Analysis of DLA-DQB1 and polymorphisms in CTLA4 in Cocker spaniels affected with immune-mediated haemolytic anaemia

BACKGROUND: Cocker spaniels are predisposed to immune-mediated haemolytic anaemia (IMHA), suggesting that genetic factors influence disease susceptibility. Dog leukocyte antigen (DLA) class II genes encode major histocompatibility complex (MHC) molecules that are involved in antigen presentation to CD4(+) T cells. Several DLA haplotypes have been associated with autoimmune disease, including IMHA, in dogs, and breed specific differences have been identified. Cytotoxic T lymphocyte antigen 4 (CTLA4) is a critical molecule involved in the regulation of T-cell responses. Single nucleotide polymorphisms (SNPs) in the CTLA4 promoter have been shown to be associated with several autoimmune diseases in humans and more recently with diabetes mellitus and hypoadrenocorticism in dogs. The aim of the present study was to investigate whether DLA-DQB1 alleles or CTLA4 promoter variability are associated with risk of IMHA in Cocker spaniels. RESULTS: There were a restricted number of DLA-DQB1 alleles identified, with a high prevalence of DLA-DQB1*007:01 in both groups. A high prevalence of DLA-DQB1 homozygosity was identified, although there was no significant difference between IMHA cases and controls. CTLA4 promoter haplotype diversity was limited in Cocker spaniels, with all dogs expressing at least one copy of haplotype 8. There was no significant difference comparing haplotypes in the IMHA affected group versus control group (p = 0.23). Homozygosity for haplotype 8 was common in Cocker spaniels with IMHA (27/29; 93 %) and in controls (52/63; 83 %), with no statistically significant difference in prevalence between the two groups (p = 0.22). CONCLUSIONS: DLA-DQB1 allele and CTLA4 promoter haplotype were not found to be significantly associated with IMHA in Cocker spaniels. Homozygosity for DLA-DQB1*007:01 and the presence of CTLA4 haplotype 8 in Cocker spaniels might increase overall susceptibility to IMHA in this breed, with other genetic and environmental factors involved in disease expression and progression

Update on the management of rosacea

Allison P Weinkle,1 Vladyslava Doktor,2 Jason Emer3 1School of Medicine, University of California San Diego, La Jolla, CA, 2Dermatology Department, St John's Episcopal Hospital, Queens, NY, 3Spalding Drive Plastic Surgery and Dermatology, Beverly Hills, CA, USA Abstract: Refining diagnostic criteria has identified key characteristics differentiating rosacea, a chronic skin disorder, from other common cutaneous inflammatory conditions. The current classification system developed by the National Rosacea Society Expert Committee consists of erythematotelangiectatic, papulopustular, phymatous, and ocular subtypes. Each subtype stands as a unique entity among a spectrum, with characteristic symptoms and physical findings, along with an intricate pathophysiology. The main treatment modalities for rosacea include topical, systemic, laser, and light therapies. Topical brimonidine tartrate gel and calcineurin inhibitors are at the forefront of topical therapies, alone or in combination with traditional therapies such as topical metronidazole or azelaic acid and oral tetracyclines or isotretinoin. Vascular laser and intense pulsed light therapies are beneficial for the erythema and telangiectasia, as well as the symptoms (itching, burning, pain, stinging, swelling) of rosacea. Injectable botulinum toxin, topical ivermectin, and microsecond long-pulsed neodymium-yttrium aluminum garnet laser are emerging therapies that may prove to be extremely beneficial in the future. Once a debilitating disorder, rosacea has become a well known and manageable entity in the setting of numerous emerging therapeutic options. Herein, we describe the treatments currently available and give our opinions regarding emerging and combination therapies. Keywords: rosacea, vascular laser, rhinophyma, management, guideline

Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs

Immune-mediated diseases are common and life-threatening disorders in dogs. Many canine immune-mediated diseases have strong breed predispositions and are believed to be inherited. However, the genetic mutations that cause these diseases are mostly unknown. As many immune-mediated diseases in humans share polymorphisms among a common set of genes, we conducted a candidate gene study of 15 of these genes across four immune-mediated diseases (immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, immune-mediated polyarthritis (IMPA), and atopic dermatitis) in 195 affected and 206 unaffected dogs to assess whether causative or predictive polymorphisms might exist in similar genes in dogs. We demonstrate a strong association (Fisher’s exact p = 0.0004 for allelic association, p = 0.0035 for genotypic association) between two polymorphic positions (10 bp apart) in exon 2 of one allele in DLA-79, DLA-79*001:02, and multiple immune-mediated diseases. The frequency of this allele was significantly higher in dogs with immune-mediated disease than in control dogs (0.21 vs. 0.12), and ranged from 0.28 in dogs with IMPA to 0.15 in dogs with atopic dermatitis. This allele has two non-synonymous substitutions (compared to the reference allele, DLA-79*001:01) resulting in F33L and N37D amino acid changes. These mutations occur in the peptide binding pocket of the protein, and based upon our computational modeling studies are likely to affect critical interactions with the peptide N-terminus. Further studies are warranted to confirm these findings more broadly, and to determine the specific mechanism by which the identified variants alter canine immune system function