T Cell Requirement for Development of Chronic Ulcerative Dermatitis in E- and P-Selectin-Deficient Mice

Abstract

C57BL/6 mice deficient in E- and P-selectin (E−/−P−/−) kept under specific pathogen-free barrier conditions have high circulating neutrophil counts and develop hypercellular cervical lymph nodes with substantial plasma cell infiltrates, severe ulcerative dermatitis, conjunctivitis, and lung pathology, which eventually lead to premature death. To test the hypothesis that the pathology in E−/−P−/− mice may be caused by dysfunctional lymphocyte activity, we crossed E−/−P−/− mice with recombination activation gene (Rag)-1−/− mice to generate E−/−P−/−Rag-1−/− mice lacking mature T and B lymphocytes. E−/−P−/−Rag-1−/− mice had circulating neutrophil counts and plasma G-CSF levels similar to E−/−P−/− mice. Remarkably, none of the E−/−P−/−Rag-1−/− mice developed conjunctivitis or ulcerative dermatitis typical of E−/−P−/− mice. These mice were overall healthier in appearance than E−/−P−/− mice, and histopathologic changes in the lung were reduced. Cervical lymph nodes in E−/−P−/−Rag-1−/− mice were much smaller than those of E−/−P−/− mice, containing few mononuclear cells and no plasma cells. These data show that the severe disease phenotype of E−/−P−/− mice depends on lymphocyte function. We conclude that a dysregulated immune response in E−/−P−/− mice causes disease development, but is not necessary for elevated neutrophil counts.

Functional Role of P-Selectin Glycoprotein Ligand 1/P-Selectin Interaction in the Generation of Tolerogenic Dendritic Cells

“…It is also conceivable that the engagement of PSGL-1 during the recirculation and extravasation of mature DCs may contribute to regulate their immunogenic activity, either in steadystate conditions or under inflammatory conditions, including allograft rejection (46). Importantly, our data provide a possible mechanism to explain the observations that P-selectin plays in vivo a protective role in the development of different experimental inflammatory conditions such as glomerulonephritis, intestinal inflammation, collagen-induced arthritis or chronic ulcerative dermatitis (47)(48)(49)(50)(51).…”

The role of selectins in inflammation and disease

“…Under vivarium conditions, these mice have only a marginally increased susceptibility to becoming overtly ill, a phenotype shared by mice lacking all three selectins [23]. However, mice lacking only P-and E-selectin develop severe skin disease [24,25], which appears to be dependent upon an inappropriate immune response to the increased bacterial load, because the skin disease is not observed in immunodeficient mice [26]. Among mice with single selectin mutations, P-selectin-deficient mice show a 2 -4 hour delay in neutrophil infiltration in many models [6] and have subtle defects in hemostasis [27].…”

A “Pedi” Cures All: Toenail Trimming and the Treatment of Ulcerative Dermatitis in Mice

“…Mice with UD spend much of their days literally tearing themselves apart in an apparent attempt to relieve a condition that we don’t fully understand. Multiple factors have been identified that may predispose mice to UD including abnormal grooming behavior prior to lesion onset, age and sex [ 2 , 4 – 7 ], excessive grooming progressing to oronasal inflammation [ 6 , 8 ], T-cell deficiencies [ 9 , 10 ], environmental factors (alterations in humidity, temperature, and diet) [ 3 , 5 – 7 ], infectious agents [ 11 ], irradiation [ 12 ], immune complex vasculitis [ 2 ], and perhaps most importantly, genetic predisposition [ 13 , 14 ]. Mice of the C57BL/6 background are particularly susceptible to the disease and are responsible for the higher end estimate of prevalence reported [ 4 ].…”