Journal of Immunology Research
Volume 2018 (2018), Article ID 5251801, 5 pages
https://doi.org/10.1155/2018/5251801

Review Article

B Cell Activating Factor, Renal Allograft Antibody-Mediated Rejection, and Long-Term Outcome

Haiyan Xu, Xiaozhou He, and Renfang Xu

Urology Department, Third Affiliated Hospital of Soochow University, Changzhou 213003, China

Correspondence should be addressed to Xiaozhou He; hexiaozhou01@163.com

Received 12 October 2017; Accepted 7 March 2018; Published 6 June 2018

Academic Editor: Nejat K. Egilmez

Copyright © 2018 Haiyan Xu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Antibody-mediated rejection (ABMR) of renal allograft lacks typical phenotypes and clinical manifestations, always resulting in delayed diagnosis and treatment. It has been considered to be an elemental factor influencing the improvement of the long-term outcome of renal allograft. The B cell activating factor (BAFF) signal plays a fundamental function in the process of antibody-mediated immune response. Data from recipients and the nonhuman primate ABMR model suggest that the BAFF signal participates in the ABMR of renal allograft, while there are objections. The challenges in the diagnosis of ABMR, different study population, and details of research may explain the discrepancy. Large quantities of dynamic, credible data of BAFF ligands and their association with renal allograft pathological characteristics would constitute a direct proof of the role of BAFF in the progression of renal allograft ABMR.

1. Introduction

New immunosuppressive reagents and gradual improvements in posttransplantation management have fostered great improvements in the short-term outcomes of renal transplantation. However, long-term outcomes have not seen similar improvements for several reasons, of which antibody-mediated rejection (ABMR), most notably chronic active ABMR, should be the elemental one [1, 2].

It is now recognized that there are two types of renal allograft ABMR [3, 4]. Type 1 ABMR results from persistence, a resurgence of preexisting donor-specific antibodies (DSA), or both in sensitized patients and usually occurs early posttransplantation. Type 2 ABMR is associated with de novo DSA and usually occurs more than one year posttransplantation. Some acknowledged risk factors may predict the risk of onset of type 1 ABMR, which facilitates timely and effective treatment. There is an absence of characteristic markers and clinical manifestations of type 2 ABMR [5], which is a significant contributor to late renal allograft loss.

2. Open Questions about Optimal Humoral Indicators

C4d was found to be a potential marker for ABMR in kidney allografts. Standardized scoring of C4d (the complement split product) staining in renal graft biopsies was set at the Banff meeting of 2003 [6]. However, multiple studies that followed strongly supported the existence of ABMR with negatively or minimal/equivocal C4d deposition within peritubular capillaries [7–9].

C4d is not an ideal humoral indicator associated with adverse kidney transplant outcomes; neither are DSA, IgG subclasses, and C1q-binding DSA [10–14]. It is important to find optimal markers or indicators of ABMR in renal allografts for improvements of the long-term outcomes of kidney transplantation.

3. B Cell Activating Factor (BAFF): An Optimal Marker for ABMR?

B cell activating factor (BAFF, also known as BLys) shares high homology with the other ligand, APRIL. These two ligands bind to three receptors, BAFF-R, TACI, and BCMA. BAFF interacts with all three receptors, whereas APRIL can only interact with TACI or BCMA (Figure 1) [15]. Early work established that total systemic BAFF signals via BAFF-R are essential for the survival and selection of preimmune B cells (Figure 2) [15, 16]. Locally produced BAFF is involved in regulating aspects of humoral immune responses. The pattern of expression of the BAFF family receptors creates independent selective and homeostatic niches [17]. Abnormal BAFF signals have been confirmed in several autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjogren’s syndrome [18, 19].

Figure 1: BAFF, APRIL, and their receptors; BAFF binds with high affinity to both BAFF-R and TACI but with weak affinity to BCMA; APRIL conversely binds TACI and BCMA but does not bind BAFF-R. BAFF-R ligation primarily results in the activation of the nonclassincal NF-κB2 pathway, whereas TACI or BCMA ligation initiates the classical NF-κB1 pathway. These downstream signaling cascades promote cell survival and growth.

Figure 2: Expression of BAFF-R, BCMA, and TACI on B cells at different stages of development and activation. (a) BAFF-R begins to be expressed at the late transitional stage and is present on all mature B cells. Its expression is reduced on B cell entry into the GC reaction and is reexpressed on memory B cells but absent on plasmablasts and plasma cells. (b) TACI expression can be detected after the late transitional stage and also on plasmablasts and plasma cells. (c) BCMA expression is restricted to plasmablasts and plasma cells. (d and e) BAFF promotes the maturation of transitional B cells and the subsequent survival of mature B cells, whereas BAFF and APRIL can both promote plasma cell survival. Memory B cell survival and reactivation are independent of BAFF or APRIL signaling. (f) BAFF-R signals interplay with BCR signals in determining B cell maturation and survival. Under conditions of limiting BAFF availability, ligation of the BCR by antigen leads to anergy and reduced lifespan in immature transitional B cells.

Thaunat et al. first published findings about BAFF in renal transplantation. They found that BAFF provides survival signals to B cells and allows them to escape rituximab-induced apoptosis in tertiary lymphoid organs [20]. Our group also carried out some early related work. We found that cell-surface BAFF was significantly highly expressed on peripheral CD3⁺ T cells in recipients over the course of 5 years and in those with abnormal renal function and was significantly correlated with anti-HLA I and II antibodies [21, 22]. These results suggested that BAFF may be involved in the development of graft loss and influences the long-term outcome of kidney allografts. Further studies have shown BAFF to be highly expressed in acute ABMR tissues and chronic rejection tissues with high C4d deposition. There was a significant correlation between pathological traits and BAFF expression levels or C4d expression levels [23]. Thus, it was presumed that BAFF participates in humoral-mediated renal allograft rejection.

Our early conclusions were consistent with those of other research groups, who later published their observations about BAFF research in renal transplantation. Some of these studies were performed on adult recipients and some on pediatric patients [24–28]. Kwun et al. confirmed this from another perspective, and they observed that neutralizing BAFF/APRIL with TACI-Ig (atacicept) could prevent early DSA formation and ABMR development in a nonhuman primate ABMR model with T cell depletion [29]. These results provided convincing proof regarding the function of BAFF signals in the ABMR of renal allografts.

However, some research groups collected data that do not support this conclusion [30–33].

4. Sustained and In-Depth Research Be Encouraged

The challenges in diagnosis, grading, and staging of ABMR are complicated by the fact that morphological features are dependent on the time point in the course of the disease and that the dynamics of disease course show significant variability among individual patients. Different study populations were investigated, and different patients’ inclusion criteria, sample sizes, and sampling times may explain the discrepancy. Large quantities of dynamic, credible data of BAFF ligands and their association with renal allograft pathological characteristics constitute direct proof of the role of BAFF in the progression of renal allograft ABMR. Multicenter combined studies should be encouraged. An optimal ABMR animal model of kidney transplantation would help resolve the difficulties in specimen acquisition. BAFF ligand detection combined with other indexes, for example, C4d, C1q-binding DSA, preexisting DSA, de novo DSA, and IgG subtypes, merits further exploration. BAFF could be a predictor of ABMR in kidney transplantation recipients, as predicted by Pongpirul et al. [34].

BAFF ligands are usually produced by myeloid cells, and the receptors are expressed by B lymphocytes. BAFF expression can increase in response to cytokine stimulation, and interferon-γ, interleukin-10, transforming growth factor-β, and granulocyte-clonal stimulator factor are all listed. Under some conditions, BAFF can also be found on some nonmyeloid cells, for example, epithelial cells, osteoclasts, and adipocytes [35–37]. However, little work has been devoted to the action of BAFF on nonmyeloid cells. In the context of kidney transplantation, an abnormally high expression of BAFF ligands and receptors has also been observed on tubular epithelial cells in renal allografts [38]. Whether they function in the biological activity of RTECs, what their mechanisms of action are, and what kind of role they play in AMBR remain unknown. Renal tubular epithelial cells are one kind of renal parenchymal cells, and they play an important role in the maintenance of renal allograft function. Resolving these issues would facilitate the mechanism underlying BAFF ligands and receptors in the progression of renal allograft ABMR.

5. Conclusion

The chronic humoral response is always insidious and sometimes mixed with T-cell-mediated rejection and nonspecific manifestations of chronic drug intoxication. Specific recipients can experience considerably different responses. However, there are always histologic, serologic, and molecular fingerprints indicating the occurrence and development of ABMR. Currently, the quality of detection reagents, cytokine techniques, cell subset analysis, and alloactivity detection are all very high. Advances in pertinent B cell research techniques may facilitate identification of markers for ABMR [39]. Other molecular detection and labelling techniques and established animal models would provide big convenience for further exploration of the BAFF ligands and receptors during the process of renal allograft ABMR. And sustained and effective investigation would finally improve the long-term outcome of renal transplantation.

Conflicts of Interest

There is no conflict of interests regarding the publication of this paper.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81272367) and the National Science Foundation of Jiangsu Province (BK2011248). And the authors thank LetPub for its linguistic assistance during the preparation of this manuscript.

References

K. Solez, R. B. Colvin, L. C. Racusen et al., “Banff 07 classification of renal allograft pathology: updates and future directions,” American Journal of Transplantation, vol. 8, no. 4, pp. 753–760, 2008.

T. Tsuji, M. Yanai, H. Itami et al., “Microvascular inflammation in early protocol biopsies of renal allografts in cases of chronic active antibody-mediated rejection,” Nephrology, vol. 20, Supplement 2, pp. 26–30, 2015.

M. Mengel, B. Sis, M. Haas et al., “Banff 2011 meeting report: new concepts in antibody-mediated rejection,” American Journal of Transplantation, vol. 12, no. 3, pp. 563–570, 2012.

M. Haas, J. Mirocha, N. L. Reinsmoen et al., “Differences in pathologic features and graft outcomes in antibody-mediated rejection of renal allografts due to persistent/recurrent versus de novo donor-specific antibodies,” Kidney International, vol. 91, no. 3, pp. 729–737, 2017.

O. Aubert, A. Loupy, L. Hidalgo et al., “Antibody-mediated rejection due to preexisting versus De Novo donor-specific antibodies in kidney allograft recipients,” Journal of the American Society of Nephrology, vol. 28, no. 6, pp. 1912–1923, 2017.

L. C. Racusen, P. F. Halloran, and K. Solez, “Banff 2003 meeting report: new diagnostic insights and standards,” American Journal of Transplantation, vol. 4, no. 10, pp. 1562–1566, 2004.

M. Haas, D. L. Segev, L. C. Racusen et al., “C4d deposition without rejection correlates with reduced early scarring in ABO-incompatible renal allografts,” Journal of the American Society of Nephrology, vol. 20, no. 1, pp. 197–204, 2009.

B. J. Orandi, N. Alachkar, E. S. Kraus et al., “Presentation and outcomes of C4d-negative antibody-mediated rejection after kidney transplantation,” American Journal of Transplantation, vol. 16, no. 1, pp. 213–220, 2016.

T. Niikura, I. Yamamoto, Y. Nakada et al., “Probable C4d-negative accelerated acute antibody-mediated rejection due to non-HLA antibodies,” Nephrology, vol. 20, Supplement 2, pp. 75–78, 2015.

J. Irure, M. López-Hoyos, E. Rodrigo et al., “Antibody-mediated rejection in kidney transplantation without evidence of anti-HLA antibodies?” Transplantation Proceedings, vol. 48, no. 9, pp. 2888–2890, 2016.

F. Eskandary, G. Bond, H. Regele et al., “Late antibody-mediated rejection in a large prospective cross-sectional study of kidney allograft recipients – preliminary results of the screening phase of the BORTEJECT trial,” Clinical Transplants, vol. 23, pp. 189–195, 2014.

C. Lefaucheur, D. Viglietti, C. Bentlejewski et al., “IgG donor-specific anti-human HLA antibody subclasses and kidney allograft antibody-mediated injury,” Journal of the American Society of Nephrology, vol. 27, no. 1, pp. 293–304, 2016.

C. L. Butler, N. M. Valenzuela, K. A. Thomas, and E. F. Reed, “Not all antibodies are created equal: factors that influence antibody mediated rejection,” Journal of Immunology Research, vol. 2017, Article ID 7903471, 9 pages, 2017.

A. Moktefi, J. Parisot, D. Desvaux et al., “C1q binding is not an independent risk factor for kidney allograft loss after an acute antibody-mediated rejection episode: a retrospective cohort study,” Transplant International, vol. 30, no. 3, pp. 277–287, 2017.

M. Chhabra, T. M. Conlon, K. Saeb-Parsy, and G. J. Pettigrew, “BAFF and associated TNF superfamily members in renal transplantation: an end to BLySful ignorance,” Transplantation Journal, vol. 96, no. 10, pp. 853–859, 2013.

F. Mackay and P. Schneider, “Cracking the BAFF code,” Nature Reviews Immunology, vol. 9, no. 7, pp. 491–502, 2009.

M. S. Naradikian, A. R. Perate, and M. P. Cancro, “BAFF receptors and ligands create independent homeostatic niches for B cell subsets,” Current Opinion in Immunology, vol. 34, pp. 126–129, 2015.

N. Thompson, D. A. Isenberg, E. C. Jury, and C. Ciurtin, “Exploring BAFF: its expression, receptors and contribution to the immunopathogenesis of Sjögren’s syndrome,” Rheumatology, vol. 55, no. 9, pp. 1548–1555, 2016.

E. Samy, S. Wax, B. Huard, H. Hess, and P. Schneider, “Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases,” International Reviews of Immunology, vol. 36, no. 1, pp. 3–19, 2017.

O. Thaunat, N. Patey, C. Gautreau et al., “B cell survival in intragraft tertiary lymphoid organs after rituximab therapy,” Transplantation, vol. 85, no. 11, pp. 1648–1653, 2008.

H. Xu, X. He, Q. Liu et al., “The abnormal high expression of B cell activating factor belonging to TNF superfamily (BAFF) and its potential role in kidney transplant recipients,” Cellular & Molecular Immunology, vol. 5, no. 6, pp. 465–470, 2008.

H. Xu, X. He, Q. Liu et al., “Abnormal high expression of B-cell activating factor belonging to the TNF superfamily (BAFF) associated with long-term outcome in kidney transplant recipients,” Transplantation Proceedings, vol. 41, no. 5, pp. 1552–1556, 2009.

H. Xu, X. He, J. Sun, D. Shi, Y. Zhu, and X. Zhang, “The expression of B-cell activating factor belonging to tumor necrosis factor superfamily (BAFF) significantly correlated with C4d in kidney allograft rejection,” Transplantation Proceedings, vol. 41, no. 1, pp. 112–116, 2009.

A. Lehnhardt, F. Dunst, M. van Husen et al., “Elevated serum levels of B-cell activating factor in pediatric renal transplant patients,” Pediatric Nephrology, vol. 27, no. 8, pp. 1389–1395, 2012.

A. Thibault-Espitia, Y. Foucher, R. Danger et al., “BAFF and BAFF-R levels are associated with risk of long-term kidney graft dysfunction and development of donor-specific antibodies,” American Journal of Transplantation, vol. 12, no. 10, pp. 2754–2762, 2012.

G. Banham, D. Prezzi, S. Harford et al., “Elevated pretransplantation soluble BAFF is associated with an increased risk of acute antibody-mediated rejection,” Transplantation Journal, vol. 96, no. 4, pp. 413–420, 2013.

C. Sango, D. Merino, D. San Segundo et al., “B-cell–activating factor levels are associated with antibody-mediated histological damage in kidney transplantation,” Transplantation Proceedings, vol. 48, no. 9, pp. 2910–2912, 2016.

A. Schuster, B. Jung, J. Hofbauer et al., “B-cell activating factor BAFF reflects patients’ immunological risk profile after kidney transplantation,” Transplant Immunology, vol. 45, pp. 35–41, 2017.

J. Kwun, E. Page, J. J. Hong et al., “Neutralizing BAFF/APRIL with atacicept prevents early DSA formation and AMR development in T cell depletion induced nonhuman primate AMR model,” American Journal of Transplantation, vol. 15, no. 3, pp. 815–822, 2015.

J. W. Min, K. W. Kim, B. M. Kim et al., “Clinical significance of pre- and post-transplant BAFF levels in kidney transplant recipients,” PLOS ONE, vol. 11, no. 9, article e0162964, 2016.

A. Slavcev, J. Brozova, J. Slatinska et al., “Soluble BAFF cytokine levels and antibody-mediated rejection of the kidney allograft,” Archivum Immunologiae et Therapiae Experimentalis, vol. 64, Supplement 1, pp. 47–53, 2016.

A. M. Lehnhardt, M. Strecker, T. Eiermann et al., “High B-cell activating factor is not associated with worse 3-year graft outcome in blood group-incompatible kidney transplantation with rituximab induction,” Clinical Transplantation, vol. 29, no. 4, pp. 359–364, 2015.

M. A. Mujtaba, W. J. Komocsar, E. Nantz et al., “Effect of treatment with tabalumab, a B cell–activating factor inhibitor, on highly sensitized patients with end-stage renal disease awaiting transplantation,” American Journal of Transplantation, vol. 16, no. 4, pp. 1266–1275, 2016.

W. Pongpirul, W. Chancharoenthana, K. Pongpirul et al., “B-cell activating factor, a predictor of antibody mediated rejection in kidney transplantation recipients,” Nephrology, vol. 23, no. 2, pp. 169–174, 2018.

M. Ittah, C. Miceli-Richard, J.-E. Gottenberg et al., “B cell-activating factor of the tumor necrosis factor family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in primary Sjögren’s syndrome,” Arthritis Research & Therapy, vol. 8, no. 2, article R51, 2006.

M. Abe, S. Kido, M. Hiasa et al., “BAFF and APRIL as osteoclast-derived survival factors for myeloma cells: a rationale for TACI-Fc treatment in patients with multiple myeloma,” Leukemia, vol. 20, no. 7, pp. 1313–1315, 2006.

V. I. Alexaki, G. Notas, V. Pelekanou et al., “Adipocytes as immune cells: differential expression of TWEAK, BAFF, and APRIL and their receptors (Fn14, BAFF-R, TACI, and BCMA) at different stages of normal and pathological adipose tissue development,” The Journal of Immunology, vol. 183, no. 9, pp. 5948–5956, 2009.

H. Xu, X. He, W. Zhao et al., “CD256 can be found in antibody-mediated renal allograft rejection tissues,” Clinical Laboratory, vol. 58, no. 5-6, pp. 411–418, 2012.

M. Crespo, S. Heidt, D. Redondo, and J. Pascual, “Monitoring B cell subsets and alloreactivity in kidney transplantation,” Transplantation Reviews, vol. 29, no. 2, pp. 45–52, 2015.