B-Cell Dysregulation in Idiopathic Nephrotic Syndrome: What We Know and What We Need to Discover

Abstract

The therapeutic efficacy of B-cell depletion by anti-CD20 treatment in pediatric and, more recently, in adult idiopathic nephrotic syndrome patients suggests a key role of B cells in the pathogenesis of the disease. However, their exact role is still unclear. B cells are able to secrete a large variety of antibodies that can protect against infections. However, B-cell dysregulation is well-established in a variety of autoimmune diseases. In parallel with their ability to produce antibodies, pathogenic B cells display altered effector functions by expressing activating surface molecules, which can strongly modify the immune homeostasis, or by producing specific cytokines, which can directly affect either podocyte structure and functions or modulate T-cell homeostasis. Herein, we report the most relevant clinical and experimental evidences of a pathogenic role of B cells in idiopathic nephrotic syndrome. We further highlight similarities and differences between children and adults affected by non-genetic forms of the disease and discuss what needs to be investigated in order to define the exact mechanisms underlying the pathogenic role of B cells and to identify more tailored therapeutic approaches.

Keywords: B cells; Idiopathic Nephrotic syndrome (INS); antibodies; cytokines; focal segmental glomerulosclerosis (FSGS); minimal change disease (MCD).

Figure 1

B cells can play a key role in the pathogenesis of idiopathic nephrotic syndrome (INS) thorough different mechanisms. 1) They can produce several potentially pathogenic antibodies targeting proteins constitutively expressed by podocytes such as anti-CD40 IgG, found in adults with recurrent focal segmental glomerulosclerosis (FSGS), anti-UCHL1 IgG, found in children with steroid-sensitive nephrotic syndrome (SSNS) and anti-nephrin IgG, found both in children and adults with minimal change disease (MCD). In addition, B cells produce hyposialylated IgM directed against T cells, which impair T-cell responses to steroid inhibition, in a subgroup of children with SSNS. 2) Activated B cells can also exert antibody-independent detrimental effects: an increased amount of serum CD23, a marker of B-cell activation, has been reported in pediatric SSNS and increased levels of serum B-cell activating factor (BAFF) and IL-21, which can contribute to B-cell activation, have been observed in adult MCD patients. In an experimental mouse model, IL-4 secreting B cells activated locally in the glomerulus induce podocyte effacement and proteinuria. In addition, specific risk alleles in the HLA region, which plays a crucial role in the antigen presentation to T cells, have been described in children with SSNS. 3) Alterations in B-cell homeostasis have been also observed during the active phase of the disease, with increased circulating levels of total B cells and memory B cells in children with SSNS (3a), and increased circulating levels of plasmablasts in adults with MCD (3b).