Flaky skin (fsn) is an autosomal recessive mutation on mouse chromosome 17 that causes severe anaemia, forestomach papillomatosis and a papulosquamous skin disease that resembles psoriasis in humans. In the present paper, it is reported that fsn causes peripheral lymphadenopathy, CD4/CD8 imbalance and hyperresponsiveness to T cell growth factors. Peripheral lymph nodes (PLN) of adult mutant (fsn/fsn) mice were found to contain almost 10‐fold more leucocytes than PLN from phenotypically normal littermates (+/fsn or +/+, hereafter referred to as +/?). Analysis of PLN cells using mAbs and flow cytometry revealed that this predominantly lymphoid hyperplasia was characterized by approximately equivalent increases in the numbers of CD3+ T cells and CD19+ B cells. However, expansion within the T cell compartment was non‐random, because fsn/fsn PLN had a considerably reduced ratio of CD4+ to CD8+ T cells (1.08 ± 0.37) compared to +/? PLN (2.47 ± 0.44, P < 0.0001). In vitro assays of cellular proliferation in response to T and B cell growth factors showed that fsn/fsn PLN cells were hyperresponsive to IL‐2, IL‐4 and IL‐7 when compared with PLN cells from +/? mice. Studies using mesenteric lymph node and peripheral blood cells showed that hyperresponsive cells are widely distributed in fsn/fsn mice. Experiments in newborn mice showed that the lymphoid disturbances caused by fsn are established at least as early as 2 weeks of age, a time that precedes the onset of the earliest clinical skin lesions. These data implicate a role for the fsn gene product in regulating the size and content of the peripheral lymphoid compartment.
Summary T-cell activation is considered to be an important element in the pathogenesis of psoriasis, a human skin disease characterized by keratinocyte hyperproliferation, altered keratinocyte differentiation and inflammation of the dermis and epidermis. Mice homozygous for the flaky skin (fsn) mutation develop a skin disorder that has histopathological and biochemical features resembling some forms of psoriasis. It has been reported recently that peripheral lymph nodes (PLN) in fsn/fsn mice exhibit various abnormalities in T-cell development suggestive of dysregulated T-and B-cell activation. In the present study, the expression of the inducible T-cell activation antigens CD69 and IL-2 receptor α chain (CD25) on PLN cells from fsn/fsn mice and their phenotypically normal littermates is examined. Expression of CD69 was significantly increased on PLN cells in fsn/fsn mice (mean ± SD, 49.9 ± 14.7% of cells) compared with control mice (14.6 ± 4.2 %). Analysis of CD4 + and CD8 + T cell subsets revealed that expression of CD69 in fsn/fsn PLN was significantly biased toward CD8 + cells. Although expression of CD25 was preferentially associated with CD4 + rather than CD8 + cells in both fsn/fsn and control PLN, with most CD4 + CD25 + cells being CD25 hi , the proportion of CD4 + cells expressing CD25 was higher in fsn/fsn than control PLN. In contrast, CD25 was expressed by 2-3 % of CD8 + PLN cells in both fsn/fsn and control mice and CD25 hi cells accounted for < 1 % of CD8 + cells in fsn/fsn PLN. The paucity of CD25 on CD8 + cells in fsn/fsn PLN did not appear to be due to a defect in the ability of these cells to upregulate CD25, because T cell receptor stimulation in vitro induced high expression of CD25 on both CD4 + and CD8 + cells. A striking and consistent finding was that most CD8 + cells in fsn/fsn PLN expressed high levels of IL-2R β chain (CD122). In contrast, CD122 was expressed at low levels on CD8 + cells in control mice. Analysis of PLN cells from newborn fsn/fsn mice revealed that the high expression of CD122 on CD8 + cells was established by 2 weeks of age, prior to the appearance of clinical skin disease. These data indicate that large numbers of T cells in fsn/fsn mice are activated and reinforce the view that fsn is an important regulator of lymphocyte development and function. The relationship between T-cell activation and flaky skin disease in these mice remains to be established.
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