Dendritic Cells from Lupus-Prone Mice Are Defective in Repressing Immunoglobulin Secretion

Gilbert, Mileka; Carnathan, Diane G.; Cogswell, Patricia C.; Lin, Li; Baldwin, Albert S.; Vilen, Barbara J.

doi:10.4049/jimmunol.178.8.4803

Cited by 16 publications

(18 citation statements)

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“…1b). Defects in DC/MΦ-mediated repression are coincident with diminished secretion of IL-6 and sCD40L and failure to sustain IL-6 mRNA production and activation of the IκB/NFκB pathways [107]. Similarly, we found that IL-6 and sCD40L fail to repress B cells from lupus-prone mice (unpublished data).…”

Section: Arresting and Silencing Sm-specific B Cellsmentioning

confidence: 76%

“…Decreased clearance of apoptotic cells and defects in phagocytosis by MΦs in SLE patients and lupus-prone mice may lead to autoimmunity [69,108,[122][123][124]. The increase in apoptotic cells and antigens could dysregulate DCs and MΦs, triggering a chronic anti-inflammatory response that downregulates the production of cytokines important for B cell tolerance [45,107].…”

Section: Apoptotic Cells: Dangerous In Deathmentioning

confidence: 99%

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The regulation of autoreactive B cells during innate immune responses

Vilen

Rutan

2008

Immunol Res

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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...

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Section: Arresting and Silencing Sm-specific B Cellsmentioning

confidence: 76%

Section: Apoptotic Cells: Dangerous In Deathmentioning

confidence: 99%

The regulation of autoreactive B cells during innate immune responses

Vilen

Rutan

2008

Immunol Res

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“…Likewise, defects in MRL/lpr DCs are associated with the MRL background. 28 These data indicate that M⌽s regulate autoreactive B cells by secreting repressive factors that inhibit the formation of ASCs. This mechanism of tolerance is diminished in lupus-prone mice, suggesting its role in the autoimmunity associated with SLE.…”

Section: Discussionmentioning

confidence: 95%

Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and interleukin-6

Kilmon¹,

Wagner²,

Garland³

et al. 2007

Blood

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Activation of the innate immune system promotes polyclonal antibody secretion to eliminate invading pathogens. Inherent in this process is the potential to activate autoreactive B cells and induce autoimmunity. We showed previously that TLRstimulated dendritic cells and macrophages regulate B cell tolerance to Smith antigen, in part through the secretion of interleukin-6 (IL-6). In this manuscript, we show that neutralization of IL-6 fails to abrogate macrophage-mediated repression and identify soluble CD40 ligand IntroductionRecognition of microorganisms by Toll-like receptors (TLRs) promotes inflammation and stimulates the innate immune system to produce antibody, responses that are beneficial in clearing infections. However, TLR ligation of autoreactive B cells can lead to transient or persistent autoimmunity. 1 Studies of rheumatoid factorspecific B cells show that immune complexes containing TLR and B-cell receptor (BCR) ligands induce proliferation of autoreactive B cells. [2][3][4] Likewise, anti-double-stranded DNA (dsDNA)-specific B cells proliferate in response to BCRmediated internalization of chromatin. 5 Because most nuclear self-antigens contain BCR and TLR ligands, these findings suggest that stimulation of autoreactive B cells through the BCR and/or TLR activates some autoreactive B cells.During T-dependent immune responses, CD40 stimulation induces B-cell proliferation, increases the expression of costimulatory molecules, and promotes germinal center formation leading to high affinity, class-switched antibodies. Continuous exposure to CD40 ligand (CD40L) promotes the formation of memory cells by blocking B lymphocyte-induced maturation protein-1 (Blimp-1) expression and arresting plasma cell differentiation. 6 CD40/CD40L interactions also regulate autoreactive B cells that encounter activated CD4 ϩ T H cells. 7 Hen egg lysozyme (HEL)-specific B cells that have been continuously exposed to self-antigen up-regulate Fas in response to CD40L stimulation. Subsequent encounter with an activated HEL-specific T cell induces Fasdependent B-cell apoptosis, thereby preventing autoimmunity. Thus, persistent exposure to self-antigen modulates Fas and CD40 to induce apoptosis or prevent terminal differentiation.We recently identified a mechanism of tolerance that regulates autoreactive B cells during innate immune responses. In response to lipopolysaccharide (LPS), dendritic cells (DCs) and macrophages (M⌽s) regulate HEL-, p-azophenylarsonate (Ars)-and low-affinity (2-12H/V8), Smith antigen (Sm)-specific B cells through the secretion of interleukin-6 (IL-6). 8 Regulation of immunoglobulin (Ig) secretion is selective in that chronically antigen-experienced (anergic) B cells are repressed, whereas transiently stimulated naive B cells are not. This indicates that tolerance within the B-cell compartment extends beyond antigeninduced receptor desensitization and that persistent BCR ligation affects other receptors. Herein, we report that in addition to IL-6, M⌽s secrete soluble CD40L (sCD40L), which selectively r...

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“…A second mechanism was defined in the Sm-specific model, in which dendritic cells (DCs) and macrophages selectively repress antibody production by self-reactive B cells but not naive B cells 53 . Repression is partly mediated by soluble factors, such as interleukin-6 (IL-6) and soluble CD40 ligand (CD40L), secreted by activated DCs and macrophages, and by an ill-defined, contact-dependent mechanism [53][54][55] . So, chronic binding of self antigen may reprogram IL-6 receptor and CD40 signalling, leading to alternative outcomes in autoreactive B cells.…”

Section: Effects Of Innate Immune Signalsmentioning

confidence: 99%

B-cell anergy: from transgenic models to naturally occurring anergic B cells?

et al. 2007

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Anergy, a condition in which cells persist in the periphery but are unresponsive to antigen, is responsible for silencing many self-reactive B cells. Loss of anergy is known to contribute to the development of autoimmune diseases, including systemic lupus erythematosus and type 1 diabetes. Multiple transgenic mouse models have enabled the dissection of mechanisms that underlie anergy, and recently, anergic B cells have been identified in the periphery of wild-type mice. Heterogeneity of mechanistic concepts developed using model systems has complicated our understanding of anergy and its biological features. In this Review, we compare and contrast the salient features of anergic B cells with a view to developing unifying mechanistic hypotheses that explain their lifestyles.The generation of B cells occurs throughout life and proceeds through several distinct stages and checkpoints (FIG. 1). After birth, B-cell generation occurs in the bone marrow, where cells progress through pro-B-cell and pre-B-cell stages of development. At the next stage (as immature B cells), they acquire antigen specificity by virtue of expression of a functional Bcell receptor (BCR); this is also the first key specificity checkpoint in B-cell development. Cells that successfully traverse this phase enter the periphery as transitional B cells.The ability of the adaptive immune system to provide protection against pathogens requires a diverse BCR repertoire that can recognize a broad range of foreign proteins. Diversity is generated early in development by random rearrangement of immunoglobulin genes. This inevitably results in the genesis of receptors that recognize self antigens. It is estimated that 75% of human early immature B cells are self-reactive 1 . About a third of these self-reactive immature B cells are purged from the repertoire by receptor editing, wherein renewed immunoglobulin gene rearrangement generates a new light chain to pair with the existing immunoglobulin heavy chain in an anthropomorphic effort to generate a non-self-reactive © 2007 Nature Publishing Group Correspondence to J.C.C. cambierj@njc.org. Competing interests statementThe authors declare no competing financial interests. DATABASES NIH Public Access Author ManuscriptNat Rev Immunol. Author manuscript; available in PMC 2013 July 17. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript BCR 2,3 . Failing this, these B cells are deleted by apoptosis 4 . Despite these mechanisms of central tolerance, many self-reactive B cells escape to the periphery where they are silenced by an induced state of unresponsiveness known as anergy (BOX 1). Anergy can be viewed as nothing more than the state of lethargy that ensues when B cells mount a normal initial response to antigen but fail to receive secondary signals that sustain their activation. Paradoxically, the maintenance of anergy requires chronic binding of antigen and signal transduction, yet the stimulation of unoccupied receptors fails to trigger signal transduction pathways that are...

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Dendritic Cells from Lupus-Prone Mice Are Defective in Repressing Immunoglobulin Secretion

Cited by 16 publications

References 60 publications

The regulation of autoreactive B cells during innate immune responses

The regulation of autoreactive B cells during innate immune responses

Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and interleukin-6

B-cell anergy: from transgenic models to naturally occurring anergic B cells?

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