Rheumatoid arthritis is a common and debilitating autoimmune disease whose cause and mechanism remain a mystery. We recently described a T cell receptor transgenic mouse model that spontaneously develops a disease with most of the clinical, histological, and immunological features of rheumatoid arthritis in humans. Disease development in K/BxN mice is initiated by systemic T cell self-reactivity; it requires T cells, as expected, but B cells are also needed, more surprisingly. Here, we have identified the role of B cells as the secretion of arthritogenic immunoglobulins. We suggest that a similar scenario may unfold in some other arthritis models and in human patients, beginning with pervasive T cell autoreactivity and ending in immunoglobulin-provoked joint destruction.

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To investigate the role of retinoid X receptors (RXRs) in epidermal homeostasis, we generated RXR␣␤ ep؊/؊ somatic mutants in which both RXR␣ and RXR␤ are selectively ablated in epidermal keratinocytes of adult mice. These mice develop a chronic dermatitis mimicking that observed in atopic dermatitis (AD) patients. In addition, they exhibit immunological abnormalities including elevated serum levels of IgE and IgG, associated with blood and tissue eosinophilia, indicating that keratinocyte-selective ablation of RXRs also generates a systemic syndrome similar to that found in AD patients. Furthermore, the profile of increased expression of cytokines and chemokines in skin of keratinocyte-selective RXR␣␤-ablated mutants was typical of a T helper 2-type inflammation, known to be crucially involved in human AD pathogenesis. Finally, we demonstrate that thymic stromal lymphopoietin, whose expression is rapidly and strongly induced in RXR␣␤-ablated keratinocytes, plays a key role in initiating the skin and systemic AD-like pathologies.keratinocyte-selective gene ablation ͉ nuclear receptors ͉ conditional mutagenesis ͉ Cre-ER T2 A topic dermatitis (AD), a chronic skin inflammatory disease with a strong genetic component that affects children (10-20%) and adults (1-3%), is characterized by pruritic and eczematoid skin lesions, associated with systemic immunological abnormalities, including peripheral eosinophilia and hyper IgE immunoglobulinemia (1). Immunological mechanisms have been involved in AD pathogenesis (2), but the possible role of epidermal keratinocytes in AD initiation and maintenance is still largely unexplored (3).Nuclear receptors (NRs) belong to a superfamily of transcriptional regulators that include ligand-dependent and orphan receptors (4, 5). NRs play critical roles as signal transducers in vertebrate development and homeostasis, including immune functions (4, 6-8). Within the NR superfamily, the retinoid X receptor isotypes (RXR ␣, ␤, and ␥) play a key role as heterodimeric partners for some 15 NRs, e.g., retinoic acid receptors, 1,25-dihydroxyvitamin D 3 receptor (VDR), peroxisome proliferator-activated receptors, and liver X activated receptors (4, 5, 9). Ligand-dependent transcriptional activation by NRs requires the integrity of the core of activation function 2 (AF-2) (the ␣-helix 12 of the ligand-binding domain; see refs. 9 and 10).In epidermis, RXR␣ is predominant, RXR␤ level is lower, and RXR␥ is undetectable (11-13). Keratinocyte-selective ablation of RXR␣ in adult mouse skin results in a number of abnormalities, including a progressive alopecia, keratinocyte hyperproliferation, and abnormal differentiation, and an inflammatory reaction (11,14). In contrast, the skin of RXR␤-null mice is apparently normal (11,14,15).To investigate the origin of this inflammatory reaction and to avoid any functional redundancies between keratinocytic RXR␣ and RXR␤, we have now generated RXR␣␤ epϪ/Ϫ somatic mutants in which both RXR␣ and RXR␤ are selectively ablated in epidermal keratinocytes of adult mice. T...