A powerful role for B cells and autoantibodies in disease

In a recent Trends article in Immunology Today Stevenson and Natvig summarized data presented at the Euroconference ‘B Cells and Autoimmunity’1xAutoantibodies revealed: the role of B cells in autoimmune disease. Stevenson, F.K. and Natvig, J. Immunol. Today. 1999; 20: 296–298Abstract | Full Text | Full Text PDF | PubMed | Scopus (10)See all References1. Despite the range of topics considered, the meeting (at least as reflected in the review) fails to address some major issues concerning human autoantibodies.First, the focus of the meeting appears to have been on non-organ-specific autoimmunity. Apart from an aside that ‘some …. autoantibodies are directly pathogenic', there is no mention of IgG class autoantibodies that are responsible for organ-specific diseases, in particular, thyrotropin receptor (TSHR) autoantibodies that stimulate the thyroid (Graves' disease), acetylcholine receptor autoantibodies that interfere with neuromuscular transmission (myasthenia gravis), or desmoglein autoantibodies that induce foliaceous skin lesions (pemphigus vulgaris). A further example of this bias towards non-organ-specific autoimmunity is the suggestion of a hyperactive receptor-editing mechanism in systemic lupus erythematosus (SLE), based on the smaller proportion of somatic mutations in light chain V regions (VL) than in the partner heavy chain V regions (VH) of patients' B cells. It is overlooked that similar findings have previously been reported for several high affinity autoantibodies to a major thyroid autoantigen, thyroid peroxidase, some of which have VL in germline conformation but multiple mutations in VH (reviewed in Ref. 2xGenetic and epitopic analysis of thyroid peroxidase (TPO) autoantibodies: markers of the human thyroid autoimmune response. McLachlan, S.M. and Rapoport, B. Clin. Exp. Immunol. 1995; 101: 200–206Crossref | PubMedSee all ReferencesRef. 2). Incidentally, ‘ectopic germinal centres’ as described for rheumatoid arthritis1xAutoantibodies revealed: the role of B cells in autoimmune disease. Stevenson, F.K. and Natvig, J. Immunol. Today. 1999; 20: 296–298Abstract | Full Text | Full Text PDF | PubMed | Scopus (10)See all References1 have long been recognized in thyroid glands of patients with thyroid autoimmunity and have been used to clone thyroid autoantibodies (reviewed in Ref. 2xGenetic and epitopic analysis of thyroid peroxidase (TPO) autoantibodies: markers of the human thyroid autoimmune response. McLachlan, S.M. and Rapoport, B. Clin. Exp. Immunol. 1995; 101: 200–206Crossref | PubMedSee all ReferencesRef. 2). Similarly, acetylcholine receptor autoantibodies have been cloned from ectopic germinal centres in thymic tissue from myasthenia gravis patients.Second, and more importantly, the report fails to mention B cells as antigen-presenting cells (APCs). Such a role is increasingly being recognized in a variety of immune responses, including infections and autoimmunity. Thus, insulin-dependent (type I) diabetes mellitus (the classical T-cell-mediated autoimmune disease) fails to develop in B-cell-deficient nonobese diabetic (NOD) mice3xB lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new ‘speed congenic’ stock of NOD Igm null mice. Serreze, D.V. et al. J. Exp. Med. 1996; 184: 2049–2053Crossref | PubMedSee all References3 because B cells are required to present islet cell autoantigens to T cells4xB lymphocytes are crucial antigen-presenting cells in the pathogenic autoimmune response to GAD65 antigen in nonobese diabetic mice. Falcone, M. et al. J. Immunol. 1998; 161: 1163–1686PubMedSee all References4. Besides capturing minute amounts of antigen, antigen-specific B cells influence the peptides that are made available for presentation to T cells5xModulation of antigen processing by bound antibodies can boost or suppress class II major histocompatibility complex presentation of different T cell determinants. Simitsek, P.D. et al. J. Exp. Med. 1995; 181: 1957–1963Crossref | PubMed | Scopus (219)See all References5. Indeed, it has been suggested that processing of antibody–antigen complexes may expose ‘cryptic’ T-cell epitopes and lead to autoimmunity6xHow can cryptic epitopes trigger autoimmunity?. Lanzavecchia, A. J. Exp. Med. 1995; 181: 1945–1948Crossref | PubMed | Scopus (201)See all References6. Moreover, the influence of antibodies on the peptides presented to T cells may be responsible for restricted epitopic recognition, a phenomenon well known for several human autoantibodies. By contrast, antibodies induced using antigen and adjuvant interact with a wide range of epitopes. Restricted recognition by spontaneously arising human autoantibodies versus diverse epitopes in experimentally immunized animals is observed for autoantibodies to thyroid autoantigens2xGenetic and epitopic analysis of thyroid peroxidase (TPO) autoantibodies: markers of the human thyroid autoimmune response. McLachlan, S.M. and Rapoport, B. Clin. Exp. Immunol. 1995; 101: 200–206Crossref | PubMedSee all References, 7xRestrictions in the response to autologous thyroglobulin in the human. Nye, L. et al. Clin. Exp. Immunol. 1980; 41: 252–263PubMedSee all References and the acetylcholine receptor8xEpitopes on human acetylcholine receptor defined by monoclonal antibodies and myasthenia gravis sera. Heidenreich, F. et al. Autoimmunity. 1988; 1: 285–297Crossref | PubMed | Scopus (30)See all References8.The rationale for studying autoantibodies is often limited to their role as markers and, consequently, is regarded as inferior to the part played by T cells. However, as APCs, B cells are beginning to strike back. Besides capitalizing on this powerful role, B cell ‘autoimmunologists’ should encompass the fascinating spectrum of autoantibodies displayed in both organ-specific and non-organ-specific autoimmunity.