The common gamma chain (gamma c) of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors is defective in humans with XSCID. Mice lacking gamma c expression had hypoplastic thymuses; the thymocytes responded to gamma c-independent mitogens, but not gamma c-dependent stimuli. Splenic T cells were diminished at 3 weeks of age, but CD4+ T cells markedly increased by 4 weeks. B cells were greatly diminished in contrast with the situation in XSCID. NK cells, gamma delta intestinal intraepithelial lymphocytes, dendritic epidermal T cells, peripheral lymph nodes, and gut-associated lymphoid tissue were absent. These findings underscore the importance of gamma c in lymphoid development. Moreover, differences in humans and mice lacking gamma c expression indicate species-specific differences in the roles of gamma c-dependent cytokines or in the existence of redundant pathways. These mice provide an important model for studying the pathophysiology provide an important model for studying the pathophysiology of and gene therapy for human XSCID.

SUMMARY Missense mutations in the C-terminal B30.2 domain of pyrin cause familial Mediterranean fever (FMF), the most common Mendelian autoinflammatory disease. However, it remains controversial as to whether FMF is due to the loss of an inhibitor of inflammation or to the activity of a proinflammatory molecule. We generated both pyrin-deficient mice and “knockin” mice harboring mutant human B30.2 domains. Homozygous knockin, but not pyrin-deficient, mice exhibited spontaneous bone marrow-dependent inflammation similar to but more severe than human FMF. Caspase-1 was constitutively activated in knockin macrophages and active IL-1β was secreted when stimulated with lipopolysaccharide alone, which is also observed in FMF patients. The inflammatory phenotype of knockin mice was completely ablated by crossing with IL-1 receptor-deficient or adapter molecule ASC-deficient mice, but not NLRP3-deficient mice. Thus, our data provide evidence for a heretofore unrecognized ASC-dependent NLRP3-independent inflammasome in which gain-of-function pyrin mutations cause autoinflammatory disease.

To assess changes in epidermis-derived cytokine mRNA levels early in the afferent phase of allergic contact sensitivity, total epidermal mRNA was analyzed at various times after painting skin with haptens. We used a sensitive reverse transcriptas-polymerase chain reaction technique to quantitatively compare the regulation patterns of the following mRNAs: class H major histocompatibility complex I-Aa, tumor necrosis factor a (TNF-a), interleukin (IL) la, IL-1l, interferon (IFN) y, granulocyte/macrophageoolonystimulaing factor, IFN-induced protein 10, and marh inflammatory protein 2. Enhanced Langerhans cell-derived IL-13 mRNA signals were detected as early as 15 min after skin painting with allergens. TNF-a, IFN-y, and granulocyte! macrophage colony-stimulating factor mRNAs were found to be upregulated after application of allergens, irritant, and tolerogens, but class H major histocompatibility complex I-Aa, IL-la, IL-ljJ, IFN-induced protein 10, and macrophage infammatory protein 2 mRNAs were upregulated only after allergen painting. Depletion of specific cell populations demonstrated that Langerhans cells were the primary source of the IL-1u and class II major histocompatibility complex I-Aa mRNAs, keratinocytes were the primary source of TNF-a, IL-Ia, IFN-induced protein 10, and macrophage inlammatory protein 2, and infiltrating T lymphocytes were the source of lFN-y. Relevance of the molecular was Wasdemonstrated by the identification of biologically active IL-la and im oreactive TNFI-a in culture supernatants. These studies demonstrate that Langerhans cell-derived and certain keratinocytederived cytokine mRNAs are selectively upregulated by allergens in the very early afferent phase of contact sensitivity.