![]() Here, we present evidence that PP2A activity is increased in in vitro–activated B cells and in B cells from lupus-prone mice. The involvement of serine/threonine phosphatases in the B cell–dependent expression of autoimmunity is not known. Given the central role of PP2A in the regulation of many key cellular processes and its role in human disease pathogenesis, therapeutic modalities targeting PP2A are being developed ( 32). ![]() In addition, studies in patients with acute ( 30) and chronic B lymphocytic leukemia have signified the importance of PP2A in B cell oncogenesis ( 31). Transgenic mice that overexpress the catalytic subunit PP2A C in T cells develop susceptibility to glomerulonephritis ( 28), whereas PP2A is requisite for Treg function ( 29). PP2A levels and activity are increased in T cells from patients with SLE and account for decreased IL-2 production ( 24– 27). There are 2 isoforms for the structural subunit (A α and A β), 2 isoforms for the catalytic subunit (C α and C β), and more than 20 regulatory subunits that enable PP2A to act on a wide range of substrates and to participate in cellular processes like cell cycle, gene transcription, and apoptosis ( 22, 23). Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase ubiquitously expressed in eukaryotic cells and comprises a scaffold-type structural subunit (A), a catalytic subunit (C), and a regulatory subunit (B) ( 21). GCs develop spontaneously without exposure to foreign antigens ( 11– 15) in murine lupus and human systemic lupus erythematosus (SLE), and this dysregulation results in the production of autoantibodies ( 12, 13, 16– 20). In vivo, activated mature B cells proliferate and form the germinal centers (GCs) where high-affinity, long-lived plasma cells and memory B cells are generated ( 1, 9, 10). CD40 engagement by its ligand, which is expressed on T cells, is essential for T cell–dependent Ab responses and represents a major contributor to Ig production ( 7, 8). T-dependent responses are elicited by proteins, such as 4-Hydroxy-3-nitrophenylacetyl-chicken γ-globulin (NP-CGG), that are processed and presented to cognate Th cells for recognition by B cells ( 6). T-independent responses are elicited by polysaccharides that engage the B cell receptor (BCR) or CpG motifs and result in polyclonal B cell activation ( 3– 5). Introductionī cells encounter antigens in secondary lymphoid organs and respond by proliferating and undergoing maturation and differentiation, which include class-switch recombination (CSR), Ab affinity maturation, and generation of memory B cells and plasma cells ( 1, 2). Our results demonstrate that PP2A is required for optimal B cell function and may contribute to increased B cell activity in systemic autoimmunity. Transcriptome and metabolome studies revealed altered nicotinamide adenine dinucleotide (NAD) and purine/pyrimidine metabolism and increased expression of purine nucleoside phosphorylase in PP2A-deficient B cells. Flox/flox mice displayed reduced spontaneous germinal center formation and decreased responses to T cell-dependent and T-independent antigens, while their B cells responded poorly in vitro to stimulation with an anti-CD40 antibody or CpG in the presence of IL-4. To understand the contribution of PP2A to B cell function, we generated a Cd19 CrePpp2r1a fl/fl ( flox/flox) mouse which lacks functional PP2A only in B cells. We found that in vitro–activated B cells and B cells from various lupus-prone mice and patients with systemic lupus erythematosus display increased PP2A activity. ![]() Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, has been shown to control T cell function.
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