Antinuclear Antigen B Cells That Down-Regulate Surface B Cell Receptor during Development to Mature, Follicular Phenotype Do Not Display Features of Anergy In Vitro

Liu, Xiaohe; Manser, Tim

doi:10.4049/jimmunol.174.8.4505

Cited by 20 publications

(32 citation statements)

References 87 publications

(92 reference statements)

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“…31), expressing the Vk10A-Jk1 L chain that combines with canonical Ig H chains to form canonical Abs and BCRs. Extensive analysis of the primary development of E4 ϩ canonical clonotypes in the resulting double transgenic mice (termed HKIR/Vk10 and HKI65/Vk10) revealed no differences from those previously published (20,22) for canonical HKIR and HKI65 clonotypes expressing endogenous Vk10A-Jk1 L chains (data not shown). Importantly, most, if not all of these clonotypes were located in follicles and were of FO phenotype in spleen and LN (in spleen Ͼ95% of …”

Section: Resultsmentioning

confidence: 99%

“…We recently reported the functional capabilities of canonical HKIR and HKI65 B cells in vitro (22). Although anti-IgM stimulation led to quantitatively reduced proximal BCR-signaling events in canonical HKIR B cells, these cells underwent similar levels of proliferation, class switching, differentiation to AFC phenotype, and induction of activation and costimulatory molecules when stimulated with LPS or anti-IgM plus anti-CD40 and IL-4.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies have shown that canonical B cells are present in similar numbers in the splenic and lymph node (LN) follicles of HK65 and HKIR mice and-with the exception of the somewhat and dramatically reduced levels of BCR they express, respectively-have the phenotypic characteristics of mature FO B cells (20,22). To determine whether canonical HKIR and HKI65 B cells differed in their ability to respond to immunization with a TD Ag, mature B cell adoptive transfer protocols were used (29,30).…”

Section: Resultsmentioning

confidence: 99%

“…These analyses did not provide evidence that these B cells were intrinsically anergic (22). For example, these B cells were comparable to nonautoreactive B cells in proliferative responses, induction of activation and costimulatory molecules, and differentiation to Ab-forming cells (AFCs) when treated with a variety of stimuli.…”

mentioning

confidence: 97%

“…Our previous studies have shown that canonical HKIR B clonotypes are capable of efficiently differentiating to IgM-and IgGproducing AFCs when stimulated with LPS or anti-IgM and IL-4 in vitro (22). To evaluate the ability of these clonotypes to participate in the Ars-driven primary AFC response in vivo, transfer protocol B was used, as preliminary studies on HKIR/Vk10 B cells indicated that this protocol produced a far more vigorous AFC response than protocol A.…”

Section: Comparable Primary Igm and Igg Afc Responses From Canonical mentioning

confidence: 99%

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Quantitatively Reduced Participation of Anti-Nuclear Antigen B Cells That Down-Regulate B Cell Receptor during Primary Development in the Germinal Center/Memory B Cell Response to Foreign Antigen

Alabyev

Rahman

Manser

2007

The Journal of Immunology

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The peripheral B cell compartment contains high levels of “polyreactivity” including autospecificities. We have described a pathway that certain autoreactive B cells may take in gaining stable access to the foreign Ag-responsive peripheral compartment. This pathway was revealed in mice expressing a targeted Ig H chain transgene encoding BCRs with “multireactivity” for the hapten arsonate and DNA-based autoantigens. B cells expressing such BCRs develop to mature follicular phenotype and locale, and are not short-lived. These B cells express very low levels of BCR, indicating that they are not “ignorant” of self Ag, but do not display features of anergy in in vitro assays. Nonetheless, a variety of states of lymphocyte anergy has been described, and some may only be manifested in vivo. As such, we analyzed the ability of these B cells to participate in a T cell-dependent immune response to arsonate in vivo. These B cells mount an early primary response similar to control B cells, including homing to follicles, migration to the T-B interface, and induction of costimulatory molecules, proliferation, differentiation to AFCs, class switching, and entry into GCs and somatic hypermutation. Nonetheless, these B cells display reduced participation in the latter stages of the GC response and in the anamnestic AFC response. In total, these data suggest that while the autoreactivity of this type of B cell does not result in anergy, the ability of such B cells to participate in a cross-reactive immune response to foreign Ag is compromised.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 97%

Section: Comparable Primary Igm and Igg Afc Responses From Canonical mentioning

confidence: 99%

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Quantitatively Reduced Participation of Anti-Nuclear Antigen B Cells That Down-Regulate B Cell Receptor during Primary Development in the Germinal Center/Memory B Cell Response to Foreign Antigen

Alabyev

Rahman

Manser

2007

The Journal of Immunology

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Functionally responsive self‐reactive B cells of low affinity express reduced levels of surface IgM

et al. 2014

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SUMMARY Somatic gene rearrangement generates a diverse repertoire of B cells, including B cell receptors (BCR) possessing a range of affinities for self-Ag. Newly generated B cells express high and relatively uniform amounts of surface IgM (sIgM), while follicular (FO) B cells express sIgM at widely varying levels. It is plausible, therefore, that down-modulation of sIgM serves as a mechanism to maintain weakly self-reactive B cells in a responsive state by decreasing their avidity for self-Ag. We tested this hypothesis by performing comparative functional tests with FO IgMhi and IgMlo B cells from the unrestricted repertoire of wildtype (WT) mice. We found that FO IgMlo B cells mobilized Ca2+ equivalently to IgMhi B cells when the same number of sIgM molecules was engaged. In agreement, FO IgMlo B cells were functionally competent to produce an antibody response following adoptive transfer. The FO IgMlo cell population had elevated levels of Nur77 transcript, and was enriched with nuclear-reactive specificities. Hybridoma sampling revealed that these BCR were of low affinity. Collectively, these results suggest that sIgM down-modulation by low-affinity, self-reactive B cells preserves their immunocompetence and circumvents classical peripheral tolerance mechanisms that would otherwise reduce diversity within the B cell compartment.

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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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Antinuclear Antigen B Cells That Down-Regulate Surface B Cell Receptor during Development to Mature, Follicular Phenotype Do Not Display Features of Anergy In Vitro

Cited by 20 publications

References 87 publications

Quantitatively Reduced Participation of Anti-Nuclear Antigen B Cells That Down-Regulate B Cell Receptor during Primary Development in the Germinal Center/Memory B Cell Response to Foreign Antigen

Quantitatively Reduced Participation of Anti-Nuclear Antigen B Cells That Down-Regulate B Cell Receptor during Primary Development in the Germinal Center/Memory B Cell Response to Foreign Antigen

Functionally responsive self‐reactive B cells of low affinity express reduced levels of surface IgM

The regulation of autoreactive B cells during innate immune responses

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