Both BAFF and APRIL play a crucial upstream role in
regulating B cell function in IgA nephropathy (IgAN)
pathogenesis.1

B cell production of both pathogenic Gd-IgA1 and autoantibodies, which form immune complexes, is the
root cause of IgAN. The cytokines B cell activating factor (BAFF) and a proliferation-inducing ligand
(APRIL) modulate B cell activity via the transmembrane activator and calcium modulatory and cyclophilin
ligand interactor (TACI). When upregulated BAFF and APRIL bind to TACI, B cells are stimulated to
increase the production of Gd-IgA1 and autoantibodies, activating a cascade of events that leads to
progressive kidney damage in IgAN.1

An overview of IgAN pathogenesis1–3

Illustration of the steps in IgAN pathogenesis, from B cell activation to the formation of immune complexes and their deposition in the kidney

What effect could disease modification
have on kidney outcomes?

Learn more
What causes B cells to produce Gd-IgA1?

Learn how B cells initiate IgAN pathogenesis from
Dr. Tumlin, Nephrologist and Director of Clinical
Research, Emory University School of Medicine and
Director of the NephroNet Clinical Trials Consortium

Hear from IgAN experts

Both BAFF and APRIL play pivotal roles in
B cell homeostasis.1

BAFF and APRIL are cytokines from the tumor necrosis factor (TNF) superfamily with key functions in B cell
homeostasis.1 Together, BAFF and APRIL have key overlapping roles in promoting B cell differentiation,
antibody production, and antibody class switching.2

In IgAN, BAFF and APRIL are crucial factors in the production of Gd-IgA1 and autoantibodies, resulting in the
formation of pathogenic immune complexes.1 BAFF and APRIL are promising targets for their role in upstream
IgAN pathogenesis.4

Illustration of the effects that cytokines BAFF and APRIL have on B cells

In IgAN, BAFF and APRIL are present at
elevated levels and are associated
with increased clinical severity.1

Clinical data

Clinical studies demonstrate an association between
higher BAFF and APRIL levels and worse IgAN outcomes.

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A study demonstrated that serum levels of BAFF were significantly higher in patients with IgAN (n=30) compared to patients with minimal glomerular abnormalities (n=30) and healthy controls (n=30). In patients with IgAN, serum levels of BAFF were positively correlated with IgA1 levels and mesangial IgA deposition density.

A study in 153 patients with IgAN, 55 healthy controls, and 20 chronic kidney disease controls found that levels of serum BAFF were significantly higher in patients with IgAN compared to controls. Higher BAFF levels were associated with clinical and pathological features of the disease, including higher levels of circulating IgA deposits in the kidney, reduced kidney function, and fibrosis and inflammation in mesangial cells.

A study in 58 patients with IgAN demonstrated that plasma BAFF levels were positively correlated with renal damage (Katafuchi score). In these patients, higher pathological damage was associated with increased proteinuria, increased plasma BAFF levels, and decreased endogenous creatinine clearance rate.

In this study, APRIL levels in patients with IgAN (n=44) were slightly but not significantly increased compared to healthy controls (n=23), and significantly increased compared to non-IgAN glomerulonephritis patients (n=22). APRIL levels positively correlated with serum creatinine and negatively correlated with eGFR.

Preclinical data

Preclinical studies show that BAFF and APRIL may have
important roles in IgAN pathogenesis.

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Transgenic mice overexpressing BAFF (BAFF-Tg) exhibited features of autoimmune disease, including B cell hyperplasia and hypergammaglobulinemia, and developed fatal nephritis with age. BAFF-Tg mice also demonstrated high levels of basal serum IgA, mesangial deposits of IgA, and high circulating levels of aberrantly glycosylated polymeric IgA. The elevated serum IgA phenotype was commensal-flora dependent.

A study using BALB/c mice and APRIL knockout mice to evaluate the survival of memory B cells and long-lived bone marrow plasma cells in the absence of BAFF and APRIL in vivo found that bone marrow plasma cell survival can be supported by either BAFF or APRIL independently in this model.

A study using TACI-Fc to block both BAFF and APRIL in the NZB/NZW F1 mouse model of SLE found that the neutralization of both BAFF and APRIL always leads to a decrease in bone marrow plasma cells and slows the formation of autoantibodies in this model.

In this study, fecal microbiota was transplanted from healthy controls, and patients with stable or severe IgAN to antibiotic-treated humanized IgAN mice. The microbiota from patients with severe IgAN induced an increase of serum BAFF and Gd-IgA1 levels and a decrease of CD89 cell surface expression on blood CD11b+ cells, which was associated with soluble CD89 and IgA1 mesangial deposits.

 BAFF and APRIL are potential targets for
future IgAN disease modification.

BAFF and APRIL are key factors in the production
of Gd-IgA1 and autoantibodies that result in the
formation of pathogenic immune complexes.4

How do BAFF and APRIL regulate B cell function in IgAN?

Learn how BAFF and APRIL regulate B cell function in
IgAN from Dr. Cheung, Consultant Nephrologist and
Honorary Associate Professor, University of Leicester
& John Walls Renal Unit, UK

Hear from IgAN experts

Unchecked B cell activity leads
to four disease markers in IgAN.

Learn more

References:

  1. Cheung CK et The role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapies. Front Nephrol. 2024;3:1346769. doi: 10.3389/fneph.2023.1346769.
  2. Knoppova B et The origin and activities of IgA1-containing immune complexes in IgA nephropathy. Front Immunol. 2016:7:117. doi: 10.3389/fimmu.2016.00117.
  3. Kwon CS et A systematic literature review of the epidemiology, health-related quality of life impact, and economic burden of immunoglobulin A nephropathy. J Health Econ Outcomes Res. 2021;8(2):36–45.
  4. Maixnerova D et New treatment strategies for IgA nephropathy: targeting plasma cells as the main source of pathogenic antibodies. J Clin Med. 2022;11(10):2810. doi: 10.3390/jcm11102810.
  5. Li W et TLR9 and BAFF: their expression in patients with IgA nephropathy. Mol Med Rep. 2014;10(3):1469–1474.
  6. Xin G et Serum BAFF is elevated in patients with IgA nephropathy and associated with clinical and histopathological features. J Nephrol. 2013;26(4):683–690.
  7. Cao Y et BAFF is involved in the pathogenesis of IgA nephropathy by activating the TRAF6/NF‑κB signaling pathway in glomerular mesangial cells. Mol Med Rep. 2020;21(2):795–805.
  8. Sallustio F et High levels of gut-homing immunoglobulin A+ B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients. Nephrol Dial Transplant. 2021;36(3):452–464.
  9. McCarthy DD et Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy. J Clin Invest. 2011;121(10):3991–4002.
  10. Benson MJ et Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol. 2008;180(6):3655–3659.
  11. Haselmayer P et A mouse model of systemic lupus erythematosus responds better to soluble TACI than to soluble BAFFR, correlating with depletion of plasma cells. Eur J Immunol. 2017;47(6):1075–1085.
  12. Lauriero G et al. Fecal microbiota transplantation modulates renal phenotype in the humanized mouse model of IgA nephropathy. Front Immunol. 2021:12:694787. doi: 10.3389/fimmu.2021.694787
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