Autoimmunity: from black water fever to regulatory function.

Autoimmunity is a field that has only been around for a little over a century. Initially, it was thought that autoimmunity could not happen, that the body would never turn on itself (i.e. "horror autotoxicus"). It was only around the First World War that autoimmunity was recognized as the pathogenesis of various diseases, including rheumatoid arthritis. The discovery of Compound E led to successful treatment of patients with autoimmune diseases, but it was not till later that the adverse effects of this class of drugs were elucidated. The "modern" age of autoimmunity began around 1945 with the description of blackwater fever, and most of the subsequent research on hemolytic anemia and the role of an autoantibody in its pathogenesis led to a description of the anti-globulin reaction. The lupus erythematous (LE) cell was recognized in the mid-1940s by Hargreaves. His research carried on into the 1960s. Rheumatoid factor was also first described in the 1940s as yet another serum factor with activity against globulin-coated sheep red blood cells. The concept of autoimmunity really gained a foothold in the 1950s, when autoimmune thyroid disease and idiopathic thrombocytopenia were first described. Much has happened since then, and our understanding of autoimmunity has evolved now to include mechanisms of apoptosis, signaling pathway derangements, and the discovery of subsets of T cells with regulatory activity. The modern day study of autoimmunity is a fascinating area of research, and full understanding of the pathogenesis of autoimmune diseases is far from being completely elucidated.

"The Leeds Idea": an historical account of the spondarthritis concept.

In the 1960s, Professor Verna Wright became increasingly interested in possible relationships between certain seronegative "variants of rheumatoid arthritis", as they were then generally known. At the Rheumatism Research Unit, a department within the division of medicine at Leeds University, he gathered around him a succession of research workers, whom he inspired to study aspects of these relationships. The focus was on family studies, as it was thought that genetic factors could be important. The striking association previously noted between sacroiliitis or full-blown ankylosing spondylitis and several of these disorders to be studied - e.g., psoriatic arthritis, ulcerative colitis, and the arthritis associated with Crohn's disease - was to be central for each of these studies. As a provisional collective name for these possibly related conditions, the term "Spondarthritides" was chosen. These were the days before HLA B27, and so the research tools were simply clinical, radiological (for sacroiliitis) and serological (for rheumatoid factor). The research programme confirmed not only links between the primary disorders with ankylosing spondylitis, but also links between the disorders themselves. Over subsequent years, the spondarthritis concept (dubbed by some "The Leeds Idea") has gained further strength from HLA studies internationally. And membership of the group of conditions fulfilling spondarthritis criteria has grown substantially. It is hoped that this now consolidated framework of spondylitis-related entities will pave the way for further research, with exciting prospects of gene-based prevention and/or cure through the increasing sophistication of molecular biology.

The history of rheumatoid factor.

The events that led to identification of rheumatoid factor are narrated, and the respective contributions of the researchers who worked to achieve this goal are clarified. Changes that have occurred over time in concepts concerning the clinical significance and pathophysiologic role of rheumatoid factor are briefly summarized.

Development of rheumatoid factor research through 50 years.

The discovery of Waaler in 1937 initiated fruitful research on RFs. It was not until the early 1960s that investigators in the field agreed that RFs are antibodies to Fc fragment of IgG. Separate factors combining with human and rabbit IgG and a factor combining with both these IgGs were at first demonstrated by mixed agglutination and then by separation through IgG-conjugated columns. Only RF combining with native autologous IgG should be considered an autoantibody. Other RFs are allo- or heteroantibodies. Cross-reacting RFs that combine with IgG of various species or with IgG and antigens of cell nuclei are of considerable interest. This cross-reactivity may be due to a combining site interacting with shared epitopes or otherwise to multispecificity of the RF molecule in that it has separate or partially overlapping combining sites acting on different epitopes. Experimental studies conducted since the mid-1950s showed that formation of RFs may be elicited by altered autologous IgG. Under natural conditions such alteration was shown to result from interaction of IgG antibody with its corresponding antigen and RF in many infectious diseases and possibly also in rheumatoid arthritis appeared to result from stimulation by immune complexes. More recently alterations of IgG by its reaction with microbial Fc receptors as well as non-specific polyclonal stimulation of B cells were shown to play a role in RF formation. RFs have been implemented in the pathogenicity of rheumatoid arthritis. Recent studies on dispersion of immune complexes in tissue sections by aggregated IgG showed that self-polymerization of IgG RFs results in formation of glomerular deposits in various nephropathies.

A century of American rheumatology.

In reviewing the development of rheumatology in the United States, I begin with the understanding of rheumatic diseases in the previous century and then consider subsequent scientific and organizational events that were important in the creation of rheumatology as a recognized medical specialty. The perception had to evolve that rheumatic diseases can be analyzed beyond their gross clinical description and that effective therapy is possible. The virtual coincidence of the discoveries of the rheumatoid factor, the lupus erythematosus cell, and cortisone in 1948-49 satisfied these requirements. The publicity that was generated is considered to have been most responsible for the unusually abrupt recognition of rheumatology as a specialty.