection uses specific stimulation and differentiates memory B cells into plasma cells. This activates viral replication and releases EBVs, which then continue to infect naive B cells. Thus, the infection can spread to different cells or even different hosts.36 EBV infection downregulates the expression of TLRs in B cells, counteracting downstream signaling from TLRs, thereby dysregulating B cell response to viral infection.37 Notably, several studies have confirmed the relationship between EBV infection and the pathogenesis of many autoimmune diseases.38 Some researchers speculated that after EBV infection, the INS pathogenesis was possibly due to the internalization of a specific anti-EB nuclear antigen (EBNA) 1 antibody into podocytes, which cross-reacted with a particular podocyte protein, eventually causing podocyte damage.39 Besides depleting B cells, RTX also cleared the anti-EBNA1 antibody from blood circulation, leading to the recovery of podocyte damage. This was also consistent with the theory proposed by Colucci et al., who stated that recovery of memory B cells was induced by RTX after B cell depletion, which may independently predict the relapse of INS.40 It is also worth exploring whether high EBV load in remission was associated with frequent relapse. Overall, Jamin’s findings suggested that the TLRs dysfunction in INS patients could be normalized by RTX treatment. This also indicated that the role of restoration of TLRs dysfunction in disease remission might be related to EBV-infected B cell depletion or direct modification by RTX in a specific manner. Function of TLRs in INS needs further confirmation studies. Figure 2 and Table 1 shows our conclusion of the possible mechanism of B-lymphocytes in the pathogenesis of INS.

Fig. 2: The possible role of B lymphocytes during the onset of INS.
figure 2

B cells may participate in the pathogenesis of idiopathic nephrotic syndrome (INS) through a variety of mechanisms. These can be divided into antibody-dependent and -independent mechanisms. The antibody-dependent mechanism involves abnormal immunoglobulin (Ig) levels in INS patients, with some autoantibodies directly acting on podocytes; the antibody-independent mechanism involves the interaction between T and B cells and the cytokines secreted by them. Regulatory T cells (Tregs) are important negative regulators of T cell immune response, which inhibit excessive activation of effector T cells (Teffs). A decrease in the ratio of Tregs/Th17 and Th1/Th2 in INS patients, along with an increase in the expression of Th-related cytokines, can directly damage podocytes and cause proteinuria. The main B cell subgroups with secretory functions include anti-inflammatory regulatory B cells (Bregs) and pro-inflammatory effector B cells (Beffs), which secrete cytokines IL-10, IL-6, IFN-γ, etc. These B cell subgroups may positively or negatively regulate the pathogenesis of INS. Additionally, some factors affecting B cell proliferation or apoptosis, including B cell-activating factor (BAFF) and follicular helper T cells (TFH), may also be related to the pathogenesis of INS.

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Table 1 The evidence of B cell dysfunction in INS.
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Functional subsets of B-lymphocytes in INS

Recently, studies have provided breakthrough information on the relationship between the functional subsets of B lymphocytes and INS. Although several teams have reported the up-regulation of CD19+ B cells during the initial onset of INS and recurrence in children, they have failed to specifically classify the functional subsets of B lymphocytes.41,42 In 2016, Colucci et al. proposed that the recovery of memory B cells post-RTX-induced B cell depletion predicted the recurrence of INS independently.43 Furthermore, multiple research teams have studied different INS patients based on different clinical types. Many others have also confirmed some abnormalities in the number and function of B lymphocytes in children with INS. The total B cells, transitional B cells, and memory B cells, especially class-switching memory B cells, were significantly higher in the recurrence group at the active stage of INS than those in the healthy control. These functional subsets returned to normal levels in the remission stage, suggesting transitional B cells and memory B cells to be the early screening marker during INS flare.44,45 Ling et al. found a significantly higher number of transitional B cells in patients with steroid-sensitive nephrotic syndrome (SSNS) compared to that in patients with SDNS, proposing the role of transitional B cells as a biomarker for earlier screening of SSNS.46

Additionally, researchers found a population of anti-RTX autoreactive memory B cells in primary immune thrombocytopenia (ITP), which developed and survived after anti-CD20 treatment. This cell population also participated in the disease relapse and was depleted by targeting CD19 in vitro. Thus, it can be considered a potential treatment method to avoid disease recurrence. However, this cell population remains undescribed for INS, unfortunately. This discovery inspired us to explore the reason for relapse in some INS patients after RTX treatment during reconstitution.47 Overall, it is necessary to specifically monitor the detailed classification of each functional subgroup of B-lymphocytes, especially the number and function of transitional and memory B cells, along with further exploration of these two functional subsets.

Immunoglobulin and INS

IgM, IgG, IgE

B cells are well-known to exert detrimental effects through antibody production, including the production of IgA, IgG, IgD, IgE, and IgM, which may indirectly alter the immune conditions in INS patients. According to pathology diagnosis, a close relationship was found between IgA and IgA nephropathy. However, RTX was not particularly useful in IgA nephropathy.48 Studies have determined that IgG, IgE, and IgM in INS patients were different from that of normal people and patients with INS remission after plasma Ig depletion.49 However, the relationship between Ig and disease activity needs further clarification. Some autoantibodies that damage tissues and organs through a variety of mechanisms have also been found in INS patients.

In focal segmental sclerosing nephropathy (FSGS), histological findings have demonstrated that pathological alterations are usually accompanied by co-deposition of glomerular IgM and complement C3.50 Mirioglu et al. conducted a retrospective analysis of 86 FSGS patients and proposed that the co-deposition of IgM and C3 was of great significance in predicting the poor prognosis of FSGS.51 The pathogenic mechanisms of IgM may involve some epitopes, which could be exposed by idiopathic glomerular damage. Upon the activation of the complement system, the membrane attack complex (MAC) was finally formed through the common terminal pathway or was mediated through C5a leukocyte chemotaxis inflammation and damaging of kidney tissues. Previously, Strassheim et al.52,53 used an animal model of Adriamycin-induced glomerulosclerosis treated with anti-CD20 antibodies and reported a successful reduction in the deposition of glomerular IgM and C3, thereby reducing proteinuria and delaying glomerulosclerosis.

Studies have also found decreased levels of IgG and some complement factors along with increased levels of IgM in patients with MCNS. This phenomenon is more pronounced in SDNS/FRNS patients.54,55 IgG levels, especially IgG/IgM levels, are positively correlated to the response to glucocorticoids and negatively correlated to the possibility of recurrence.56,57 Few researchers conducted in vitro experiments by culturing B lymphocytes and studied the comparison between the expression of IgG in MCNS patients and the normal control groups. The results confirmed abnormal IgG production in MCNS patients.58 Delbe-Bertin et al. reported no significant effect of RTX-induced B cell depletion on IgG serum levels after RTX treatment, doubting its pathogenic role.59 However, a weakened immune function due to reduced IgG levels in INS patients may lead to susceptibility to other infections.

A study revealed that 30–40% of children with SSNS were prone to suffer from a few allergic diseases.60 Abdel-Hafez et al. proposed that allergy may also play a role in the pathogenesis of the nephrotic syndrome and found elevated serum IgE levels associated with disease flare in children with INS.61 Other reports described that elevated levels of IgE in INS patients were the result of excessive activation of Th2 immune cells.62,63 However, whether the levels of serum IgE changes after the treatment with RTX has not been clearly elucidated yet.

Autoantibodies

In patients with INS disease, some autoantibodies were also found to destroy tissues.

Musante et al. proposed the hypothesis the IgM antibodies deposition in glomeruli included autoantibodies against the ATP synthase β chain/actin. Alpha-actin-4 (ACTN4) possesses homology with the target antigen of autoantibody IgM, which plays a major role in the damage of the glomerular filtration barrier through targeting ACTN4 in podocytes.64 Some autoantibodies, including anti-ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) IgG, were found in INS patients. These are podocyte targeting autoantibodies that indirectly induce podocyte apoptosis and cause podocyte damage by activating monocytes/macrophages between the glomerular GBM endothelial cells. Eventually, the podocytes fall off, causing the disappearance of the foot process.65 Recently, a study reported new findings on autoantibody IgG against nephrin in adults and children with MCNS. Nephrin is a structural component of the slit diaphragm, which is essential for the maintenance of the glomerular filtration barrier. Although this discovery was inconsistent with the fact that immune complex deposition was lacking in renal biopsies from MCNS patients, it changed our understanding of the role of B cells in the pathogenesis of INS, providing the theoretical basis for precision therapeutics.66 Additionally, some researchers immunized the recombinant extracellular domain of transmembrane protein Crb2 expressed in mice podocyte foot processes, which produced anti-Crb2 autoantibodies and proteinuria, inducing NS with clinical and pathological features similar to MCNS patients, which providing a valuable B cells autoimmune-mediated mouse MCNS model and stressing the pathogenic role of anti-Crb2 autoantibodies in podocyte injury, consistent with the findings above that B cells and antibodies have a role in MCNS pathogenesis.67

The role of B lymphocyte influencing factors and INS

A study confirmed less deposition of immune complexes on kidney biopsies in patients with INS. Since most autoantibodies still existed after B cell depletion, B lymphocytes were suggested to act on kidney damage in an antibody-independent manner.68,69

Interaction between T and B lymphocytes and INS

Besides the production of antibodies, activated B cells could act directly as antigen-presenting cells (APC) to promote T cell activation. The BCR on the B cell surface binds to soluble antigens and presents them to CD4+ T cells (Th cells) in the form of antigen peptide-MHC-II molecular complexes. B cells also induce the secretion of regulatory T cells (Tregs). Moreover, T and B cells provide co-stimulatory signals and cytokines to each other, which are necessary for the activation of CD40-CD40L, CD80 (CD86)-CD28, PD-1-PD-L1, etc.70,71,72. The co-stimulatory molecule CD80 is expressed by B cells bound to CD28 on CD4+ T cells, mediating their activation into effector T cells (Teffs). The depletion of B cells by RTX possibly affected antigen presentation and cellular mediator production, which altered the stability and response of T cells. An increasing number of studies have confirmed that the pathogenesis of several diseases depends on cognate B cell-T cell interactions.

Researchers found that the dysfunction of Tregs and abnormal overactivation of Th cells, along with the related factors expressed by Th cells, might participate in the pathophysiological process of INS. To prevent the overactivation of Teffs, Tregs inhibit the overexpression of CD80 by expressing cytotoxic T lymphocyte antigen-4 (CTLA-4), effectively preventing the occurrence of autoimmune reaction.73,74 Although the physiological number of Tregs was found to be low, their transformation from immature CD4+ T cells in response to stimulation was rapid.75 Chebotareva et al. reported a significant reduction in the number of Tregs in the kidney tissues of INS patients.76 Tregs and CTLA-4 are also associated with the induction of remission in INS patients, exhibiting higher levels in remission than that at the onset. Tregs play a critical protective role in MCNS.77 In steroid-resistant nephrotic syndrome (SRNS) patients, Tunçay et al. demonstrated that after the RTX treatment, the percentage of Tregs showed a significant increase compared to before.78 Some studies have reported decreased ratios of Th1/Th2 and Th17/Tregs in INS patients.62,79,80 Th2 plays a dominating role in the Th1/Th2 ratio and activates cytokine expression, including IL-4, IL-13, and IL-5, etc., which are closely related to podocyte damage, proteinuria, and frequent relapses in MCNS.81 Some researchers have found decreased absolute count of Th17, Th1, and Th2 cells but increased Tregs in children with SDNS. However, after the RTX treatment, a decrease was observed in the ratio of Th17/Treg, while an increase was observed in the ratio of Th1/Th2, which was induced by depletion of memory B cells.82 Moreover, Fribourg et al. indicated no significant differences in CD4+ and CD8+T cell subsets among relapsed and non-relapsed INS patients. RTX possibly affected Tregs and T follicular helper (TFH) homing by reducing the interaction with B cells.83 A study used a mouse model of autoimmune encephalomyelitis and multiple sclerosis and confirmed that B cell depletion alleviated clinical symptoms due to B cells being able to regulate T cells.84 Another study has reported a significantly increased level of sCD40L in serum soluble SSNS and SRNS children. The sCD40L is reported to directly act on glomerular epithelial cells to increase their permeability.85 Further studies are necessary to observe the curative effect of RTX’s B cell depletion treatment on the direct pathogenic effect of B cells or the indispensable indirect effect of B cells on T cell activation.

Bregs/Beffs and INS

B cells play an immunomodulatory role in regulating the immune response. However, they may secrete cytokines involved in the occurrence and development of disease progression. For instance, activated B cells are believed to secrete cytokines related to the pathogenesis of INS. However, their relationship with the disease has not been confirmed yet.86 The secretory function of B cells is mainly related to two subsets, namely regulatory B cells (Bregs) and pro-inflammatory effector B cells (Beffs). Any B cell subgroup can differentiate into Bregs under appropriate stimulation conditions, such as TLR ligand stimulation and CD40 activation. Bregs can secrete anti-inflammatory cytokines IL-10, TGF-β, and IL-35 to promote the transformation of CD4+ T cells into Tregs, which then regulate immune response, reduce inflammation, and maintain immune tolerance.87,88 Researchers found that some Bregs subgroups, including B10 cells, CD19+CD24hiCD38hiIL-10+ B cells, and CD19+CD24hiCD27+IL-10+ B cells were significantly decreased in the acute period of NS in children compared to those in remission. This affected the immune balance of Th17/Treg cells participating in the occurrence, development, and outcome of NS in children.89 Beffs exert an opposite effect of Bregs and produce pro-inflammatory cytokines IL-6, IFN-γ, and so on. Matsushita proposed that the depletion effect of RTX on B cells had both advantages and disadvantages, as confirmed in SLE and SSC models. Bregs exerted a protective effect on the occurrence of diseases while cytokines secreted by Beffs promoted the occurrence of systemic inflammatory responses in diseases.90

IL-10 is secreted by Bregs, which is a negative regulator of immunomodulatory efficacy and a protective factor for INS. However, it may increase the activity of certain vascular permeability factors.91,92 In INS patients, IL-10 levels in serum are lower than that in the control.93 Roca found IL-6 levels in INS patients to be higher than the healthy control; hence, it was suggested as a predictive biomarker in SRNS. Similarly, IL-6 has also been proven to serve a vital function in the pathogenesis of other autoimmune diseases.94 Li et al. revealed elevated serum levels of IFN-γ in MCNS patients. Moreover, Prasad et al. found a significant difference in IFN-γ concentrations between INS patients in remission and recurrence. The expression of permeability glycoprotein (P-gp) was positively correlated with IFN-γ levels, indicating a poor response upon GC therapy.95 Therefore, depletion of proinflammatory cytokine producing B cells by RTX treatment may contribute to the therapeutic effect.

Factors related to stimulation of B lymphocyte proliferation and activation

Under normal conditions, the number of B lymphocyte functional subsets was in a consistently stable state. The destruction of homeostasis was generally attributed to the following two reasons: First was the increase in factors promoting the proliferation and activation of B lymphocytes. The second was the factor associated with B lymphocyte apoptosis or weakened inhibition of proliferation and activation. These conditions may result in an abnormal number and function of B lymphocyte subsets.

B cell-activating factor

B cell-activating factor (BAFF), also known as B lymphocyte stimulating factor (BLys) or tumor necrosis factor ligand superfamily member 13B (TNFSF13B), contributes to B cell activation and plays a significant role in the proliferation and differentiation of B cells. Overall, three different receptors are involved, namely BAFF-R, TACI, and BCMA, also known as TNFRSF13B and TNFRSF17. Insufficient expression of BAFF typically leads to inadequate activation of B cells and immunoglobulin production. Overexpression of BAFF may also promote the survival of autoreactive B cells and the secretion of antibodies, leading to autoimmune diseases. APRIL (TNFSF13) is a member of the TNF superfamily and is structurally similar to BAFF. It shares common receptors with BAFF, including TACI and BCMA.96,97 Möckel showed elevated levels of BAFF in some autoimmune diseases like SLE.98 Belimumab, a BAFF antibody, plays an effective inhibitory role in the treatment of SLE and other diseases, confirming the pathogenic effect of BAFF.99 Additionally, BAFF facilitates the generation of Beffs but inhibits the production of Bregs. This mediates increased levels of IL-6 and reduced levels of IL-10, which balances Beffs/Bregs and breaks down immune homeostasis, consequently.100 Some studies indicated that BAFF/APRIL was closely related to the survival of transitional B cells during the transition from T1 to T2 along with the survival of memory B cells, plasma cells, and plasmablasts.101,102,103,104 In some autoimmune diseases, including systemic lupus erythematosus (SLE) or systemic sclerosis (SSC), abnormal overexpression of BAFF or other unknown reasons offset the pro-apoptotic signals, allowing autoreactive transitional B cells to escape from the deletion causing the disease attack, eventually.105 We speculated that the role of BAFF in INS pathogenesis might be similar to its role in other autoimmune diseases. However, currently, high BAFF levels are found to be related to the increased percentage of plasmablasts in MCNS adult patients.106 Serum BAFF concentrations are found to be elevated after RTX therapy. Overexpression of BAFF may represent a host defense mechanism that increases the activation of remaining B cells. This enhances their function against infection or decreases inhibitory feedback for BAFF, which is followed by receptor loss leading to overproduction.98,107 Besides the reported alterations in B cell functional subsets in INS patients, we need further exploration of the correlation between the changes in BAFF/APRIL levels in INS patients along with B cell subsets to find more effective therapeutic targets for INS.

Follicular helper T cells

Follicular helper T cells (TFH) are found in the GC of the lymph nodes, which are essential for the formation and maintenance of GC. TFH allows B cell differentiation of GC into memory B cells and plasma cells along with the production of antibodies.108,109 TFH cells specifically express CXC motif chemokine receptor 5 (CXCR5), inducible T cell co-stimulator (ICOS), programmed death-ligand (PD-1), CD40L, transcription factor Bcl-6, regulatory cytokine IL-21, IL-4, and other factors,110 which mediate their development and function. TFH cells are known to play a critical role in SLE111 and are also inextricably related to the pathogenesis of INS. Zhang detected TFH cells in peripheral blood using flow cytometry and found an elevated proportion of PD-1+ TFH cells and ICOS+TFH cells in adult patients with MCNS.112 Tao Li et al. confirmed an increase in PD-1+CD154+ TFH cells and serum IL-21 in MCNS adult patients, which might be involved in the promotion of abnormal proliferation of B cells through CD40/CD40L interactions.113 Their findings were also consistent with the changes in the number of B lymphocyte functional subsets in INS patients as described previously. Additionally, B cell depletion resulted in a marked decrease in splenic TFH. CXCL13 and IL-21 are the two cytokines produced primarily by TFH, which are required to maintain B cells.114

Summary

The accurate immune mechanisms underlying INS pathogenesis remain to be clarified, which compels evidence to show that INS results from immune disorders resulting in the release of circulating glomerular permeability factors, possibly derived from T and/or B cells. This, in turn, alters the glomerular filtration barrier and promotes the podocyte lesion. A well-established use of anti-CD20 antibodies may provide additional evidence of the potential role of B cells in the pathophysiological processes of glomerular disease. B cells may contribute to the disease by crosstalking T cell responses, producing autoantibodies against podocyte proteins and releasing circulating cytokines, but further investigations are necessary to explore the precise mechanisms underlying INS pathogenesis.