Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires.

Abstract

Immunological self-tolerance is ensured by eliminating or inhibiting self-reactive lymphocyte clones, creating physical or functional holes in the B- and T-lymphocyte antigen receptor repertoires. The nature and size of these gaps in our immune defenses must be balanced against the necessity of mounting rapid immune responses to an everchanging array of foreign pathogens. To achieve this balance, only a fraction of particularly hazardous self-reactive clones appears to be physically eliminated from the repertoire in a manner that fully prevents their recruitment into an antimicrobial immune response. Many self-reactive cells are retained with a variety of conditional and potentially flexible restraints: (i) their ability to be triggered by antigen is diminished by mechanisms that tune down signaling by their antigen receptors, (ii) their ability to carry out inflammatory effector functions can be inhibited, and (iii) their capacity to migrate and persist is constrained. This balance between tolerance and immunity can be shifted, altering susceptibility to autoimmune disease and to infection by genetic or environmental differences either in the way antigens are presented, in the tuning molecules that adjust triggering set points for lymphocyte responses to antigen, or in the effector molecules that eliminate, retain, or expand particular clones.

Loss of a single allele of SHIP exacerbates the immunopathology of Pten heterozygous mice

“…5,6 It is well established that the strength of antigen receptor signals is a key determinant in tolerance induction, as it dictates the positive and negative selection of B and T cells. 7 As the proteins involved in antigen receptor signalling must operate within complex biochemical pathways, it is plausible that quantitative or qualitative perturbations owing to heterozygosity of multiple genes might have additive or synergistic effects with respect to immune regulation. In keeping with this notion, studies of compound heterozygote mice have revealed the importance of threshold levels of proteins in controlling immune responses.…”

Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma

“…3 Cell apoptosis is one of the mechanisms involved in the control of T-cell homeostasis, 4 causing the deletion of autoreactive T cells. 5 Most T cells in the airways of untreated asthmatic patients are not apoptotic. 6 Moreover, in patients with asthma, peripheral blood T cells (PBTs) are characterized by an increased activation state and by reduced apoptosis.…”

Transgenic Expression of a Human Polyreactive Ig Expressed in Chronic Lymphocytic Leukemia Generates Memory-Type B Cells That Respond to Nonspecific Immune Activation

“…Although BCR expression is critical for B cell differentiation (37,38), engagement of the BCR with self-Ag can profoundly influence the fate of B cell development. The ultimate fate of an autoreactive B cell depends upon several factors, such as the form and location of Ag, Ag concentration, structure, the affinity of the expressed BCR, and the availability of T cell helper activity (34,36). Mice that are made transgenic for both Ig with high Ag-binding affinity and specific Ag, experience either anergy or deletion of B cells that expressed the Ig transgenes, unless they undergo Ig receptor editing to express BCR that no longer react with the transgenic Ag (39).…”