Soluble antigen can cause enhanced apoptosis of germinal-centre B cells

Pulendran, B.; Kannourakis, George; Nouri, Sara; Smith, Kenneth G. C.; Nossal, G. J. V.

doi:10.1038/375331a0

Cited by 290 publications

(175 citation statements)

References 30 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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“…In this version of the Tilman model populations grow in response to resources following a Monod (saturating) growth function that plateaus to a maximum for large amounts of resource. For antigen there is evidence to suggest that too much antigen is detrimental to the survival of peripheral B cells (18,19) so that the curve describing the peripheral net growth rate in response to resources may fall off from its peak value as antigen concentrations exceed their optimum level. We also would like to know about the production and decay characteristics of each resource (a and S) and finally about the consumption of resources by B cells (g).…”

Section: Models Of Resource Competition With Immigrationmentioning

confidence: 99%

Resource competition as a mechanism for B cell homeostasis

McLean

Rosado

Agenès

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Cellular competition for survival signals offers a cogent and appealing mechanism for the maintenance of cellular homeostasis [Raff, M. C. (1992) Nature (London) 356, 397-400]. We present a theoretical and experimental investigation of the role of competition for resources in the regulation of peripheral B cell numbers. We use formal ecological competition theory, mathematical models of interspecific competition, and competitive repopulation experiments to show that B cells must compete to persist in the periphery and that antigen forms a part of the resources over which B cells compete.''The most basic qualities of a natural community are the kinds and numbers of species living in them.'' This quotation from a classic ecological monograph (1) could equally well apply to immunology, where the communities in question are populations of lymphocytes present within individual organisms. Motivated by this similarity in basic questions we have used ecological competition theory in studies of B cell homeostasis and diversity. A combination of laboratory and mathematical models lead us to propose that the size of the peripheral B lymphocyte pool results from a process of immigration from the bone marrow, competition for resources in the periphery (2), and rapid death of cells that fail to secure resources. Our models allow us to quantify the contribution of each of these three processes to the final size of the peripheral B cell pool.Immunologists often use the word competition and most would probably agree that they define competition as ''an interaction between two populations, in which, for each, the birth rates are depressed or the death rates increased by the presence of the other population'' (3). However, this type of interaction can arise through a number of different processes. In resource competition (1) the negative effects come about because the two populations both have a need for the same substrate that is in limited supply. In apparent competition (4) the two populations affect each others' growth via a shared predator rather than a shared resource. Other schemes have been proposed where populations affect each other directly or indirectly via populations on the same trophic level (5). It is useful to be precise about which type of process is envisaged when competition is invoked. Because such a formalism already exists in the ecological literature, it makes sense to adapt it to the special situation of cells competing within an organism. To go further and ask ''does the formalism fit the data?'' it becomes necessary to express the formal model in mathematical equations and see if those equations behave like the populations that we observe. This is the strategy we have adopted in the work presented here. We have developed formal schemes for competition among B lymphocytes that give rise to two models; one of competition in its broadest sense and one that is specifically a model of resource competition. We show detailed comparisons of our first model with our data on B lymphocyte population dynamic...

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“…If the Ag is present in the bone marrow, newly generated B cells can be deleted (7), rendered anergic (8 -11), or subjected to receptor editing (12,13). In contrast, if these high affinity B cells encounter the autoantigen in the periphery, they are deleted (14,15). Murine models expressing tg BCR with moderate affinity for soluble autoantigens were also studied in the case of rheumatoid factors (RF) (16) and single-stranded DNA (11); the models indicated that anergy is the main tolerance mechanism.…”

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confidence: 99%

Natural Autoreactive B Cells in Transgenic Mice Reproduce an Apparent Paradox to the Clonal Tolerance Theory

Koenig-Marrony

Soulas

Julien

et al. 2001

The Journal of Immunology

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Naturally occurring autoreactive B cells are thought to be physically eliminated or rendered functionally silent through different mechanisms of tolerance. However, multireactive low affinity natural autoantibody-producing B cells seem to escape these mechanisms in normal adults and could constitute the B cell pool from which pathological autoantibodies can emerge. To analyze this apparent paradox to the clonal tolerance theory, we have made two transgenic mouse lines (μk, μ∂k) producing a natural low affinity multireactive human autoantibody. These models enable us to test both the central tolerance mechanisms (reactivity with single-stranded DNA) and the peripheral tolerance mechanisms after Ag administration. Not only are the multireactive B cells not deleted in the bone marrow, they circulate and remain in the periphery even after the prolonged administration of Ag, the presence of membrane IgD increasing the number of mature autoreactive B cells. Self-reactive B cells are shown to be autoantigen ignorant both in vivo and in vitro, but they are not anergic because they can be easily activated through both B cell receptor-dependent and -independent pathways. Thus, these mouse lines reproduce an apparent paradox to the clonal tolerance theory meriting further investigation of the biological significance of this phenomenon.

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Soluble antigen can cause enhanced apoptosis of germinal-centre B cells

Cited by 290 publications

References 30 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

Resource competition as a mechanism for B cell homeostasis

Natural Autoreactive B Cells in Transgenic Mice Reproduce an Apparent Paradox to the Clonal Tolerance Theory

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