Bcl-2 increases memory B cell recruitment but does not perturb selection in germinal centers

Smith, Kenneth G. C.; Weiß, Ursula; Rajewsky, Klaus; Nossal, G. J. V.; Tarlinton, David M.

doi:10.1016/s1074-7613(94)80022-7

Cited by 122 publications

(122 citation statements)

References 39 publications

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“…In the bcl-2-Tg mice used in the present study, the Bcl-2 protein is expressed in B cells of the germinal center [28], and these Tg B cells are thus protected, though not completely, from apoptotic death following high-affinity interaction with their corresponding antigen [29]. It has also been shown that autoreactive anti-DNA B cells generated through somatic hypermutations are rescued as a result of the overexpression of the bcl-2 transgene [30].…”

Section: Discussionmentioning

confidence: 72%

Enforced Bcl‐2 expression in B lymphocytes induces rheumatoid factor and anti‐DNA production, but the Yaa mutation promotes only anti‐DNA production

et al. 2004

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The presence of rheumatoid factors (RF) is a characteristic feature of patients with rheumatoid arthritis, but not systemic lupus erythematosus. In this study, we have explored the role of the anti-apoptotic Bcl-2 protein and the Y-linked autoimmune acceleration (Yaa) mutation in the production of IgG RF in comparison with IgG anti-DNA autoimmune responses. Analysis in C57BL/6 mice, in their F1 hybrids with lupus-prone NZW mice, and in bone marrow chimeras containing mixtures of C57BL/6 bcl-2-transgenic and BXSB non-transgenic cells demonstrated that an enforced Bcl-2 expression in B cells promoted the induction of IgG anti-DNA production in these mice, while significant IgG RF responses were observed only in mice developing high levels of gp70-anti-gp70 immune complexes and lethal glomerulonephritis. Moreover, in contrast to a synergistic interaction between the Yaa mutation and Bcl-2 overexpression on IgG anti-DNA production, the Yaa mutation failed to enhance the production of IgG RF induced in bcl-2-transgenic mice. Our results reveal that defects in the regulation of B cell apoptosis play a critical role in the production of IgG RF, and that the Yaa mutation differentially modulates RF and anti-DNA autoimmune responses, likely related to the nature of autoantigens involved in each autoimmune response.

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Section: Discussionmentioning

confidence: 72%

Enforced Bcl‐2 expression in B lymphocytes induces rheumatoid factor and anti‐DNA production, but the Yaa mutation promotes only anti‐DNA production

et al. 2004

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“…However, xid/bcl-2 transgenic mice still show a number of defects typical of xid mice, although there is increased B cell survival. The survival of Ag-selected germinal centre cells is likely to depend on Bcl-2 expression [16] and can be influenced by enforced expression of a bcl-2 transgene [3]. The reduced memory B cell frequency of xid mice may therefore reflect reduced survival of antigen specific germinal centre cells, caused by reduced Bcl-2 expression.…”

Section: Resultsmentioning

confidence: 99%

“…It is, however, unknown whether the Bcl-2 levels of xid germinal centre cells are actually reduced. Weiss & Rajewsky, 1990 [17] calculated the number of memory cells induced by the hapten NP in the spleen of primed C57BL/6 mice to be in the order of 2-4 × 10 3 , whereas Smith and colleagues [3] estimated, by flow cytometry, the number of NP specific isotype switched cells to be in the range of 1-2 × 10 4 per spleen around 40 days after primary immunization. In the response to other antigens such as phycoerythrin and p-azophenylarsonate [4,18,19] the frequency of antigen specific memory cells was found to be in the range of 1-5 × 10 4 per spleen.…”

Section: Resultsmentioning

confidence: 99%

“…Memory B cells from bcl-2 transgenic mice can overcome this requirement for antigen in that they persist for at least 4-5 weeks in the absence of antigen when transferred to unimmunized recipients, as demonstrated by their ability to generate an antigen specific secondary response when challenged [7]. Similarly, the memory B cell population in bcl-2 transgenic mice is about 20 times larger than in non-transgenic mice and persist at this level for over 200 days [3]. These studies may suggest a role for Bcl-2 and Bcl-2 like proteins in the longevity of memory B cells.…”

Section: Introductionmentioning

confidence: 99%

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B Cell Memory in xid Mice is Long‐Lived Despite Reduced Memory B Cell Frequency

Ridderstad

Tarlinton

1997

Scand J Immunol

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Ridderstad A, Tarlinton DM. B Cell Memory in xid Mice is Long-Lived Despite Reduced Memory B Cell Frequency. Scand J Immunol 1997;45:655-659 Brutons tyrosine kinase (Btk) deficient xid mice have a diminished primary T cell dependent immune response, resulting in a reduced memory B cell frequency. Boosting at 35 days post primary immunization, however, generates a normal secondary immune response, indicating a functional memory B cell compartment. The longevity of B cell memory appears to depend on both the presence of antigen and expression of cell survival genes such as bcl-2. Since there is a natural decay in the number of memory B cells over time and since xid B cells have been demonstrated to have reduced Bcl-2 levels, we aimed at determining whether B cell memory of xid mice would be long-lasting. This report demonstrates that memory B cell precursors are detectable in xid mice more than 100 days after primary immunization. Furthermore, a secondary immune response of normal magnitude and kinetics can be generated in xid mice at 150 days after primary immunization indicating that B cell memory is long-lived in xid mice. Thus, although survival of B cell memory is presumably dependent on immunoglobulin (Ig)-mediated interaction with antigen, this interaction does not depend solely on signalling through Btk.

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“…Sera were collected at the indicated times (before, and 7, 14 and 21 d after immunization). High-affinity anti-NP and total anti-NP IgG2b and IgG2c were measured by ELISA using NP 2 -bovine serum albumin (NP 2 -BSA, a low hapten density to detect high-affinity NP antibodies) and NP 24 -BSA (a high hapten density to detect both low-and highaffinity NP antibodies; Biosearch Technologies), respectively, as the target antigens 45,46 . IgG2b or IgG2c that bound to the plate was detected with an HRP-conjugated goat anti-mouse IgG2c or an HRP-conjugated goat antimouse IgG2b (Southern Biotech) and 3,3¢,5,5¢-tetramethylbenzidine (Sigma) was used as the substrate.…”

Section: Methodsmentioning

confidence: 99%

Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice

et al. 2007

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Interleukin 17 (IL-17) is a cytokine associated with inflammation, autoimmunity and defense against some bacteria. Here we show that IL-17 can promote autoimmune disease through a mechanism distinct from its proinflammatory effects. As compared with wild-type mice, autoimmune BXD2 mice express more IL-17 and show spontaneous development of germinal centers (GCs) before they increase production of pathogenic autoantibodies. We show that blocking IL-17 signaling disrupts CD4 + T cell and B cell interactions required for the formation of GCs and that mice lacking the IL-17 receptor have reduced GC B cell development and humoral responses. Production of IL-17 correlates with upregulated expression of the genes Rgs13 and Rgs16, which encode regulators of G-protein signaling, and results in suppression of the B cell chemotactic response to the chemokine CXCL12. These findings suggest a mechanism by which IL-17 drives autoimmune responses by promoting the formation of spontaneous GCs.

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Bcl-2 increases memory B cell recruitment but does not perturb selection in germinal centers

Cited by 122 publications

References 39 publications

Enforced Bcl‐2 expression in B lymphocytes induces rheumatoid factor and anti‐DNA production, but the Yaa mutation promotes only anti‐DNA production

Enforced Bcl‐2 expression in B lymphocytes induces rheumatoid factor and anti‐DNA production, but the Yaa mutation promotes only anti‐DNA production

B Cell Memory in xid Mice is Long‐Lived Despite Reduced Memory B Cell Frequency

Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice

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