Annual Review of Immunology - Volume 11, 1993

The past five or six years has seen a resurgence of interest in immunological memory. Areas in which important advances have been made of late or in which problems in understanding persist are covered here: (i) Selection of virgin B cells for entry into the peripheral pool. (ii) Expression of immunoglobulin isotypes and other markers on memory B cells. (iii) Development of memory B cells as a separate lineage from primary response B cells. (iv) Sites of production of memory B cells. (v) Signals that rescue mutating B cells in germinal centers, forming the basis of affinity selection, and programming further differentiation. (vi) The myriad markers of memory T cells, in particular CD45R isoforms. (vii) Selective migration pathways of memory T cells and its possible molecular basis. (viii) The lifespan of memory cells and factors that influence their long-term survival. The data accumulated during this period which have vastly increased our understanding of memory have at the same time highlighted unresolved problems that could block further progress in the field. The thorny question that we cannot at present answer is: How does a memory cell differ from an activated cell and, in the case of T cells, from an effector cell? The problem bears on the interpretation of any study that sets out to correlate memory phenotype with memory function. Immunologists may have donned an intellectual straitjacket in their search for the memory cell.

In autoimmune diseases, autoantibodies may be the actual pathogenetic agents of the disease, the secondary consequences of tissue damage, or the harmless footprints of an etiologic agent. Establishing a pathogenetic role for autoantibodies requires that they meet stringent criteria. It appears that the location of the presumptive target antigen most critically influences the pathogenetic potential of autoantibodies. Autoantibodies directed against cell surface targets, such as hormone receptors, are clearly pathogenetic; those directed against extracellular targets, such as circulating molecules or extracellular matrix, may or may not cause any damage. Those apparently directed against intracellular targets are usually not pathogenetic unless it can be clearly demonstrated (a) that the antigen is released from within the cell so that it can bind onto a cell surface receptor or other extracellular location, such as proteinase 3; (b) that the antigen moves to an aberrant site on the cell surface, such as, perhaps, the small ribonucleoprotein antigen Ro; or (c) that a cross-reactive molecule, the actual target, such as the membrane ribosomal P-like protein, is at an accessible location.