Origins of systemic lupus erythematosus: genes, environment, and host immune response

Systemic lupus erythematosus (SLE) appears to be a consequence of immune dysfunction mediated by errors in self-recognition that cause autoimmunity. A component of the environmental origin of SLE was suggested by data showing that the earliest autoantibody recognition structure in the anti-Sm response was very similar to and cross-reacted with Epstein–Barr virus nuclear antigen-1 (EBNA-1). Subsequently, an earliest epitope of the anti-Ro system has been identified and this structure also imitates a structure of EBNA-1. The initial structures bound by anti-Sm and anti-Ro generate SLE-like autoimmunity in animals immunized with these peptides. In pediatric SLE, anti-EBNA-1 is more frequently present and its fine specificity is qualitatively more diverse in SLE than in normals. Anti-EBNA-1 responses also precede the onset of SLE. The well-known association of Epstein–Barr virus infection with SLE may be present because of the particular immunoregulatory details of the anti-EBNA-1 response in SLE patients. The genetic origins of SLE are the other major component of SLE etiology. At this time, to our knowledge, 11 genetic linkages have been both established and independently confirmed. For three of these linkages, an associated candidate gene is known. They are located in the human genome as follows: 1q23 (FcγRIIIA), 1q41, 2q34, 2q37 (PDCD-1), 4p16, 5p15, 6p21 (HLA-DR), 10q22, 11p13, 11q14, and 16q13. Genetic effects tend to concentrate in the major human racial groups (e.g. 1q23, 2q34, 11p13, and 11q14 dominate in African-Americans). Some clinical and laboratory features of SLE have powerful genetic influences and can be used to generate genetic homogeneity (e.g. nephritis with 2q34 and 10q22, hemolytic anemia with 11q14, and pedigrees multiplex for self-reported rheumatoid arthritis with 5p15). The origins of SLE are obviously complicated and involve multiple influences from the environment, the host immune response, perhaps involving EBNA-1, and the genetic constitution of the patient.