Multiple Pathways Driving IgE Production and Chronic Dermatitis in Mice: A Model for Atopic Dermatitis?

In this month’s Journal of Investigative Dermatology, Tomimori et al (2004) describe interesting data derived from the study of the inbred NC/Nga mouse strain. These mice develop a spontaneous and chronic dermatitis when they live in conventional (non-sterile) animal housing conditions. These same animals, in specific-pathogen-free (aseptic) conditions, do not develop such dermatitis, suggesting that microbial flora, possibly the skin microflora, may play a critical role in such a process (Matsuda et al, 1997). The genetic defect(s) in these mice resulting in this chronic dermatitis are not known. What is known is that these NC/Nga mice, when living in conventional (non-sterile) housing conditions, exhibit constitutive hyperphosphorylation and exaggerated responsiveness of Janus-activated kinase 3 (JAK3). This molecule is an integral part of the signal transduction apparatus of the interleukin (IL)-4 receptor. This hyperphosphorylation of JAK3 is a finding similar to that observed in B-lymphocytes from patients with atopic dermatitis (Matusmoto et al, 1999). It is not known whether this is a primary defect in these NC/Nga mice or a result of inflammation due to abnormal regulation of other pathways that control inflammation or immune responses. IL-4 is a T helper (Th)-2 lymphocyte-derived cytokine known to play a role in supporting allergen-specific IgE after exposure to experimental antigens (Gauchat et al, 1990). Thus, the chronic activation of the IL-4 receptor signaling pathway is highly relevant to the increased serum IgE in these mice, and possibly related chronic dermatitis. Haptens such as dinitrofluorobenzene (DNFB), when applied to the skin of normal C3H/HeN or C57BL/6 mice as a single sensitizing dose, induce allergic contact dermatitis with predominant Th1-lymphocyte immune responses (interferon (IFN)-g-producing T cells, i.e., delayed type hypersensitivity), and no detectable hapten-specific IgE in their sera. After a sensitizing dose of hapten, however, followed by repeated elicitations on the pinna of the ear over 3–4 weeks, Th2-lymphocytes cytokine profiles appear in skin challenge sites, hapten-specific IgE becomes detectable in the sera, and immediate ear swelling responses are then observed after hapten challenge (Kitagaki et al, 1995). It is thought that chronic inflammation from the repeated challenges along with repetitive antigen stimulation (with possible clonal exhaustion of hapten-specific Th1-lymphocytes) lead to the emergence of Th2-lymphocytes as the dominant effector cells under these circumstances. In NC/Nga mice, sensitization followed by repeated challenges with haptens such as DNFB, results in chronic dermatitis and IgE overproduction, but paradoxically, in the relative absence of classic Th2-lymphocyte-derived cytokines such as IL-4. In fact, these animals exhibit excessive production of IL-12, IL-18 (both Th1-lymphocyte promoting monokines), and IFN-g (the prototypical Th1-lymphokine) compared with a common mouse strain that responds in a typical fashion to repeated elicitations with a hapten such as DNFB. It is noteworthy that other IgE-promoting cytokines (such as IL-13) and chemical mediators (prostaglandins) were not studied, and may possibly play a role in supporting this type of immune response. It is thus possible that IL-4-independent pathways could drive this IgE response in the NC/Nga mice. This apparently paradoxical response suggests that elevation of serum IgE can occur even in the setting of a vigorous Th1-lymphocyte immune response, and that somehow these Th1-promoting cytokines (such as IL-18) provide support in promoting allergen-specific IgE responses. Alternatively, NC/Nga mice may exhibit a resistance to the suppressive effects of the Th1-lymphocyte cytokines for the development of Th2-lymphocyte-dependent phenomenon (i.e., IFN-g does not suppress the development of Th2lymphocytes, and their help for subsequent IgE production). Studies of the immunology of human atopic dermatitis indicate that cytokines from Th2-lymphocytes (Yamada et al, 1995) as well as Th1-lymphocytes (Grewe et al, 1995) can be detected in skin lesions and the peripheral blood at various stages of evolution of the disease process. Thus, clinical, histologic, and immunologic studies all suggest that both Th1-lymphocytes and Th2-lymphocytes contribute to the immunopathology of human atopic disease in which both delayed type hypersensitivity (type IV allergy) and IgE-mediated processes (type I allergy) are thought to be important. Another interesting parallel between these NC/Nga mice and the atopic dermatitis is the role of microbial flora in the disease process. It is well-known that perturbations in the skin flora of patients with atopic dermatitis, particularly overgrowth of Staphylococcus aureus and associated IgEmediated immune responses against bacterial superantigens, serve as exacerbating factors for atopic skin disease (Hofer et al, 1999; Yarwood et al, 2000). NC/Nga mice living in standard (non-sterile) housing conditions exhibit spontaAbbreviations: IL, interleukin; TLR, toll-like receptor