title: Mannose binding lectin (MBL) polymorphisms associated with low MBL production in patients with dermatomyositis.
abstract: One theory for the pathophysiology of photosensitive autoimmune skin diseases is that photoinduction of tumor necrosis factor alpha (TNFalpha) secretion leads to keratinocyte apoptosis and translocation of previously sequestered cellular antigens that then activate the immune system. We previously found an association of the overproducing TNFalpha-308 A variant with adult dermatomyositis and with subacute cutaneous lupus erythematosus. Here we focused on mannose binding lectin (MBL), which is one of several proteins involved in clearance of apoptotic cells and could thereby lessen photosensitive autoimmunity. We examined three variant MBL polymorphisms associated with decreased MBL protein (Asp54, Glu57, and the LX promoter polymorphism) in adult dermatomyositis, subacute cutaneous lupus erythematosus, and discoid lupus, and controls. The variant Asp54 allele was positively associated with adult dermatomyositis in a dose-responsive fashion (p=0.0004), as was the Glu57 allele (p=0.004). None of the three variant MBL alleles considered individually was significantly associated with either subacute cutaneous lupus erythematosus or discoid lupus. In adult dermatomyositis patients homozygous for the wild-type TNFalpha-308G allele (GG), i.e., presumably without elevated TNFalpha production, 69% had at least two of the MBL polymorphisms, versus 20% of healthy GG controls (p=0.0011). Combinations of low-producing MBL variants were over-represented in adult dermatomyositis in a dose-responsive fashion (p=0.0002). In adult dermatomyositis patients with one variant TNFalpha-308 A allele (GA), 46% had at least two MBL polymorphisms, versus 7% of GA controls (p=0.0077). Thus, low-producing MBL genes are very strongly associated with adult dermatomyositis. Our model is that genetic polymorphisms leading to overproduction of apoptotic keratinocytes and then impaired clearance of these cells contribute to the pathogenesis of adult dermatomyositis, a photoinduced autoimmune skin disease.
authors.affiliation: Philadelphia V.A. Medical Center Department of Dermatology Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, PA 19104, USA. werth@mail.med.upenn.edu
authors.forename: Victoria P
authors.initials: VP
authors.lastname: Werth
authors.forename: Jesse A
authors.initials: JA
authors.lastname: Berlin
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Callen
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Mick
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Sullivan
mesh_terms: D017209:Apoptosis; D003882:Dermatomyositis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous / Q000235:genetics; D037601:Mannose-Binding Lectin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011401:Promoter Regions, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D037601:Mannose-Binding Lectin; D014409:Tumor Necrosis Factor-alpha