Skinbase

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.

HogenEsch H; Gijbels MJ; Offerman E; van Hooft J; van Bekkum DW; Zurcher C, A spontaneous mutation characterized by chronic proliferative dermatitis in C57BL mice., Am J Pathol 1993 Sep;143(3):972-82

Gallardo Torres HI; Gijbels MJ; HegnEsch H; Kraal G, Chronic proliferative dermatitis in mice: neutrophil-endothelium interactions and the role of adhesion molecules., Pathobiology 1995;63(6):341-7

Gijbels MJ; HogenEsch H; Blauw B; Roholl P; Zurcher C, Ultrastructure of epidermis of mice with chronic proliferative dermatitis., Ultrastruct Pathol 1995 Mar-Apr;19(2):107-11

Gijbels MJ; HogenEsch H; Bruijnzeel PL; Elliott GR; Zurcher C, Maintenance of donor phenotype after full-thickness skin transplantation from mice with chronic proliferative dermatitis (cpdm/cpdm) to C57BL/Ka and nude mice and vice versa., J Invest Dermatol 1995 Dec;105(6):769-73

Gijbels MJ; Zurcher C; Kraal G; Elliott GR; HogenEsch H; Schijff G ; Savelkoul HF ; Bruijnzeel PL, Pathogenesis of skin lesions in mice with chronic proliferative dermatitis (cpdm/cpdm)., Am J Pathol 1996 Mar;148(3):941-50

HogenEsch H; Boggess D; Sundberg JP, Changes in keratin and filaggrin expression in the skin of chronic proliferative dermatitis (cpdm) mutant mice., Pathobiology 1999;67(1):45-50

HogenEsch H; Janke S; Boggess D; Sundberg JP, Absence of Peyer's patches and abnormal lymphoid architecture in chronic proliferative dermatitis (cpdm/cpdm) mice., J Immunol 1999 Apr 1;162(7):3890-6

Schon MP, Animal models of psoriasis - what can we learn from them? [see comments], J Invest Dermatol 1999 Apr;112(4):405-10

Sundberg JP; Boggess D; Shultz LD; Fijneman RJA; Demant P; Hogenesch H; Cox GA, The chronic proliferative dermatitis mouse mutation (cpdm): mapping of the mutant gene locus, J Exp Anim Sci 2000;41():101-8

Gijbels MJ, Elliott GR, HogenEsch H, Zurcher C, van den Hoven A, Bruijnzeel PL. Therapeutic interventions in mice with chronic proliferative dermatitis (cpdm/cpdm), Exp Dermatol. 2000 Oct;9(5):351-8.

HogenEsch H; Torregrosa SE; Boggess D; Sundberg BA; Carroll J; Sundberg JP, Increased expression of type 2 cytokines in chronic proliferative dermatitis (cpdm) mutant mice and resolution of inflammation following treatment with IL-12., Eur J Immunol 2001 Mar;31(3):734-42