Christopher C. Goodnow

POLYGENIC AUTOIMMUNE TRAITS : LYN, CD22, AND SHP-1 ARE LIMITING ELEMENTS OF A BIOCHEMICAL PATHWAY REGULATING BCR SIGNALING AND SELECTION

A B lymphocyte hyperactivity syndrome resembling systemic lupus erythematosus characterizes mice lacking the src-family kinase Lyn. Lyn is not required to initiate B cell antigen receptor (BCR) signaling but is an essential inhibitory component. lyn-/- B cells have a delayed but increased calcium flux and exaggerated negative selection responses in the presence of antigen and spontaneous hyperactivity in the absence of antigen. As in invertebrates, genetic effects of loci with only one functional allele can be used to analyze signaling networks in mice, demonstrating that negative regulation of the BCR is a complex quantitative trait in which Lyn, the coreceptor CD22, and the tyrosine phosphatase SHP-1 are each limiting elements. The biochemical basis of this complex trait involves a pathway requiring Lyn to phosphorylate CD22 and recruit SHP-1 to the CD22/BCR complex.

Expansion or Elimination of B Cells In Vivo: Dual Roles for CD40- and Fas (CD95)-Ligands Modulated by the B Cell Antigen Receptor

Signals from CD4+ T cells induce two opposite fates in B cells: clonal proliferation of B cells that bind specifically to foreign antigens and clonal deletion of equivalent B cells that bind self-antigens. This B cell fate decision is determined by the concerted action of two surface proteins on activated T cells, CD40-and Fas-ligands (CD40L and FasL), whose effects are switched by signals from the B cell antigen receptor (BCR). Foreign antigens that stimulate the BCR acutely cause CD40L and FasL to promote clonal proliferation. CD40L and FasL trigger deletion, however, when the BCRs become desensitized by chronic stimulation with self-antigens or when BCRs have not bound an antigen. The need for both Fas and CD40L to correctly regulate self-reactive B cell fate may explain the severe autoantibody disorders in Fas- or CD40L-deficient children.

T Cell–Mediated Elimination of B7.2 Transgenic B Cells

Transgenic mice were generated to explore the effects on lymphoid development and immune function of constitutive expression of murine B7.2 on B and T cells. The number of B lymphocytes in primary and secondary lymphoid tissues is normal in B7.2 transgenic lines expressing low levels of B7.2 on B cells, but markedly reduced in transgenic lines expressing moderate to high levels of the transgene on B cells. This reduction is not due to an intrinsic abnormality of the transgenic B cells, but is rather the consequence of an elimination by an immune mechanism requiring the engagement of CD28 on T cells. Interestingly, during cognate antigen-specific interaction with T cells in vivo, B7.2 transgenic B cells are not eliminated, but proliferate and differentiate normally. Our findings suggest that, in the absence of high affinity ligand for the TCR, the CD28-B7.2 system participates in the regulation of B cell homeostasis.

Autoimmunity: The Fas track

Abstract The discovery of mutations in the gene encoding Fas in patients with an autoimmune lymphoproliferative syndrome, and studies of Fas-deficient mice provide the first molecular view of the pathogenesis of autoimmunity.

Tolerant Autoreactive B Lymphocytes in the Follicular Mantle Zone Compartment: Substrates for Receptor Editing and Reform

Publisher Summary This chapter discusses tolerant autoreactive B lymphocytes in the follicular mantle zone compartment. The selective accumulation of tolerant lysozyme-reactive B cells in the follicular mantle zones raises questions of whether significant numbers of self-reactive B cells exist in a similar state in normal polyclonal repertoires and what possible function such cells might serve. Under normal conditions, IgD high follicular mantle zone B cells are predominantly long-lived and recirculate between follicles via the lymph and blood. Although a selected set of V genes appears to be expressed by these cells, they differ from the predominant population of antigen-expanded memory B cells in that they show little or no V gene hypermutation. One possible physiological rationale for the persistence of moderately self-reactive B cells within the follicular mantle zone is that they may help to minimize the occurrence of holes in the B cell repertoire, as might occur if all self-reactive B cells were eliminated. It is now apparent that considerable Ig diversity is generated in B cells following antigenic stimulation, by Ig gene hypermutation within germinal center reactions.