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Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus (LE) and other autoimmune and dermatologic conditions. Photosensitivity is associated with increased keratinocyte apoptosis, but mechanisms that modulate keratinocyte apoptosis that are dysfunctional in photosensitivity are poorly understood. Here, we identify a Langerhans cell (LC)-keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. LCs express EGFR ligands and ADAM17, the metalloprotease that activates EGFR ligands. LC ADAM17 is required for skin protection and is activated by UVR, suggesting that LCs protect by providing activated EGFR ligands to keratinocytes. Photosensitive systemic LE (SLE) models have reduced LC ADAM17, and topical EGFR ligand reduces photosensitivity. Human SLE skin shows reduced EGFR activation. Together, our data identify a new tissue protective function for LCs, delineate a novel mechanism that limits skin injury, and suggest EGFR stimulation as a treatment for photosensitivity and possibly other dermatologic conditions.
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Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus and other autoimmune and dermatologic conditions, but the mechanistic underpinnings are poorly understood. We identify a Langerhans cell (LC)-keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. We show that the absence of LCs in Langerin-diphtheria toxin subunit A (DTA) mice leads to photosensitivity and that, in vitro, mouse and human LCs can directly protect keratinocytes from UVR-induced apoptosis. LCs express EGFR ligands and a disintegrin and metalloprotease 17 (ADAM17), the metalloprotease that activates EGFR ligands. Deletion of ADAM17 from LCs leads to photosensitivity, and UVR induces LC ADAM17 activation and generation of soluble active EGFR ligands, suggesting that LCs protect by providing activated EGFR ligands to keratinocytes. Photosensitive systemic lupus erythematosus (SLE) models and human SLE skin show reduced epidermal EGFR phosphorylation and LC defects, and a topical EGFR ligand reduces photosensitivity. Together, our data establish a direct tissue-protective function for LCs, reveal a mechanistic basis for photosensitivity, and suggest EGFR stimulation as a treatment for photosensitivity in lupus erythematosus and potentially other autoimmune and dermatologic conditions.

Background There are no longitudinal studies regarding thelong term cardiac health of children with cardiac manifestations of neonatal lupus (NL). This study was performed toevaluate risk factors for morbidity and provide evidence-basedguidance regarding the course of cardiac NL.Methods Echocardiograms throughout life were evaluated in240 individuals born with cardiac NL from the ResearchRegistry for Neonatal Lupus: 142 were available from ages 0 1 years, 174 from ages 1 17 years, and 65>17 years. A composite adverse outcome defined as qualitatively decreased leftventricular (LV) function or concurrent use of cardiac medications was assessed. Aortic dilation (root or ascendingaorta z-score >2.0) was also recorded. Analyses were performed to associate the composite adverse outcome and aorticdilation with maternal medications, pacing, and fetal diseasestatus, including a severity score based on mortality risk factors such as lower fetal heart rate and extranodal disease.Results The composite adverse outcome for cardiac dysfunctionwas identified in 21.1% of echos in children ages 0 1, 13.2% ages1 17% and 29.2% ages>17. In 89 children in which echos wereavailable at ages 0 1 and 1 17, 6/16 with dysfunction at ages 0 1were also affected at ages 1 17, while 10 reverted to normal.Among those without dysfunction at age 0 1, 8/90 developednew worsening of cardiac function during age 1 17. In 35 caseswith echos at ages 1 17 and >17, 3/3 cases with dysfunction atage 1 17 were also affected at >17, and 2/32 developed new dysfunction in adulthood. Cardiac dysfunction was significantly associated with number of years paced at all ages (p<0.001, 0.001,<0.001). A lower fetal ventricular heart rate at the first time ofheart block detection was associated with cardiac dysfunction age0 1 and >17 (p=0.048, 0.005 respectively) and lowest heart ratein utero associated with dysfunction at age <1 and 1 17(p<0.001, 0.015). Fetal extranodal cardiac disease was associatedwith dysfunction in ages1 17 and >17 (p=0.026, 0.023). Higherfetal severity score associated with postnatal dysfunction in ages0 1 and 1 17 groups (p=0.013, 0.001). Aortic dilation waspresent in 13.4% at ages 0 1% and 14.9% at ages 1 17, butat >17, dilation only occurred in 9.2%. There was no associationof postnatal cardiac dysfunction or aortic dilation with maternalmedication use, maternal rheumatic disease, fetal age at heartblock detection or gestational age of birth.Conclusions Cardiac dysfunction in the first year normalizesby later childhood in the majority of cases, possibly due tothe short term effects of cardiac pacing or resolution ofinflammation with the clearance of maternal autoantibodies.However, new onset dysfunction can occur after the first yearof life. Aortic dilation can continue for longer periods, butmay decrease in frequency with age. Nevertheless, cardiac dysfunction is present in roughly 30%, and in adulthood thereare associations with fetal extranodal disease and heart rate atdetection. Patients who develop morbidity in utero may havesubclinical damage or be more susceptible to future insultsthat manifest later in life, which can be exacerbated by prolonged pacing. Close monitoring and aggressive treatment ofearly extranodal disease in cardiac NL may have long termbenefit in preventing subsequent morbidity