Pathogenesis of systemic lupus erythematosus revisited 2011: End organ resistance to damage, autoantibody initiation and diversification, and HLA-DR

• Published in: Journal of autoimmunity Vol. 37; no. 2; pp. 104 - 112
• Main Authors: Fu, Shu Man, Deshmukh, Umesh S., Gaskin, Felicia
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.09.2011; Elsevier
• Subjects: Allergy and Immunology; Animals; Antibody Diversity; Autoantibodies - genetics; Autoantibodies - immunology; B-Lymphocytes - immunology; Biological and medical sciences; Cross-reactive T and B cell epitopes; Epitope spreading; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene-Environment Interaction; Genetic Predisposition to Disease; History, 20th Century; History, 21st Century; HLA-D and end organ damage; HLA-DR Antigens - genetics; HLA-DR Antigens - immunology; Humans; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - history; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - physiopathology; Medical sciences; Models, Immunological; Multiple Organ Failure; Pathogenesis; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Systemic lupus erythematosus; T-Lymphocytes - immunology; Cross-reactive T and B cell epitopes; Epitope spreading; Systemic lupus erythematosus; Pathogenesis; HLA-D and end organ damage; Autoimmunity; HLA-System; Skin disease; Antigenic determinant; Class II histocompatibility antigen; Autoimmune disease; HLA-DR-Locus; Immunology; Systemic disease; T-Lymphocyte; Cross reaction; Initiation; Immunopathology; Connective tissue disease; Antibody; Autoantibody; B-Lymphocyte; Diversification; Resistance; Lesion; Organ
• DOI: 10.1016/j.jaut.2011.05.004
• ISSN: 0896-8411; 1095-9157

Systemic lupus erythematosus (SLE) is a multi-system disorder resulting from interaction of susceptibility genes and environmental factors. SLE has protean clinical presentations at the initial diagnosis and relapses. SLE-related autoantibodies have unique patterns of diversification to linked proteins such as the snRNP particle and the diversification takes years before clinical diagnosis. There are both clinical and experimental evidence to indicate that separate genes contribute to autoimmunity and end organ damage and these genes are independent and interactive. Among the numerous susceptibility genes, HLA-D complex is dominant. Results from the authors’ laboratories led us to postulate a unified hypothesis for SLE pathogenesis. This hypothesis states that SLE-autoantibodies are initiated by environmental T cell epitope mimics of the SLE-related autoantigens in hosts with susceptible HLA-D alleles. These autoantibodies diversify over a period of years due the accumulation of cross-reactive T cells. This process ultimately leads to the generation of organ specific autoantibodies and autoreactive effector T cells due to the polyreactive nature of T and B cell receptors from hosts with susceptibility genes to end organ damage, resulting in protean clinical presentations. This hypothesis accounts for most of the features unique to SLE and has clinical implications as to how patients should be treated.