Abstract
Cutaneous lesions feature prominently in lupus erythematosus (LE). Yet lupus and its cutaneous manifestations exhibit extraordinary clinical heterogeneity, making it imperative to stratify patients with varying organ involvement based on molecular criteria that may be of clinical value. We conducted several in silico bioinformatics-based analyses integrating chronic cutaneous lupus erythematosus (CCLE)-skin and blood expression profiles to provide novel insights into disease mechanisms and potential future therapy. In addition to substantiating well-known prominent apoptosis and interferon related response in both tissue environments, the overrepresentation of GO categories in the datasets, in the context of existing literature, led us to model a “disease road-map” demonstrating a coordinated orchestration of the autoimmune response in CCLE reflected in three phases: (1) initiation, (2) amplification, and (3) target damage in skin. Within this framework, we undertook in silico interactome analyses to identify significantly “over-connected” genes that are potential key functional players in the metabolic reprogramming associated with skin pathology in CCLE. Furthermore, overlapping and distinct transcriptional “hot spots” within CCLE skin and blood expression profiles mapping to specified chromosomal locations offer selected targets for identifying disease-risk genes. Lastly, we used a novel in silico approach to prioritize the receptor protein CCR2, whose expression level in CCLE tissues was validated by qPCR analysis, and suggest it as a drug target for use in future potential CCLE therapy.
Highlights
Lupus erythematosus (LE) is a complex [1] autoimmune disease that spans a tremendous variety of forms, degrees, and phenotype expressions ranging from relatively well-defined cutaneous manifestations to a rapidly progressive, lethal, multi-organ involvement in the systemic disease (SLE) [2, 3]
demonstrating a coordinated orchestration of the autoimmune response in CCLE reflected in three phases
identify potential key functional players associated with the skin disease
Summary
Lupus erythematosus (LE) is a complex [1] autoimmune disease that spans a tremendous variety of forms, degrees, and phenotype expressions ranging from relatively well-defined cutaneous manifestations to a rapidly progressive, lethal, multi-organ involvement in the systemic disease (SLE) [2, 3]. Cutaneous features represent a major and medically significant component of LE and are evidenced as a wide range of clinical manifestations, some of which are disfiguring and debilitating. CCLE, which encompasses discoid lupus erythematosus (DLE), represents the most common category of cutaneous lupus erythematosus (CLE). A number of trigger factors have been reported to influence the course and prognosis of cutaneous lupus including, UV light, medication, and smoking. Additional factors such as race, sex, age of onset and genetic predisposition, among others impact disease manifestation [4,5,6,7,8,9]. Susceptibility to CCLE has been linked to genes within the HLA (HLA-DQ and/or DR), as well as outside the HLA region (HSP70-1, TNF– α/β, C4 null, C2, IL-1, and IL10) [10,11,12,13,14,15,16,17,18,19] the molecular and genetic basis of disease initiation, progression, and response to treatment is poorly understood
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