J Immunol 2013;191:4926C39. information and a separate group with normal B-cell profiles. The former group was more serologically active and more likely to have disseminated skin lesions. Conclusion CCLE displays perturbations in B-cell homeostasis and partial B-cell tolerance breakdown. Our study demonstrates that this entity is immunologically heterogeneous and includes a disease segment whose B-cell compartment resembles SLE and is clinically associated with enhanced serological activity and more extensive skin Noopept disease. This picture suggests that SLE-like B-cell changes in primary CCLE may help identify patients at risk for subsequent development of SLE.B-cell profiling Noopept in CCLE might also indentify candidates who would benefit from B-cell targeted therapies. INTRODUCTION Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by heterogeneous clinical manifestations and the production of diverse autoantibodies resulting from defective B cell tolerance and B cell hyper-responsiveness to stimulation.1 While skin involvement is common in SLE,2 it may also be present in patients with primary chronic cutaneous lupus erythematosus (CCLE), in the absence of systemic involvement. Rabbit Polyclonal to PLD1 (phospho-Thr147) CCLE includes discoid lupus erythematosus (DLE) and other conditions that often lead to permanent skin scarring,3 Noopept and up to 20% of these patients develop SLE over several years.3C5 However, the presence of DLE in patients with SLE has been found to reduce the risk of severe systemic manifestations, including lupus nephritis.6 These findings suggest potential immunopathogenic differences across lupus categories. In SLE, B cell hyperactivity is illustrated by the diversity and abundance of autoantibodies,7 the concentration of risk alleles on B cell signalling pathways,8 and the clinical benefit imparted by anti-B cell therapies.9 10 In contrast, limited autoantibody production and poor response to B cell depletion in CCLE (relative to the dermatological improvement observed in SLE), have called into question the pathogenic role of B cells in this condition.11 12 Multiple B cell abnormalities have been consistently documented in SLE including the expansion of plasmablasts (PB), transitional and pregerminal centre cells13 14; increased IgD?CD27? double negative (DN) B cells,15 16 owing to the preferential expansion of the effector DN2 compartment,17C19 and the contraction of IgD+CD27+ USM B cells.19 Moreover, SLE is characterised by profound defects Noopept in the censoring of autoreactive B cells both centrally (antinuclear reactivity),20 21 and peripherally, as illustrated by autoreactive VH4.34 antibodies that are recognised by the rat anti-human idiotypic antibody 9G4 (9G4+),22 whose expansion is promoted by Noopept defective germinal centre censoring.23 These defects lead to the accumulation of high levels of serum 9G4+ IgG in 45%C70% of patients with SLE with very high disease specificity (>90%).24 These autoantibodies are associated with higher renal, neurological, haemato-logical and cardiovascular activity, but not skin manifestations.22 9G4+ IgG antibodies also correlate with anti-double-stranded DNA (dsDNA) IgG and contribute a substantial proportion of anti-dsDNA antibodies and a majority of autoantibodies recog-nising apoptotic cells, a major immunogenic source in SLE.22 25 In contrast to SLE, little is known about the regulation and potential role of B cells in CCLE. Similarly, little information is available regarding B cell tolerance in this condition. In this study, we compared B cell and autoantibody profiles between patients with primary CCLE and patients with SLE with and without CCLE. Our results demonstrate CCLE heterogeneity with SLE-like abnormalities in a significant fraction of patients. This profile was associated with selective breakdown of B cell tolerance and the expression of autoantibodies. We postulate that B cell profiling may help identify patients with CCLE likely to progress to SLE and more likely to respond to B cell therapies. PATIENTS AND METHODS Patient samples We collected blood samples among participants of the Georgia Organized Against Lupus (GOAL), a population-based cohort of individuals with a validated diagnosis of either SLE or primary CCLE. GOAL recruitment and data collection are described in the online supplemental methods and published elsewhere.26 Medical records review, physician assessment and picture review were conducted to validate the lupus diagnosis. Cases with a dermatologist-documented diagnosis of either DLE, lupus erythematosus panniculitis (LEP), lupus erythematosus tumidus (LET) or chilblain lupus erythematosus (ChLE) were classified as CCLE. The 1997 Revised American College of Rheumatology Classification Criteria for SLE,27 and the attending rheumatologist/dermatologist judgement.
J Immunol 2013;191:4926C39