B Cells in Primary Membranous Nephropathy: Escape from Immune Tolerance and Implications for Patient Management

Abstract

Membranous nephropathy (MN) is an important cause of nephrotic syndrome and chronic kidney disease (CKD) in adults. The pathogenic significance of B cells in MN is increasingly recognized, especially following the discovery of various autoantibodies that target specific podocytic antigens and the promising treatment responses seen with B cell depleting therapies. The presence of autoreactive B cells and autoantibodies that bind to antigens on podocyte surfaces are characteristic features of MN, and are the result of breaches in central and peripheral tolerance of B lymphocytes. These perturbations in B cell tolerance include altered B lymphocyte subsets, dysregulation of genes that govern immunoglobulin production, aberrant somatic hypermutation and co-stimulatory signalling, abnormal expression of B cell-related cytokines, and increased B cell infiltrates and organized tertiary lymphoid structures within the kidneys. An understanding of the role of B cell tolerance and homeostasis may have important implications for patient management in MN, as conventional immunosuppressive treatments and novel B cell-targeted therapies show distinct effects on proliferation, differentiation and reconstitution in different B cell subsets. Circulating B lymphocytes and related cytokines may serve as potential biomarkers for treatment selection, monitoring of therapeutic response and prediction of disease relapse. These recent advances in the understanding of B cell tolerance in MN have provided greater insight into its immunopathogenesis and potential novel strategies for disease monitoring and treatment.

Serum 25-hydroxyvitamin D as a predictive biomarker of clinical outcomes in patients with primary membranous nephropathy

“…Logistic regression analysis further verified that a lower level of 25 (OH)D was related to the higher likelihood of seropositivity of anti-PLA2R Ab (OR 2.4 95%CI 1.6, 3.7, P < 0.001) in the fully adjusted model. Our findings supplied evidence for the association of VD and B cell homeostasis since autoantibodies generated by autoreactive B cells were a key driver in the immunopathogenesis of MN ( 40 ). Numerous studies have reported that active VD suppresses the proliferation of activated B cells, generation of switched memory B cells, differentiation of antigen-secreting plasma cells, and Ig secretion ( 32 , 53 ).…”

“…The changes in immunoglobulin heavy chain (IGH) repertoire in B cell receptors (BCR) were observed in patients with PMN ( 38 ). Rituximab (RTX), an agent targeting CD20 + B cells, was recommended as the first-line treatment option for PMN, which further demonstrated the key role of B cells in the pathogenesis of PMN ( 39 , 40 ). Treg cells were also a useful predictor for RTX treatment ( 36 ).…”

“…Primary membranous nephropathy was a typical organ-specific autoimmune disease, arising from a loss of normal immune tolerance to podocyte antigens with the formation of disease-causing antibodies that resulted in a pathognomonic pattern of injury in glomeruli ( 40 , 49 ). PLA2R, a landmark podocyte antigen, was associated with 70–80% PMN ( 2 ).…”

Identification of biomarkers for the diagnosis of chronic kidney disease (CKD) with non-alcoholic fatty liver disease (NAFLD) by bioinformatics analysis and machine learning

“…B cells are thought to be involved in the progression of The immune landscape of CKD samples in GSE104954 and correlation analysis. Membranous nephropathy (MN) by releasing antibodies against podocytes, so depletion therapy targeting B cells may be a potential treatment (49). However, existing data suggest that depletion of B cells does not achieve the expected effect in lgA nephropathy (50).…”

Homeostatic Modulation of CD4+ T Cell Subsets Using the Chinese Medicine Jianpi Qushi Heluo Formula During the Alleviation of Primary Membranous Nephropathy

“…[1] It is the most common cause of nephrotic syndrome in the adult population and one of the leading causes of end-stage kidney disease, of which 80% are primary membranous nephropathy (pMN) mediated by specific nephritogenic autoantibodies against glomerular podocytes. [2,3] The prevalence of pMN in China has recently increased, second only to that of IgA nephropathy among primary glomerular diseases. [4] PMN is a kidney-specific, autoimmune-mediated glomerular disease whose specific pathogenic mechanisms remain to be further investigated, although significant progress has been achieved.…”