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BLyS and APRIL Cytokines as Biomarkers of Kidney Diseases

  • Natavudh Townamchai
  • Wannarat Pongpirul
  • Asada Leelahavanichakul
  • Yingyos AvihingsanonEmail author
Living reference work entry

Abstract

Kidney damages mediated by the immune system have been reported for glomerular diseases, tubulointerstitial nephritis, and rejection of the allograft posttransplantation. B-lymphocytes have an important role in the pathogenesis for these kidney diseases. There are increasing evidences that TNF-like ligands which regulate B-cell homeostasis such as B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) can be used to detect kidney diseases as well as acute rejection of the kidney allograft. This chapter will review these two ligands, BLyS and APRIL, and its promising prospect in detecting glomerular diseases and acute rejection of the kidney allograft.

BLyS and APRIL are found in the plasma and membrane proteins of macrophages, monocytes, and dendritic cells. Both can activate the proliferation of B-cells and plasma cells. They are expressed on tissues of the lymph node, bone marrow, synovium, and kidney. Even though both cytokines share a common receptor on the B-cells, however, their roles in B-cell activation are significantly different. When BLyS is activated, this will result in severe B-cell hyperplasia in BLyS-transgenic mice. In contrast, when APRIL is activated, there is no effect on the homeostasis of the lymphoid in APRIL-transgenic mice.

BLyS was initially discovered to be a potential therapeutic target for lupus patients. Later, it was shown that both BLyS and APRIL were somehow associated with lupus nephritis. Both cytokines are expressed on the infiltrating monocytes and/or macrophages of patients with lupus nephritis. It remains unknown whether the blockade of both cytokines can be used to treat the lupus disease. However, serum APRIL has been shown to be a useful biomarker in detecting lupus nephritis in patients with a poor prognosis.

In kidney transplantation, B-cell is an important factor for the long-term survival of the kidney allograft. High levels of BLyS or APRIL can activate alloreactive B-cells by inducing antibodies against the donor antigens (donor-specific antibody, DSA) and result in rejection of the allograft. Aside from that, BLyS is an important growth factor for IL-10-producing B-cells known as the regulatory B-cells. It has been shown that BLyS from the mice can increase a proportion of regulatory B-cells ex vivo. These evidences indicate that BLyS plays a major role in the activation and regulation of the immune system affecting the success and/or outcome of the kidney transplantation.

Keywords

Biomarker BLyS BAFF APRIL Kidney disease SLE Kidney transplantation B-cell 

Abbreviations

ABMR

Antibody-mediated rejection

AKD

Acute kidney disease

APRIL

A proliferation-inducing ligand

BAFF

B-cell-activating factor

BAFF-R

B-cell-activating factor receptor

BCMA

B-cell maturation antigen

BCR

B-cell receptor

BLyS

B-lymphocyte stimulator

CD

Cluster of differentiation

CKD

Chronic kidney disease

CR

Complement receptor

Cr

Creatinine

DSA

Donor-specific antibody

GFR

Glomerular filtration rate

HLA

Human leukocyte antigen

IF/TA

Interstitial fibrosis/tubular atrophy

IL

Interleukin

NSTDA

National Science and Technology Development Agency

PLA2R

M-type phospholipase A2 receptor

SLE

Systemic lupus erythematosus

suPAR

Soluble urokinase-type plasminogen activator receptor

TACI

Transmembrane activator and calcium modulator and cyclophilin ligand interactor

TNF

Tumor necrosis factor

Summary Points

  • BLyS and APRIL are key cytokines of B-cell growth and maturation.

  • The effects of the innate immune system and homeostasis of the B-cells affect the serum levels of BLyS and APRIL.

  • B-cell markers such as BLyS and APRIL cytokines are good examples of biomarkers that can be used to prognose lupus kidney disease and outcome of the kidney transplantation.

  • Data interpretations of BLyS biomarkers should be done per patient together with clinical data and other biomarkers to increase the accuracy of the prognosis for patients with kidney diseases or those who have had a kidney transplantation.

  • BLyS biomarkers can be used to diagnose, prognose, and help guide the treatment for B-cell-associated kidney disease particularly lupus nephritis and kidney transplantation.

Key Facts

Key Facts of BLyS and APRIL

  • BLyS is required for the early stages of B-cell development, whereas APRIL is needed much later for the survival of the plasma cell.

  • BlyS and APRIL are mainly produced by innate immune cells such as macrophages, monocytes, and B-cells.

  • BLyS and APRIL contribute to the development of the immune-mediated kidney disease (i.e., SLE) and rejection of the kidney allograft.

  • BLyS and APRIL are new biomarkers that can be used to detect active B-cell-mediated kidney disease and antibody-mediated rejection in kidney transplantation.

  • BLyS and APRIL are markers for B-cell homeostasis required by both the regulatory and allo-/autoreactive B-cells for their survival.

  • Current B-cell target therapy such as belimumab, atacicept, or rituximab can affect the serum levels of BLyS and APRIL.

Key Facts of Lupus Nephritis

  • An autoimmune kidney disease that typically affected young adult female.

  • A leading cause of secondary glomerular diseases worldwide.

  • Typical symptoms and signs are leg edema and foamy urine.

  • Autoreactive B-lymphocyte cells play a pivotal role in the mechanism of the disease.

Key Facts of Kidney Transplantation

  • Kidney transplantation is the best treatment of end-stage kidney disease.

  • The important barrier of kidney transplantation is alloreactive cellular immunity.

  • Biomarkers are required to monitor for an immune response to kidney allograft so-called “rejection.”

Introduction

Unmet Needs for AKD and CKD

The kidney is one of the most vulnerable organs that can be damaged by several factors. The damages of the kidney function can appear early or much later during the course of the destruction of the kidney and tend to result in end-stage kidney disease. Kidney diseases are simply classified according to its severity which can be either acute or chronic. A 3-month observational period can distinguish between an acute kidney disease (AKD) and the chronic kidney disease (CKD). An impaired kidney function is defined as having a glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2. The gold standard for determining GFR is via the inulin clearance or radioisotope nuclear clearance (Stevens and Levey 2009). However, the most commonly used kidney function test is the serum creatinine or creatinine clearance. Both tests have long been used in the medical field despite the fact that they are not sensitive enough for detecting early stages of the kidney disease. Also, creatinine is not involved in any part of the processes that causes damage to the kidney so it is not recommended to solely use it to diagnose kidney injury (Shemesh et al. 1985; Yurasov et al. 2005; Meyer-Bahlburg et al. 2008). Thus a more accurate diagnostic test that can specifically detect each type of kidney disease is needed.

This is possible if mechanisms involved in various kidney diseases are targeted. It has been shown that the B-lymphocyte is a major player in causing immune-mediated kidney diseases such as glomerulonephritis, renal vasculitis, or rejection of the kidney allograft (Yurasov et al. 2005; Parsons et al. 2009; Redfield et al. 2011; Wilde et al. 2013). Therefore further investigations of the B-cells have dramatically improved the performances of the diagnostic and prognostic tests for immune-mediated kidney diseases as well as provide better targets for therapy. A perfect example of this can be seen with the treatment for systemic lupus erythematosus (SLE) and nephritis. Because the B-lymphocytes and plasma cells are involved in the development of SLE and nephritis (Odendahl et al. 2000; Arce et al. 2001; Liu et al. 2011), hence, the only way to counteract that would be by blocking the specific autoreactive B-lymphocytes which have proved to be quite helpful (Sfikakis et al. 2005; Anolik et al. 2007). But it should be mentioned that none of the targeted B-cell treatments have been recognized or approved by the regulatory health agency to treat the disease. Many clinical trials failed to show the benefit of targeted B-cell therapy which can partly be explained by their poor inclusion criteria (Merrill et al. 2010; Furie et al. 2011; Rovin et al. 2012). This can be rectified by stratifying the SLE patients based on their B-cell markers. This technique will allow the detection of a subgroup of SLE patients that will benefit from the targeted therapy. Therefore it is recommended that serum B-cell cytokine levels such as B-lymphocyte stimulator (BLyS) or a proliferation-inducing ligand (APRIL) be used to identify groups of people who will benefit from the B-cell therapy.

Biology of BLyS and APRIL

BLyS and APRIL do not directly destroy the kidney but enhance the activities of the B-cells and plasma cells resulting in the immune-mediated kidney disease. The cytokines are associated with the development of autoreactive B-cell in autoimmune diseases. One of the autoreactive B-cells is the B2 cells which come from the bone marrow and are highly dependent on BLyS and APRIL to survive. The other autoreactive B-cell is the B1 cell or innate immune response B-cell which is less dependent on BLyS and APRIL because it is originated from the fetal liver, the peritoneum, and the mucosa. In general, harmful autoreactive B-cell is controlled by the bone marrow and spleen. During the development of the B-cell, these processes are neutralized by apoptosis or changes in the morphological structure of the B-cell receptor (BCR). Thus the affinity of BCR (BCR engagement) and availability of survival cytokines such as BLyS and APRIL are important for the survival of the B-cell.

It should be noted that APRIL plays a different role compared to that of BLyS during the autoimmune reactivation process (Fig. 1). While BLyS is required earlier during the development of the B-cell, in contrast, the APRIL cytokine is needed much later post-development for the survival of the plasma cell (Mackay and Schneider 2009). The plasma cells of APRIL-deficient mice mature normally but have a poorer survival rate and impaired switching of the isotype class (Dillon et al. 2006; Belnoue et al. 2008; Benson et al. 2008). The functions between BLyS and APRIL are different even though they use the same receptor. BLyS can bind to any of the three receptors at a time: B-cell-activating factor receptor (BAFF-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) receptor, and B-cell maturation antigen (BCMA) receptor. Among the three receptors, APRIL can bind to TACI and BCMA. The only receptor that is not shared between BLyS and APRIL is the BAFF-R which is expressed on the immature B-cell . BAFF-R is important for the survival of the B-cell and upon its activation produces a large volume of cells that can synthesize proteins and translate mRNAs but cannot undergo cell division (Mackay and Schneider 2009). Unlike BAFF-R, TACI and BCMA are expressed on mature B-cells and important for switching of the immunoglobulin isotype class as well as the survival of the plasma cell. When BLyS is attached to either TACI or BCMA, it will cause the B-cell to mature because its affinity for BAFF-R is stronger than TACI and BCMA. On the other hand, when APRIL is attached to TACI or BCMA, this will help increase the life-span of the plasma cell because its affinity for BCMA is very strong (Marsters et al. 2000; Day et al. 2005).
Fig. 1

The interactions between BAFF/BLyS-APRIL and cellular receptors . BAFF appears in the early stages of B-cell differentiation. The survival of the mature B-cell (plasma cell) is highly dependent on APRIL

Notable characteristics and key features of BLyS and APRIL were derived from the mouse models so are worthy to be mentioned here (Fig. 1):
  1. 1.

    Animal models for BAFF-R

    In BAFF-R-deficient mice, BAFF-R is expressed initially on immature B-cells and strongly on follicular and marginal zone B-cells (Meyer-Bahlburg et al. 2008; Hsu et al. 2002; Stadanlick et al. 2008). The expression of BAFF-R increases when the BCR is activated. Upon the activation of BAFF-R, increased levels of CD21 (complement receptor 2, CR2) and an additional signal released by the C3d receptor will help activate B-cells (Gorelik et al. 2004). BAFF –/– mice (BAFF-deficient mice) and transgenic A/WySnJ BAFF-R mice (mutated BLyS rendered to be nonfunctional) have similar characteristics such as impaired maturation of the B-cell, low levels of immunoglobulin, and weaker B-cell immune responses (Mackay et al. 2003; Shulga-Morskaya et al. 2004; Mackay and Leung 2006). When there is an overexpression of BAFF-R activity, this will induce B-cell hyperplasia and phenotypic characteristics of the autoimmune diseases (i.e., glomerulonephritis and destruction of the salivary gland) (Mackay et al. 2005; Groom et al. 2007).

     
  2. 2.

    Animal models for APRIL

    APRIL –/– mice (APRIL-deficient mice) are able to form a normal germinal center formation, but its plasma cells have a shorter life-span (Dillon et al. 2006; Belnoue et al. 2008; Benson et al. 2008). On the other hand, the life-span of B1 cell in the transgenic APRIL mice shows a longer life-span and possibly develops a neoplasia (Dillon et al. 2006). These data support the importance of APRIL as an important survival factor.

     
  3. 3.

    Animal models for BCMA and TACI

    BCMA , a receptor for BLyS and APRIL, is expressed on B-cells of the germinal center, memory B-cells, and plasma cells (Gras et al. 1995; Darce et al. 2007; Hildebrand et al. 2010). BCMA –/– mice (BCMA-deficient mice) have a normal B-cell response and B-cell development, but its plasma cells have a shorter life-span (Xu and Lam 2001; O’Connor et al. 2004).

    TACI is expressed on both mature B-cells and plasma cells. TACI can be activated only by the oligomeric or membrane-bound form of either BLyS or APRIL (Bossen et al. 2008). TACI –/– mice (TACI-deficient mice) have excessive amount of B-cells, B-cell hyperplasias, overproduction of autoantibodies, and an extensive presence of B-cell lymphomas (Mackay and Schneider 2008).

     

Current Biomarkers Used to Diagnose and Prognose Kidney Diseases

Physicians or nephrologists usually require certain laboratory tests for diagnosing or prognosing the kidney diseases. For example, serum creatinine has been used to determine the kidney function but its interpretations are quite limiting. A patient with a subtle kidney disease or focal histological changes may have a normal level of the serum creatinine or kidney function. Hence, the measurement of serum creatinine level alone cannot detect any significant changes of the kidney function (Doolan et al. 1962; Levey 1990; van Acker et al. 1992).

Another biomarker used to diagnose glomerular disease is the use of albuminuria. One of its limitations is that it is unable to differentiate the scars of the kidney from the presence of active disease. High levels of albuminuria are associated with having an active disease which requires higher doses of immunosuppressant such as steroids (Yamagata et al. 1996). This can ultimately harm the patient unnecessarily if the wrong diagnosis is made.

Other biomarkers such as urine cells or sediments can also be used to detect glomerular diseases. These cells can be easily seen with a simple microscope but it requires a skilled medical technician. However, the red blood cells or white blood cells from the urine can appear during an infection of the urinary bladder, tumor, or inflammation making it difficult to correctly diagnose for glomerular diseases. In addition, the urine cells can also be found in the kidney stones, the ureter, or the area up to the kidney so it cannot be used to specifically detect for glomerular diseases.

However, the gold standard for diagnosing glomerular diseases is the kidney biopsy because histopathology can provide the basic pathology of the glomerular disease and the area of the damaged tissues. Unfortunately its invasive procedure can result in various complications that can range from mild hematuria to serious bleeding. Yet like the other biomarkers previously discussed, one of its limitations is that it is a cross-sectional observation so it is difficult to predict the course of glomerular disease. Furthermore, if the condition of the patient becomes worse or resistant to treatment, another biopsy will be required. Many clinicians try to avoid repeating the procedure and most of the patients will also refuse to have it done again.

As a result of this, there is an urgent need for noninvasive techniques utilizing biomarkers that can clinically and accurately detect kidney diseases. An ideal biomarker should be accurate, reproducible, and not invasive. Such a biomarker has not been discovered but there are many promising biomarker candidates. The most interesting biomarkers are from soluble proteins that are involved in the mechanisms of the glomerular diseases such as lupus nephritis’ anti-DNA antibody (Cortes-Hernandez et al. 2004; Forger et al. 2004; Alba et al. 2003), membranous nephropathy’s anti-M-type phospholipase A2 receptor (anti-PLA2R) antibody (Beck et al. 2009), or focal segmental glomerulosclerosis’ soluble urokinase-type plasminogen activator receptor (suPAR) (Wei et al. 2012; Li et al. 2014).

BLyS and APRIL as a Therapeutic Biomarker to Guide the Treatment for Kidney Diseases

The biomarkers that are of interest are BLyS and APRIL because both are involved in the mechanisms of SLE and lupus kidney disease. Serum BLyS level is associated with SLE disease activity and complement levels (Table 1, Fig. 2). Hence the blockage of BLyS can attenuate the disease activity (Morimoto et al. 2007; Vincent et al. 2014). In contrast, the level of serum APRIL is associated with lupus nephritis (Table 1, Fig. 2). When the cutoff level for serum APRIL was used at 3.6 ng/mL, it proved to be very useful in predicting resistance to treatment (Treamtrakanpon et al. 2012; Eilertsen and Nossent 2014) as well as difficult-to-treat lupus nephritis patients. High levels of serum APRIL are indicative of active nephritis and associated with resistance to steroids and cyclophosphamide therapy. The expression of APRIL in the kidney tissue can identify refractory nephritis (Treamtrakanpon et al. 2012). Based on these information, a new schema using BLyS and APRIL has been proposed to guide the treatment for kidney diseases (Fig. 3).
Table 1

Serum levels of BLyS and APRIL in SLE patients

BLyS

APRIL

 

Spearman

p-value

 

Spearman

p-value

 

r

  

r

 

R_SLEDAI

0.255

0.057

Duration of disease

0.353

0.017*

Anti-dsDNA

−0.362

0.090

R_SLEDAI

0.219

0.148

C3

0.560

0.002*

Uprotein

0.438

0.002*

C4

0.621

0.002*

WBC

0.267

0.061

CH50

0.568

0.003*

PMN

0.262

0.006

WBC

−0.485

<0.001*

Activity score

0.335

0.017*

PMN

−0.402

<0.001*

Lymphocyte

−0.417

0.002*

Prednisolone (dose)

0.543

<0.001*

Mycophenolate (dose)

0.369

0.007*

ACEI (dose)

0.272

0.051

BLyS at 6 months apart

0.580

0.005*

Serum BLyS and APRIL levels are associated with different stages of systemic lupus erythematosus (SLE) and lupus nephritis. Serum APRIL is associated with kidney activity of lupus nephritis (i.e., urine protein, active score of renal pathology). In contrast, serum BAFF is associated with the activity indices of systemic lupus disease (i.e., serum complement levels, total leukocyte count, and renal systemic lupus erythematosus disease activity index (R_SLEDAI))

Fig. 2

An association of serum APRIL and pathology of the lupus nephritis. For patients with SLE, a level of APRIL more than 3.6 ng/mL is associated with active renal pathology which consists of endocapillary proliferation, fibrinoid necrosis, infiltrations of the polymorphonuclear (PMN) cells, and depositions of hyaline in the glomerular capillaries

Fig. 3

Biomarker-guided strategy. Biomarker-guided strategy can provide early diagnosis and appropriate treatment for the kidney diseases. The early stages of the kidney diseases can be detected by serum levels of BLyS and APRIL or urine cytokines. However, the subclinical pathology occurs at the late stage so an invasive tissue biopsy is needed. An alternative noninvasive method currently utilizes the serum creatinine to diagnose the late stage of kidney disease. The prognosis of the kidney disease becomes more accurate when the biomarkers are used together to diagnose and prognose the disease

Other Roles of BLyS

One of the factors in having successful kidney transplantation is dependent on the use of immunosuppressant agents at the right dosage. Overdose of these agents can result in infections and cancers, whereas underusage can result in the loss of the allograft. Currently, therapeutic drug monitoring of the immunosuppressive drug is the standard of care for managing kidney transplantation. However, the pharmacokinetic monitoring of the drug cannot predict the future biological changes of the kidney allograft. Hence a better understanding of the allograft rejection and regulation of the immune system can provide newer methods to appropriately monitor the outcome of the kidney transplantation (Fig. 4).
Fig. 4

Mechanism of antibody-mediated kidney allograft rejection. Recipient’s antigen-presenting cells recognize donor antigen. The antigen-presenting cells bring antigens to regional lymph nodes. Alloreactive T-cells recognize donor antigen. The alloreactive immune response is activated. B-cells differentiate to plasma cells and produce antibodies against donor HLA. The anti-HLA antibodies, produced by plasma cells, continuously injure the kidney graft

It has been known for a long time that the immunosuppression of the T-cell contributes to the rejection of the allograft. This information is used to prevent the rejection of the kidney allograft. Over the years, there have been many new advances in the field of T-cell immunology and immunosuppression. Despite this, only short-term graft outcomes have improved. To date, long-term graft outcome and the condition of the patient have not changed (Kasiske et al. 2005). The reason for this may be due to the involvement of other parts of the immune system. Recent studies highlighted the role of the humoral response, such as the B-cells, plasma cells, and anti-HLA, as the key factor in providing a successful long-term outcome of the kidney allograft (Everly et al. 2013; Wiebe and Nickerson 2013). Previous murine cardiac allograft model showed that the BLyS-deficient mice have a longer allograft survival rate compared to the wild type (Ye et al. 2004). In humans, the presence of BLyS in the recipients’ kidney allograft was associated with acute rejection. The interstitial fibrosis/tubular atrophy (IF/TA) of the graft can be detected when stained with C4d (Xu et al. 2009). These studies confirm the role of BLyS in transplantation. BLyS has been proposed to be used as a noninvasive monitoring biomarker for both pre- and post-kidney transplantation. Clinical trials manipulating the levels of BLyS by anti-BLyS agents are still ongoing.

Factors that Affect the BLyS Level During Kidney Transplantation

The production of BLyS by innate immune cells and consumption of BLyS by various B-cells at different stages of development can affect the levels of BLyS. High levels of BLyS indicate an increased production and/or decreased consumption of BLyS by B-cells (Fig. 5). Besides this, other important factors that affect the BLyS levels after a kidney transplantation are the characteristics of the recipients and the duration posttransplantation.
Fig. 5

Factors associated with B-lymphocyte stimulator (BLyS) factor. B-lymphocyte stimulator (BLyS) factor is the key factor for the development of plasma cells and production of antibodies. The innate immune responses enhance BLyS levels, whereas immunosuppressive drugs inhibit the production of BLyS. Immunosuppressive drugs currently used to inhibit the activity of BlyS are belimumab and atacicept. Other immunosuppressive drugs such as rituximab, bortezomib, and alemtuzumab are used to suppress the antibody production of B-cells/plasma cells

Levels of BLyS Pretransplantation

There are various degrees of sensitized patients that can affect the pretransplant BLyS level. Patients with high titer of anti-HLA antibodies also have high BLyS levels, but this has not been positively correlated with the rejection rate posttransplantation (Snanoudj et al. 2014). However, there are a subgroup of patients who have a higher pre-desensitization or pretransplant BLyS level which was positively correlated with the amount of posttransplant antibody-mediated rejection (ABMR) (Banham et al. 2013). These findings indicate that the recipient with high pretransplant BLyS levels will need a more intensive pretransplant desensitization protocol and immunosuppressive regimen. In addition, anti-BLyS treatment may be beneficial for these groups of kidney transplant recipients.

BLyS Levels Posttransplantation

Thibault-Espitia A et al. assessed the BLyS level in 143 recipients posttransplantation and showed that there was an association between the high levels of BLyS and the development of the donor-specific antibody (DSA) (Thibault-Espitia et al. 2012). However, the trial was a cross-sectional study and did not mention the use of any immunosuppressant agent such as rituximab which can also alter the BLyS level. Moreover, the study did not show the BLyS level prior to transplantation. In another study, recipients who received antirejection therapy such as rituximab had a significant peak of BLyS levels at 3 months posttreatment (Zarkhin et al. 2009). The high BLyS levels were positively correlated with more than 6 months of B-cell depletion after therapy. These results confirm that the B-cells can lower the levels of BLyS by consuming it. On the other hand, patients treated with a different immunosuppressant agent such as alemtuzumab had a higher rate of ABMR and excessive amount of serum BLyS (Bloom et al. 2009). The BLyS levels from the alemtuzumab-treated patients did not correlate with the amount of CD20 B-cells. This can be explained by the effects of alemtuzumab which has an activity against B-cells as well as other innate immune cells. On the other hand, data from a well-designed, longitudinal study of BLyS levels in pediatric recipients found no correlation between BLyS levels and the development of de novo DSA. Therefore the monitoring of BLyS could not be used to predict the development of DSA and chronic ABMR in the pediatric recipients (Comoli et al. 2015). However, the recipients with and without de novo DSA have similar BLyS kinetics. The BLyS levels are seen to gradually increase in the first 12 months after transplantation and eventually reach a plateau indicating the presence of early pan-activated B-cells in both unsensitized and previously sensitized patients. Hence BLyS may contribute to the rejection or tolerance of the kidney allograft.

Immunoregulation of BLyS

The immune system has a mechanism to counterbalance all types of immune responses. When the immune system is activated, there are regulatory systems that counterbalance the inflammatory immune response. There are evidences that regulatory B-cells can influence the levels of BLyS. This regulatory function is of concern especially during the anti-BLyS therapy. ELISPOT data showed that the regulatory IL-10-producing B-cells were significantly abundant when B-cells were cocultured with BLyS. Mice treated with BLyS also had an increased amount of IL-10-producing B-cells (Yang et al. 2010). The regulatory role of BLyS was later confirmed in a placebo-controlled, double-blind phase 2 trial of atacicept, a BLyS signal inhibitor. This study was conducted in patients with multiple sclerosis whose clinical activity peaked and relapsed after receiving atacicept (Kappos et al. 2014). As a result of this, the manipulation of the BLyS system with an inhibitor is a double-edged sword that can affect both the activated B-cells and regulatory B-cells.

BLyS as a Biomarker for Transplantation

To date, BLyS can significantly impact the outcome of the kidney transplantation . The concerns to use BLyS as a biomarker for the kidney transplantation are discussed here. First, the production of BLyS from the innate immune system is counterbalanced by the B-cells’ consumption of BLyS. To further complicate the matter, high levels of BLyS are not always associated with B-cell activation, but a direct inhibition of the B-cells can increase the BLyS level by reducing the consumption of BLyS. Second, there are evidences that BLyS can regulate the immune system. BLyS can activate B-cells, plasma cells, and regulatory B-cells of the immune system. Certain, favorable conditions of the BLyS level can induce tolerance posttransplantation.

Thus additional studies of the BLyS levels in different, specific conditions are needed to rule out the potential effects of the confounding factors and assess the benefits of using this noninvasive method to monitor the outcome of the transplantation. Since there is no single best biomarker, hence, the monitoring of BLyS should be done with other biomarkers and interpreted by correlating the results to the clinical data. A longitudinal follow-up of the BLyS level may yield future potential benefits when monitoring the immune system posttransplantation.

Potential Applications to Prognosis, Other Diseases, or Conditions

BLyS and APRIL may in the future be used to diagnose various B-cell-/plasma cell-related diseases such as multiple myeloma, mixed cryoglobulinemia, and other autoimmune diseases including Sjögren’s syndrome and multiple sclerosis. The level of serum BLyS may be useful in predicting the activity and severity of the disease. Additional studies looking at serial monitorings of BLyS are warranted for future treatment guidelines.

For example, the combined use of BLyS levels and donor-specific antibody (DSA) may enhance the accuracy to detect antibody-mediated rejection of the graft. DSA alone can only detect ABMR in one-third of the patients (Wu et al. 2013). So a combination of its use with BLyS may be useful for future diagnostic tests of solid organ transplantation.

As for APRIL, its other uses may be its ability to prognose various B-cell -mediated diseases. The reason for this is based on the data obtained from Treamtrakanpon et al. who showed that a high serum APRIL level was associated with treatment failure and early loss of kidney function (Treamtrakanpon et al. 2012). There are evidences that have shown APRIL’s ability to accurately prognose lupus kidney disease. Hence APRIL is considered a good prognostic biomarker for lupus kidney disease. Thus the use of APRIL should also be beneficial for other diseases caused by memory and/or plasma cells.

Conclusions

Biomarkers to detect kidney diseases are an unmet medical need. Noninvasive tests can be repetitively used to safely monitor the injury of the kidney. Levels of B-cell-activating cytokines may be potential candidates for detecting immune-mediated kidney injury.

Notes

Acknowledgement

This work is supported by the National Science and Technology Development Agency (NSTDA), Thailand (P-13-00505).

Definitions

Antibody-mediated rejection (ABMR)

Allograft rejection due mainly to anti-HLA antibody.

Anti-HLA

Alloantibody to HLA antigen. Patients sensitive to self-antigen will have high levels of anti-HLA.

Autoreactive B-cell

B-cells that can differentiate into plasma cells and produce antibody to the self-antigen.

Donor-specific antibody (DSA)

Anti-HLA that is specific to the donor HLA.

Glomerulonephritis

Glomerular disease is caused by the inflammation of the glomeruli and has the following clinical presentations of proteinuria, red blood cells/casts in the urine, and elevated levels of the serum creatinine.

IL-10-producing B-cell

Regulatory B-cell with immunoregulatory function can inhibit inflammation by controlling the production of IL-10. Regulatory B-cell plays an important role in the long-term survival of the allograft post-kidney transplantation.

Immune-mediated kidney disease

Kidney disease caused by the immune system (e.g., lupus nephritis, membranoproliferative glomerulonephritis (MPGN), membranous nephropathy).

Immunoregulation

The immune mechanism which regulatory cells counterbalance an inflammation. Those cells include regulatory T-lymphocyte and regulatory B-lymphocyte cells.

Renal vasculitis

Kidney disease is caused by the inflammation of mainly small vessels (e.g., Wegener granulomatosis and microscopic polyangiitis).

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Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Natavudh Townamchai
    • 1
  • Wannarat Pongpirul
    • 1
    • 4
  • Asada Leelahavanichakul
    • 2
    • 3
  • Yingyos Avihingsanon
    • 1
    • 3
    Email author
  1. 1.Division of Nephrology, Department of Medicine, Faculty of MedicineChulalongkorn University and King Chulalongkorn Memorial HospitalBangkokThailand
  2. 2.Division of Immunology, Department of Microbiology, Faculty of MedicineChulalongkorn UniversityBangkokThailand
  3. 3.Center of Excellence in Immunology and Immune-Mediated Diseases, Faculty of MedicineChulalongkorn UniversityBangkokThailand
  4. 4.Department of Medicine, Bamrasnaradura Infectious Diseases InstituteMinistry of Public HealthNonthaburiThailand

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