In Vivo Assessment of the Relative Contributions of Deletion, Anergy, and Editing to B Cell Self-Tolerance

Hippen, Keli L.; Schram, Brian R.; Tze, Lina E.; Pape, Kathryn A.; Jenkins, Marc K.; Behrens, Timothy W.

doi:10.4049/jimmunol.175.2.909

Cited by 74 publications

(66 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Finally, we tested the influence of PMA and ionomycin on pre-BCR editing to self-Ag in a newly developed in vivo model system (31). In this model, mice that carry an anti-HEL H chain transgene, an anti-HEL L chain knockin allele, and a mHEL transgene have an expanded pre-B cell compartment and show vigorous L chain editing responses that lead to the accumulation of high numbers of non-HEL-binding (edited) B cells in the periphery (31).…”

Section: Pma and Ionomycin Suppress L Chain Receptor Editing In Pre-bmentioning

confidence: 99%

“…In this model, mice that carry an anti-HEL H chain transgene, an anti-HEL L chain knockin allele, and a mHEL transgene have an expanded pre-B cell compartment and show vigorous L chain editing responses that lead to the accumulation of high numbers of non-HEL-binding (edited) B cells in the periphery (31). For the experiments described here, a human C knockin allele (12) was introduced into these mice (generating H chain Tg/ϩ /L chain KI/hCk /mHEL animals) so that we could monitor the frequency of editing to the alternate L chain allele by staining cells for hC .…”

Section: Pma and Ionomycin Suppress L Chain Receptor Editing In Pre-bmentioning

confidence: 99%

See 1 more Smart Citation

B Cell Receptor Basal Signaling Regulates Antigen-Induced Ig Light Chain Rearrangements

Schram

Tze

Ramsey

et al. 2008

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

BCR editing in the bone marrow contributes to B cell tolerance by orchestrating secondary Ig rearrangements in self-reactive B cells. We have recently shown that loss of the BCR or a pharmacologic blockade of BCR proximal signaling pathways results in a global “back-differentiation” response in which immature B cells down-regulate genes important for the mature B cell program and up-regulate genes characteristic of earlier stages of B cell development. These observations led us to test the hypothesis that self-Ag-induced down-regulation of the BCR, and not self-Ag-induced positive signals, lead to Rag induction and hence receptor editing. Supporting this hypothesis, we found that immature B cells from xid (x-linked immunodeficiency) mice induce re-expression of a Rag2-GFP bacterial artificial chromosome reporter as well as wild-type immature B cells following Ag incubation. Incubation of immature B cells with self-Ag leads to a striking reversal in differentiation to the pro-/pre-B stage of development, consistent with the idea that back-differentiation results in the reinduction of genes required for L chain rearrangement and receptor editing. Importantly, Rag induction, the back-differentiation response to Ag, and editing in immature and pre-B cells are inhibited by a combination of phorbol ester and calcium ionophore, agents that bypass proximal signaling pathways and mimic BCR signaling. Thus, mimicking positive BCR signals actually inhibits receptor editing. These findings support a model whereby Ag-induced receptor editing is inhibited by BCR basal signaling on developing B cells; BCR down-regulation removes this basal signal, thereby initiating receptor editing.

show abstract

Section: Pma and Ionomycin Suppress L Chain Receptor Editing In Pre-bmentioning

confidence: 99%

Section: Pma and Ionomycin Suppress L Chain Receptor Editing In Pre-bmentioning

confidence: 99%

B Cell Receptor Basal Signaling Regulates Antigen-Induced Ig Light Chain Rearrangements

Schram

Tze

Ramsey

et al. 2008

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…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].…”

Section: Learning Tolerance: a B Cell's Storymentioning

confidence: 99%

The regulation of autoreactive B cells during innate immune responses

Vilen

Rutan

2008

Immunol Res

View full text Add to dashboard Cite

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...

show abstract

“…Clonal deletion is the process through which the autoreactive B cells are depleted from the repertoire (12, 30). Recent studies have indicated that clonal deletion operates as a default pathway to get rid of autoreactive B cells that cannot be rescued by receptor editing (11,14).Receptor editing at the immature B-cell stage is induced by a self-reactive BCR, and it can also be induced by a BCR with an insufficient amount of tonic signaling (18). Receptor editing is a process through which self-reactive heavy or light chain is replaced with a product of secondary V(D)J rearrangement (29).…”

mentioning

confidence: 99%

A Role for Interferon Regulatory Factor 4 in Receptor Editing

Pathak

Trinh

et al. 2008

Molecular and Cellular Biology

View full text Add to dashboard Cite

B-cell development in the bone marrow is characterized by sequential rearrangement of immunoglobulin (Ig) heavy-and light-chain loci through a somatic DNA rearrangement event called the V(D)J rearrangement. Although the total randomness of V(D)J rearrangement is essential for the diversification of the B-cell-receptor (BCR) repertoire, it also unavoidably brings autoreactivity to the repertoire of newly generated immature B cells. Indeed, it has been estimated that 40 to 60% of newly synthesized B cells are autoreactive (29). Central tolerance is the mechanism through which developing B cells are rendered nonreactive to self. Central tolerance consists of receptor editing, anergy, and deletion (29). During receptor editing, autoreactive B cells undergo prolonged V(D)J rearrangement to replace the autoreactive heavy and/or light chain (9, 40). Anergy is a mechanism through which the autoreactive B cells are rendered inactive and, thus, unable to harm the host (10). Clonal deletion is the process through which the autoreactive B cells are depleted from the repertoire (12, 30). Recent studies have indicated that clonal deletion operates as a default pathway to get rid of autoreactive B cells that cannot be rescued by receptor editing (11,14).Receptor editing at the immature B-cell stage is induced by a self-reactive BCR, and it can also be induced by a BCR with an insufficient amount of tonic signaling (18). Receptor editing is a process through which self-reactive heavy or light chain is replaced with a product of secondary V(D)J rearrangement (29). Secondary rearrangement occurs mainly at the Ig and loci. The murine locus contains four functional J elements: J1, J2, J4, and J5. During receptor editing, the primary VJ rearrangement can be replaced by secondary rearrangement between V and a downstream J element. Secondary rearrangement can also occur between V and a recombination sequence (RS) located ϳ25 kb downstream of the C or between a site located in the J-C intron and the RS (7). The RS rearrangement leads to functional inactivation of the whole locus and the initiation of Ig rearrangement (41). Interferon regulatory factor 4 (IRF-4) and IRF-8 are immune system-specific transcription factors that have been shown to play critical roles in innate and adaptive immunity (39). Previous studies have demonstrated that IRF-4 and -8 function redundantly to control pre-B-cell development (21). B-cell development is blocked at the pre-B stage in mice lacking IRF-4 and -8; mutant pre-B cells are hyperproliferative and defective in light-chain rearrangement and transcription (21). Recently, we have shown that IRF-4 and -8 induce the expression of Ikaros and Aiolos to downregulate pre-BCR and inhibit pre-B-cell expansion (22). In addition, we and others have also demonstrated that IRF-4 and -8 induce chromatin modifications at the locus, thereby promoting locus activation in pre-B-cell development (20,23). Thus, the roles of IRF-4 and -8 in pre-B-cell development are twofold: one is to limit pre-B-cell expansion and the o...

show abstract

In Vivo Assessment of the Relative Contributions of Deletion, Anergy, and Editing to B Cell Self-Tolerance

Cited by 74 publications

References 23 publications

B Cell Receptor Basal Signaling Regulates Antigen-Induced Ig Light Chain Rearrangements

B Cell Receptor Basal Signaling Regulates Antigen-Induced Ig Light Chain Rearrangements

The regulation of autoreactive B cells during innate immune responses

A Role for Interferon Regulatory Factor 4 in Receptor Editing

Contact Info

Product

Resources

About