The chronic proliferative dermatitis mutation arose spontaneously in 1991 in a colony of C57BL/KalwRij mice at the TNO Institute in the Netherlands. This is an autosomal recessive mutation that was mapped to mouse Chr. 15. Mutant mice appear to be normal until 2-3 weeks of age when they develop erythema, thinning of the hair, and fine scaling on the dorsal and ventral skin beginning at the thorax and dorsal cervical regions of the skin. Lesions expand to cover the entire body but not the ears, footpads, or tail. Mice become pruritic resulting in severe cutaneous ulcers requiring euthanasia by 20 to 30 weeks of age, sometimes at younger age depending upon husbandry conditions and IACUC regulations.
Histologically, there is marked epidermal hyperplasia that is patchy in young mice but diffuse in mice 5 weeks of age and older. Acanthosis with orthokeratotic hyperkeratosis and patchy parakeratotic hyperkeratosis are the prominent features. Focal apoptotic keratinocytes are scattered throughout the Malphigian layer of the epidermis and hyperplastic infundibulum of hair follicles. Such cells are usually isolated, shrunken, and brightly eosinophilic. They are positive in TUNEL assays. The epidermis is often infiltrated with eosinophils forming intracorneal pustules. Dermal infiltration consists primarily of eosinophils with lesser numbers of mast cells, macrophages, and neutrophils. The eosinophils were identified by transmission electron microscopy, expression of potassium cyanide resistant peroxidase, and by immunohistochemistry using an antibody directed against eosinophil major basic protein. High levels of circulating eosinophils can be quantitated using automated blood analysis tools. Bromodeoxyuridine uptake is markedly increased in the epidermis reflecting the rapid production of new keratinocytes.
As the skin is abraded by scratching, ulcers develop to various degrees. These heal by second intention through formation of granulation tissue, eventually covered by pseudoepitheliomatous hyperplasia, and resolved by re-epithelialization and dermal fibrosis. Large ulcers can extend to the level of the panniculus muscle.
Lesions are not limited to the skin, although this is the most prominent phenotype. Inflammation is prominent in older mice in the portal and centrolobular regions of the liver, peribronchiolar and perivascular regions of the lung, perisynovial tissues in joints, along with marked medullary and extramedullary hematopoeisis in many organs. Systematic longitudinal studies of the mutant phenotype revealed that cpdm/cpdm mice have no Peyer’s patches and lack lympoid follicles in the lymph nodes and nasal associated lymphoid tissue in adult mice. The white pulp of the spleen is abnormal with no defined follicles and marginal zone.
Until the mutated gene is identified, direct comparisons and confirmation as to which human disease this most likely resembles can only be speculated upon. Chronic atopy and eosinophilic esophagitis are two groups of diseases that have some similarities to this mutant mouse phenotype and will be the focus of future and ongoing studies.
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