ARRA IMPACT REPORT:
Public Health Burden
Lupus (systemic lupus erythematosus) is a serious and potentially fatal inflammatory autoimmune disease with diverse manifestations. It can affect many parts of the body, including the joints, skin, kidneys, heart, lungs, blood vessels, and brain. An estimated 240,000 Americans have lupus. The disease tends to be more common and generally more severe in patients of African, Hispanic, and Asian descent than of European descent, and afflicts women at a rate nine times that of men.
Diagnosis and Disease Monitoring
Symptoms and disease course vary widely across lupus patient populations. Diagnosis and prediction of patient outcomes are hampered by the complexity of the disease. Genetic analyses provide insight into disease susceptibility and processes contributing to disease onset and progression. Through ARRA support, the following research projects were conducted.
Genetic analyses were conducted on DNA samples from lupus patients from across North and South America for greater understanding of the differences in disease severity that might be influenced by their ancestral backgrounds, including Hispanic (defined as Amerindian in this study), European, Asian, and African origins. In comparison with a European cohort, a greater degree of Amerindian genetic ancestry was associated with a higher risk for early disease onset and lupus-associated kidney disease, as well as protection against photosensitivity and oral ulcers. Lower socioeconomic status in this patient population may contribute to the severe clinical manifestations.1
Additional studies in lupus patients with diverse ethnic backgrounds have revealed new disease-associated gene variants that may affect immune function.2
Lupus patients are often more susceptible to infections, primarily due to immunosuppressive treatments, such as the steroid prednisone, and other underlying abnormalities in their immune function: Seasonal influenza can lead to severe outcomes in the general U.S. population, and lupus patients may be more vulnerable. In an evaluation of the effects of influenza vaccination, African American lupus patients were more likely to have strong antibody responses than their Caucasian counterparts, suggesting a higher degree of protection against infection; this may be due to immune system gene variants. Patients on prednisone had notably weaker antibody responses to influenza vaccination.3
Members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA), a consortium of North American pediatric rheumatology researchers, developed treatment plans for initial immunosuppressive treatment of children with newly-diagnosed lupus nephritis, a severe kidney disorder: Lupus nephritis is also a risk factor for permanent organ damage in pediatric lupus. These protocols can also be used for future research to evaluate therapies for effectiveness and toxicity.4
Understanding Disease Development
The cause of lupus is complex and poorly defined, and appears to involve interplay between genetic predisposition and environmental triggers. Identifying the gene defects associated with lupus, and the potential impact on immune dysfunction and inflammation, may guide the development of new treatments. Examples of ARRA supported projects include the following.
A study of lupus patients from five ethnic populations revealed variants in the gene which encodes the protein A20, an important regulator of immune function; mice lacking A20 develop systemic organ inflammation and a lupus-like disease: These gene variants were strongly associated with lupus in patients of European and Korean descent, but were less frequent in African American, African American-Gullah (from the Sea Islands of South Carolina), and Hispanic patients. The results also indicated alterations in A20 that could affect its ability to control inflammation. The findings represent a significant step forward in unraveling the causal genetic variants for lupus, with potential implications for differences in disease course and therapeutic response across the patient population.5
The subtypes of T cells, white blood cells related to immune function, have diverse functions: T helper 17 (Th17) cells produce interleukin 17, a molecular messenger that induces tissue inflammation and autoimmune diseases. In contrast, regulatory T cells suppress undesirable immune responses and play a protective role in autoimmune diseases. Smad3, a protein that regulates gene expression, was shown to be important in directing the choice of developmental pathways to Th17 versus regulatory T cells. Mice lacking Smad3 have fewer regulatory T cells and more Th17 cells, suggesting that treatment targeting Smad3 could shift the balance from disease-associated inflammatory T cells to protective T cells.6
Contributing NIH Institutes & Centers
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)