B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice

Abstract

IntroductionB cells play essential roles during protective immune responses to invading pathogens. On encounter of foreign antigen and with cognate T-cell help, B lymphocytes proliferate and form distinct histologic structures, termed germinal center (GC). In the GC, they undergo somatic hypermutation and class-switch recombination. During somatic hypermutation, they introduce random mutations into their immunoglobulin variable regions while they exchange the heavy chain constant region during class-switch recombination to allow for different effector functions. After a selection process by antigen, B cells differentiate into memory B cells and plasma cells (PCs), which secrete antibodies. 1 The deregulation of this process is heavily implicated in human disease. Production of class-switched antibodies against self-antigens causes or contributes to various autoimmune syndromes and unrestrained B-cell proliferation and survival can result in lymphomas. 1,2 It is thought that the majority of human lymphomas derive from the GC, probably because the DNA damage inherent to the GC reaction facilitates mutations and chromosomal translocations. 1,3 Recently, the ubiquitin-editing enzyme A20, encoded by the tumor necrosis factor-␣-inducible gene 3 (TNFAIP3), has been associated with both autoimmunity and lymphomagenesis. Polymorphisms and mutations in or near the TNFAIP3 genomic locus have been linked with various human autoimmune syndromes with a strong humoral component, such as systemic lupus erythematosus (SLE), 4,5 rheumatoid arthritis, 6,7 and celiac disease. 8 Loss of A20 function through mutations, chromosomal deletions, and/or promoter methylation is a frequent event in several human lymphomas, 9-12 all of which are characterized by constitutive activation of nuclear factor-B (NF-B). 13 These factors regulate a plethora of genes encoding for proinflammatory mediators, antiapoptotic proteins, cell adhesion molecules and, for negative feedback control, inhibitory proteins, such as p100, IB␣, and A20. 14,15 During the transmission of NF-B activating signals from cell-surface receptors such as the B-cell receptor (BCR), CD40, or Toll-like receptors (TLRs), signal transduction occurs via the attachment of polyubiquitin chains to key proteins, including MALT1 or TRAF6. Polyubiquitin chains, linked via K63 or linear assembly, serve to recruit different kinase complexes. In the case of canonical NF-B, induced proximity allows the upstream kinase TAK1 to phosphorylate its target IKK2, which then effects NF-B activation. A20, whose transcription is induced by NF-B, dampens signaling through 2 main activities. First, as deubiquitinase A20 removes K63-linked polyubiquitin chains from essential signaling intermediates, such as TRAF6. Second, A20 induces, in concert with other proteins, degradation of some of its molecular targets, through addition of K48-linked ubiquitin chains. 14,16 Degradation of RIP1 limits TNF-induced signaling, 14 whereas degradation of the K63-chain-specific E2 ligases Ubc13/UbcH5c generally affects t...

Histone Arginine Methylation by PRMT7 Controls Germinal Center Formation via Regulating Bcl6 Transcription

“…In this study, we found that there was only a minor increase in total B cell numbers, whereas myeloid cells and T cells increased significantly in the enlarged spleens in 8-wk-old mice. The similar phenomenon, which is that the expanded myeloid cells and T cells are induced in reaction to autoimmunity and inflammation, was found in mice lacking genes involved in NF-kB activation (45)(46)(47). Previously, NF-kB was also reported to be regulated by other PRMTs (48)(49)(50), suggesting that arginine methylation plays unique roles in NF-kB activation.…”

NF‐κB‐inducing kinase is essential for B‐cell maintenance in mice

“…Mutations in B cells were previously shown to also affect other immune cells such as T cells, as shown with mice that lack A20 in B cells [25,26]. Except for memory T cells, which were increased in total cell numbers (Supporting Information Fig.…”

“…3I). This effect might indicate a survival advantage of GC B cells in NIK BKO mice, as seen for B-1, or that these cells escaped Cre-mediated deletion more efficiently compared to other B cells.Mutations in B cells were previously shown to also affect other immune cells such as T cells, as shown with mice that lack A20 in B cells [25,26]. Except for memory T cells, which were increased in total cell numbers (Supporting Information Fig.…”

A20 and CYLD Do Not Share Significant Overlapping Functions during B Cell Development and Activation

“…Cell type-specific deletion of A20 in immune cells and other tissues like intestinal epithelial cells and skin further confirmed its crucial role in the maintenance of tissue homeostasis and to prevent inflammatory diseases including autoimmunity (9)(10)(11)(12)(13)(14)(15). In B cells, loss of A20 causes hyperreactivity, general immune activation, and the production of autoantibodies (10,11,16).…”

“…All mouse strains employed in this study are published and were originally generated using C57BL/6 embryonic stem cells or backcrossed to C57BL/6 at least six times (11,32). Mice were housed in a specific pathogen-free environment in the animal facility of the Max Planck Institute of Biochemistry, Martinsried, Germany, and all animal procedures were approved by the Regierung of Oberbayern.…”