Immune regulation in adjuvant disease and other arthritis models: relevance to pathogenesis of chronic arthritis.

Experimental models of arthritis and their human counterparts fall into three distinct classes: (a) responses of T cells to disseminated microbial antigens (Ags) as such; (b) responses of T cells to cartilage autoAgs; and (c) responses of T cells to major histocompatibility complex (HLA-B27, DRB1) or other membrane components (LFA-1) expressed on bone marrow-derived cells. The primary immune response is driven, in naturally occurring disease, by microbial infection, e.g. with streptococci, enteric gram-negative rods or spirochetes, or is experimentally induced with mycobacterial and other adjuvants. The response to cartilage components, such as collagen type-II and various proteoglycans, may be driven by cross-reactive microbial Ags, heat shock proteins (HSPs) in particular, or the adjuvant effect of intense primary joint inflammation, as in rheumatoid arthritis and the spondyloarthropathies. Adjuvant disease appears to be purely T-cell-mediated, whereas both T cells and antibody play a role in collagen and many other forms of arthritis. Experimental evidence suggests a pathogenetic role for T-cell receptor gammadelta T cells in some lesions. Arthritis may be regulated by microbial and tissue HSPs, when these are administered by a nonimmunizing route or as altered peptide ligands, by anti-idiotypic responses that block the action of effector T cells, and by competing Ags. Immune regulation involving natural killer (NK), NK T and certain subsets of gammadelta and alphabeta T cells, which may affect the occurrence, localization and character of this group of diseases, presents a challenge for further investigation.

Thymus and tolerance. Is regulation the major function of the thymus?

This paper will serve as a contribution to the current reassessment of the relative roles of clonal selection and regulation in specific immunologic tolerance. We review basic studies in the Waksman laboratory that first established the importance of the thymus in tolerance and the possible contribution of regulatory cells generated in the thymus to self-tolerance. Experimental evidence is presented to suggest that there exists a wide range of immunoregulatory mechanisms, many of which deserve more intensive investigation in relation to the tolerance question. These include regulation based on idiotype-specific recognition, multiple forms of immune deviation, two well-described and quite distinct forms of T-cell receptor alphabeta "suppressor cell", and several regulatory systems involving multiple cells acting in concert. We do not comment on more recently described regulatory cells, such as certain gammadelta T-cell subsets, natural killer T cells, CD4-CD8- T cells, and others. Basic studies in our laboratory and in other laboratories pointed to antigen-presenting cells (APC) generated in the thymus as possible mediators of tolerance. Certain cytokines, first described in our laboratory, including lymphotoxin and the "inhibitor of DNA synthesis" produced by T cells and interleukin-1 produced by macrophages, also may act as significant components of regulatory systems. The rapid entry of exogenous and self-antigens into the thymus and the free migration of specific regulatory T cells and of APC in both directions between thymus and periphery are also stressed.

Demyelinating disease: evolution of a paradigm.

Multiple sclerosis was at one time viewed as a spiritual (God-given) disorder; only much later was it recognized as a scarring process. With advancing scientific knowledge, it was seen as a primarily demyelinating disease, later as thromboembolic in origin, and finally as inflammatory and destructive, probably an immunologic response to exogenous (infectious) agents or to one or more autoantigens. The pathogenesis of lesions was first ascribed to antibody, later to inflammatory cells, acting via a panoply of mediators, such as cytokines, adhesion molecules, chemokines, and complement components. It is now recognized as a complex disorder, in which many genetically controlled elements interact. Research on model diseases in experimental animals, both autoimmune and initiated by viral infection, has guided research on MS and similar demyelinating disorders of the CNS and PNS.

Science training for European journalists.

"Immunology", it was stated recently in a leading European national newspaper, "is a complicated and obscure discipline...that immunologists don't understand much about themselves". Set against this background, Byron Waksman reports on a recent meeting*, which was attended by journalists and scientists from all over Europe, on the attitude of the general public towards science and the need for scientific training among journalists.

Psychoneuroimmunology.

Complex interactions among the nervous, endocrine, and immune systems have been documented and these are currently being studied at the cellular and molecular levels with ever more powerful tools. They have an important impact on diseases affecting the three systems, in particular on autoimmune and infectious diseases of the nervous system. In time neuroimmunological diseases and psychoneuroimmunological relationships may become as "respectable" as the more familiar neuroendocrine diseases and relationships.

Astrocytes: auxiliary cells for immune responses in the central nervous system?

Active and replicating astrocytes are prominent in multiple sclerosis (MS) lesions and in experimental demyelinating diseases resembling MS. As evidence is amassed supporting an autoimmune etiology for MS, the possible contribution of astrocytes as auxiliary/effector cells in the generation of tissue damage and subsequent scar formation has attracted considerable attention. A recent workshop fostered interaction between neurobiologists interested in astrocytes and investigators interested in demyelinative diseases. Key issues were attempts to relate the behavior of astrocytes in demyelinative lesions to findings in model systems in vitro, to distinguish various astrocyte functions (auxiliary, effector, scar formation) and to identify the regulatory mechanisms associated with each function.

Autoimmunity in demyelinating diseases.

Demyelinative diseases of the CNS and peripheral nervous system can be distinguished on the basis of primary mediation by antibody or T lymphocytes (or failure of the T-cell-mediated response) and on the basis of chronicity. The principal mechanisms are autoimmunization to myelin antigens after actual immunization with tissue or infection with cross-reactive viruses or, alternatively, persistent infection of the nervous system (viral or spirochetal) with an associated immune response to the pathogen.

Genetic and molecular aspects of demyelination.

Three groups of investigators came together to learn from each other in a workshop: neurologists and neuropathologists interested in the pathogenesis of multiple sclerosis (MS) and other demyelinative diseases of man and similar autoimmune and virus-induced model diseases in animals; immunologists and virologists concerned with the genetic controls found to play a role in these diseases; and geneticists and molecular biologists investigating specific gene products and their role in recognition function and cell interactions in model immunological systems.