T Lymphocytes in Histiocytic Sarcomas of Flat-Coated Retriever Dogs.

Flat-Coated Retriever dogs are predisposed to the development of histiocytic sarcoma (HS), a poorly differentiated, highly malignant neoplasm. The authors have previously documented a significant lymphocytic infiltrate in such tumors. The objective of this study was to examine the presence and expression of regulatory T cells in HS tumor samples. Forty tumors were included in this study. All tumors were immunolabeled for CD3, CD79a, CD25, CD45RA, and FOXP3. The proportion of positive cells was compared between tumors presenting as a localized primary soft tissue mass (soft tissue origin HS) and disseminated HS affecting viscera, especially the spleen (splenic origin HS). By immunohistochemistry, 95% of infiltrating T cells were positive for Foxp3 in all sections, suggesting the presence of regulatory T cells. The proportion of cells positive for FOXP3 was higher in the tumors arising in soft tissues, whereas the proportion of CD45RA-positive cells was higher in the splenic origin HS. Canine HS has an aggressive clinical behavior and is uniformly fatal. The difference in the proportion of tumor-infiltrating lymphocytes positive for these 2 markers in the 2 locations may represent differences in tumor microenvironment between the 2 sites

Reduced Lentivirus Susceptibility in Sheep with TMEM154 Mutations

Visna/Maedi, or ovine progressive pneumonia (OPP) as it is known in the United States, is an incurable slow-acting disease of sheep caused by persistent lentivirus infection. This disease affects multiple tissues, including those of the respiratory and central nervous systems. Our aim was to identify ovine genetic risk factors for lentivirus infection. Sixty-nine matched pairs of infected cases and uninfected controls were identified among 736 naturally exposed sheep older than five years of age. These pairs were used in a genome-wide association study with 50,614 markers. A single SNP was identified in the ovine transmembrane protein (TMEM154) that exceeded genome-wide significance (unadjusted p-value 3×10−9). Sanger sequencing of the ovine TMEM154 coding region identified six missense and two frameshift deletion mutations in the predicted signal peptide and extracellular domain. Two TMEM154 haplotypes encoding glutamate (E) at position 35 were associated with infection while a third haplotype with lysine (K) at position 35 was not. Haplotypes encoding full-length E35 isoforms were analyzed together as genetic risk factors in a multi-breed, matched case-control design, with 61 pairs of 4-year-old ewes. The odds of infection for ewes with one copy of a full-length TMEM154 E35 allele were 28 times greater than the odds for those without (p-value<0.0001, 95% CI 5–1,100). In a combined analysis of nine cohorts with 2,705 sheep from Nebraska, Idaho, and Iowa, the relative risk of infection was 2.85 times greater for sheep with a full-length TMEM154 E35 allele (p-value<0.0001, 95% CI 2.36–3.43). Although rare, some sheep were homozygous for TMEM154 deletion mutations and remained uninfected despite a lifetime of significant exposure. Together, these findings indicate that TMEM154 may play a central role in ovine lentivirus infection and removing sheep with the most susceptible genotypes may help eradicate OPP and protect flocks from reinfection

Clinical manifestations of chronic pancreatitis in English cocker spaniels.

Publication status: PublishedFunder: Norbert Ribbon FundFunder: Kennel Club Charitable TrustFunder: The Cocker Spaniel ClubBACKGROUND: Chronic pancreatitis (CP) is common in English cocker spaniels (ECS). It is histologically similar to IgG4-related disease (IgG4-RD) in humans and is characterized by duct destruction, interlobular fibrosis, and dense periductular and perivenous lymphocytic aggregates. However, the clinical manifestations of CP in ECS have not been previously described. OBJECTIVES: Characterize the clinical manifestations of CP in a group of ECS, including similarities and differences to IgG4-RD in humans. ANIMALS: One-hundred four ECS with CP and 44 client owned control ECS without CP (both healthy and diseased controls). METHODS: Affected dogs were divided into 2 groups according to the methods used to diagnose CP. Case records were searched for signalment, clinical, and clinicopathological findings, and evidence of keratoconjunctivitis sicca (KCS), proteinuria, other immune-mediated diseases, and anal sacculitis. RESULTS: Involvement of other organs was common. Affected ECS presented with a high frequency of KCS (n = 49), proteinuria (n = 47), anal gland disease (n = 36), atopy (n = 21), and other immune-mediated diseases (n = 16). Those with parti-color hair coats, particularly blue roan, had a strong association with CP, suggesting a link between coat color and autoimmune conditions in this breed. CONCLUSIONS AND CLINICAL IMPORTANCE: English cocker spaniels with CP show clinical similarities to humans with IgG4-RD and common involvement of other organs. Clinicians should evaluate affected Cocker Spaniels for proteinuria, keratoconjunctivitis sicca, and other potential immune-mediated diseases

H2-M3 Major Histocompatibility Complex Class Ib-Restricted CD8 T Cells Induced by Salmonella enterica Serovar Typhimurium Infection Recognize Proteins Released by Salmonella Serovar Typhimurium

Salmonella enterica serovar Typhimurium causes a typhoid-like disease in mice which has been studied extensively as a model for typhoid fever in humans. CD8 T cells contribute to protection against S. enterica serovar Typhimurium in mice, but little is known about the specificity and major histocompatibility complex (MHC) restriction of the response. We report here that CD8 T-cell lines derived from S. enterica serovar Typhimurium-infected BALB/c mice lysed bone marrow macrophages infected with S. enterica serovar Typhimurium or pulsed with proteins from S. enterica serovar Typhimurium culture supernatants. Cytoxicity was beta-2-microglobulin dependent and largely TAP dependent, although not MHC class Ia restricted, as target cells of several different MHC haplotypes were lysed. The data suggested the participation of class Ib MHC molecules although no evidence for the presence of Qa1-restricted T cells could be found, unlike in previous reports. Instead, the T-cell lines lysed H2-M3-transfected fibroblasts infected with S. enterica serovar Typhimurium SL3261 or treated with Salmonella culture supernatants. Thus, this report increases the number of MHC class Ib antigen-presenting molecules known for Salmonella antigens to three: Qa-1, HLA-E, and now H2-M3. It also expands the range of pathogens that induce H2-M3-restricted CD8 T cells to include an example of gram-negative bacteria