Direct TB Cell Interactions Receptormediated Contacts

During normal immune responses involving T-dependent antibody production, T cells are primed with antigen by antigen-presenting cells (APC), such as dendritic cells, in the T-cell zone of the secondary lymphoid organs [4] (Fig. 5.1). These activated T cells migrate to the follicular border where they interact, via MHC class II as well as costimulatory molecules such as CD28 and CD40, with activated B cells that have also encountered antigen, leading to B-cell activation, follicular entry, and germinal center (GC) formation. These transient structures foster somatic hypermutation and immunoglobulin isotype class switching, allowing the generation of high-affinity antibodies.

In model animal systems, self-reactive B cells are usually excluded from the follicular microenvironment due to (1) the lack of activated self-reactive T cells; (2) death via CD95-induced apoptosis; and/or (3) the lack of costimulatory mole-

naive autoreactive ( B Beeil

High-affinity, autoreactive plasma cell or memory B cell switching. Somatic hyiermutation ïturation

Autoantigen

Complex

s

Costimulatory

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molecules

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B-celi

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receptor

(BOR)

T-cell

receptor

(TOR)

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Peptide-

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MHC class II

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Fig. S.I (legend see page 87)

cule-mediated survival signals [5-7]. In autoimmune diseases, the activation and maturation of autoreactive B cells presumably reflect the loss of such control mechanisms. Autoantibodies in autoimmune diseases characteristically are iso-type-switched and display high affinity for autoantigen, implicating somatic hypermutation and affinity maturation in T-dependent germinal centers [8-10]. In addition, abnormal spontaneous germinal center formation has been observed in lupus-prone mice, including (NZBxNZW) F1, MRL/+, MRL/lpr, and BXSB [11]. Consequently, many studies have investigated the role of costimula-tory molecules in disease pathogenesis, particularly in terms of their role in germinal center formation.

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