The regulation of autoreactive B cells during innate immune responses

Abstract

Systemic lupus erythematosus (SLE) highlights the dangers of dysregulated B cells and the importance of initiating and maintaining tolerance. In addition to central deletion, receptor editing, peripheral deletion, receptor revision, anergy, and indifference, we have described a new mechanism of B cell tolerance wherein dendritic cells (DCs) and macrophages (MΦs) regulate autoreactive B cells during innate immune responses. In part, DCs and MΦs repress autoreactive B cells by releasing IL-6 and soluble CD40L (sCD40L). This mechanism is selective in that IL-6 and sCD40L do not affect Ig secretion by naïve cells during innate immune responses, allowing immunity in the absence of autoimmunity. In lupus-prone mice, DCs and MΦs are defective in secretion of IL-6 and sCD40L and cannot effectively repress autoantibody secretion suggesting that defects in DC/MΦ-mediated tolerance may contribute to the autoimmune phenotype. Further, these studies suggest that reconstituting DCs and MΦs in SLE patients might restore regulation of autoreactive B cells and provide an alternative to immunosuppressive therapies. KeywordsSystemic lupus erythematosus; B cell tolerance; Autoimmunity; Dendritic cell; Macrophage; Smith antigen Learning tolerance: a B cell's storyA diverse B cell repertoire is critical in combating pathogens, but inherent in generating diversity is the threat of autoimmunity. In the bone marrow, central tolerance mechanisms such as deletion or receptor editing remove high-affinity autoreactive B cells before they exit to the periphery [1][2][3][4][5][6][7][8][9][10]. Those that escape are subject to receptor revision [8,[11][12][13][14], peripheral deletion [15,16], or a shortened lifespan because they fail to enter B cell follicles [17][18][19][20][21][22]. In rare cases, autoreactive B cells are fully functional but indifferent to their specific antigen [23][24][25]. Finally, many low-affinity autoreactive B cells are maintained in an unresponsive state known as anergy. Anergic B cells do not receive sufficient activation signals to differentiate into plasma cells or secrete immunoglobulin (Ig) in response to antigenic or mitogenic stimulation [26][27][28][29]. Their proliferative responses to B cell receptor (BCR) or toll-like receptor (TLR) signaling as well as their lifespans vary in different models [18,[30][31][32][33][34][35]. Some anergic B cells transduce BCR-derived signals [30, 32,[36][37][38][39][40], while others exhibit desensitized BCRs [30, 33,41]. Quiescence is dependent on chronic exposure to self-antigen and occupancy of the BCR [42,43] The affinity and avidity of the antigen-BCR interaction determines whether developing B cells will be deleted, edited, anergized, or ignored [46]. Self-reactive B cells that survive these developmental checkpoints tend to bind self-antigens with low affinity and they remain anergic in the absence of costimulation by cognate T cells. Many of the early transgenic (Tg) models expressed BCRs with high affinities. However, concerns were raised that these models...

Myeloid Cells Limit Production of Antibody-Secreting Cells after Immunization in the Lymph Node

“…These effects seem to be ameliorated over time as new myeloid cells repopulate the lymphoid tissues, based on our time course, and seems to implicate short-lived plasmablasts as the target of regulation. This is consistent with studies that show in mouse models of lupus, macrophages and DCs can inhibit ASC responses (13, 14). However, in those models, IL-6 played a role in signaling to the ASCs.…”

“…Signaling through the IL-6 cytokine pathway can enhance antibody secretion and plasma cell differentiation (12), but IL-6 may also dampen B cell responses in lupus-prone mice (13, 14). In these conditions, DCs and macrophages have been shown to secrete IL-6, which reduces B cell responses.…”

Dendritic Cells in Systemic Lupus Erythematosus

“…These DCs could be providing nearby autoreactive B cells with a source of self antigen and suppressive factors to impose a state of anergy. Furthermore, whether autoreactive B cells are repressed may depend on their anatomical location in lymphoid tissues(7). MZ B cells may be repressed by sCD40L secreted by MZ macrophages but when activated, the B cells may move to periarteriolar lymphoid sheaths (PALS) where they encounter DCs and become repressed by IL-6(182).…”

Innate pathways to B‐cell activation and tolerance

“…All of the above mechanisms are thought to require recognition of the BCR with soluble or membrane‐bound self‐antigen. However, it is becoming more appreciated that signals from the innate immune system can also help determine the fate of autoreactive as well as foreign‐antigen‐specific B cells 20,21 . Herein, we review the most recent literature describing methods the innate immune system uses to drive as well as dampen B‐cell responses.…”