Researchers have puzzled for decades over why many autoimmune diseases like systemic lupus erythematosus (SLE) disproportionately affect women. Until now the population in whom to address this essential clue to autoimmunity, children with autoimmune disease who are progressing through puberty, has not been available in sufficient numbers for study. We will take advantage of an alliance of pediatric rheumatology investigators in the North America (Childhood Arthritis and Rheumatology Research Alliance, CARRA) to facilitate research in this rare population. We propose a 5-yr. multi-center longitudinal prospective study of variations in SLE disease activity and its characteristic immunologic aberrations, examining children with SLE as they progress through the orderly sequence of hormone production seen in puberty. We formed a collaboration of 17 CARRA investigators who will enroll children with SLE as they near puberty (90 girls, 25 boys). We will use a generalized linear model to examine disease flare rates, tracking flares for each stage of puberty. We will collect clinical data, blood, RNA and urine serially to identify hormones that correlate with increased flare rates. To understand the causes of sex differences in autoimmunity in general, and SLE in specific, we will measure immunologic factors important in lupus pathogenesis, and will correlate changes in these immunologic parameters with pubertal progress and with the specific hormones produced at times of immunologic change. We will study gene expression using blood microarray to learn how pubertal hormones affect the immunologic milieu in pubertal children with SLE, and to identify changes in the interferon signature known to correlate with disease activity. To do this, we are partnering with Dr. Virginia Pascual, who has extensively studied gene expression in a variety of diseases including SLE. The proposed study will focus on the hormones most different between the sexes in adults and late adolescents: androgenic steroids and estrogen, leptin and prolactin. The last three hormones rise in both sexes early in puberty then diverge in boys and girls, mirroring the incidence of SLE in adolescents. Androgens rise through puberty in males as SLE incidence falls in boys. Stored samples will allow other hormones and disease markers to be examined in future studies by us and by other investigators. This research effort will generate a large longitudinal database that will detail the biologic features of early SLE in this important cohort. We will also create a tissue repository of DNA and serial samples of serum, plasma, urine, and RNA from this precious cohort that will be a resource to investigators for years. This will be the first large cohort of boys with lupus studied, and comparison of their disease and immunologic features to those of girls should lead to important insights into autoimmunity. Understanding the differences in autoimmune disease risk in men and women, and how hormones affects autoimmunity may lead to novel hormone-based therapies, and insights into this essential riddle in autoimmune disease.
This 5-year prospective longitudinal study will address a crucial question in autoimmunity: why are women at vastly greater risk for autoimmune diseases than men? We will do this using a rare disease population that is available only through collaboration of a large number of investigators: children with systemic lupus erythematosus who are entering puberty; an important informative time period. We will examine disease flares during the course of puberty; correlating disease activity and flare rates with stage of sexual development; hormones actively secreted at the time; and immunologic changes that are taking place. Although focused on a single autoimmune disease; systemic lupus erythematosus; this study should advance the field of autoimmunity in general by determining the critical hormones that expressed differently in males and females; and how they affect autoimmune diseases.
