Lymphadenopathy, elevated serum IgE levels, autoimmunity, and mast cell accumulation in flaky skin mutant mice

Abstract

The autosomal recessive mutation "flaky skin" (fsn) causes pleiotropic abnormalities in the immune and hematopoietic systems accompanied by pathologic changes in the skin. Homozygotes (fsn/fsn) showed increased size and histological alterations in the spleen and lymph nodes. Abnormalities in lymphoid architecture of the spleen in fsn/fsn mice were accompanied by marked increases in total numbers of B cells, macrophages, and immature erythroid cells. Splenic B cells displayed elevated MHC class II expression. Serum IgE levels were greater than 100 microg/ml by 10 weeks of age, representing > 7000-fold increase compared with normal littermates. This increased IgE level was associated with elevated IL-4 production by spleen cells and with increased amounts of serum IL-4. Serum IgM, IgG1, and IgG2b levels were also increased in fsn/fsn mice while IgG3 was decreased. Autoimmunity in fsn/fsn mice was evidenced by glomerulonephritis accompanied by immune complex deposition in the kidneys, increased serum blood urea nitrogen levels, and the presence of circulating anti-double-stranded DNA autoantibodies. Pathological changes in the skin of fsn/fsn mice were characterized by epidermal hyperplasia and mixed dermal inflammation. Increased numbers of mast cells were also observed in the dermis of the truncal skin as well as in the epithelial stomach. These marked immunological abnormalities suggest that the fsn locus encodes a major immunoregulatory molecule important in multiple immune and hematopoietic functions.

Developmental Abnormalities of the Thymus in hea/hea Mutant Mice

“…The Ttc7(fsn-Jic) is allelic for the Ttc7(fsn-hea) mutation, and it caused a variety of somatic immune deficiencies from 3 to 4 weeks of age in fsn mice [1,2,10,13]. The functions of the immune system in hea mice remain the same as those of normal littermate mice with respect to cell-mediated and humoral immunity, at least until around 15 days of age.…”

“…The hematopoetic and immune systems of fsn mice are abnormal. The abnormalities of the immune system in fsn mice include alterations in the cellular populations in the spleen and peripheral lymph nodes, lymphadenopathy, autoimmu-nity with anti-dsdnA [24], elevated serum IgE and a disrupted peripheral lymphoid compartment [1,13]. The fsn mutation (Ttc7(fsn-Jic)) also causes pleiotropic defects such as severe anemia, gastric papillomas of the forestomach [19], and pathological changes in the skin that resembles psoriasis in humans [10,14,15,20].…”

A Mutant Mouse with Severe Anemia and Skin Abnormalities Controlled by a New Allele of the Flaky Skin (fsn) Locus

“…As shown in Table 2, peripheral blood collected from fsn Jic homozygotes showed increases of nucleated cells (including erythroblasts and WBC) and PLT and reductions in Hct and RBC. It has been reported that fsn homozygotes show increases of B cells, macrophages, mast cells, eosinophils and immature erythroid cells (erythroblasts and reticulocytes) and decreases of T cells, lymphocytes, monocytes, neutrophils and mature RBC [2,12]. These results suggest that fsn homozygotes have abnormal differentiation of hematopoietic stem cells.…”

“…Abnormal phenotypes in skin of fsn homozygotes at the postnatal stage have been explained by immunological defects [12,18]. These results suggest that pleiotropisms observed in fsn homozygotes are caused by functional defects of hematopoietic progenitor cells [14,17].…”

Dysregulated expression of CD69 and IL‐2 receptor α and β chains on CD8+ T lymphocytes in flaky skin mice

“…12 Peripheral lymph nodes (PLN) from fsn/fsn mice contain almost 10-fold more lymphocytes as PLN than their phenotypically normal littermates (+/+ or +/fsn, hereafter designated +/? 13 suggest that T-cell development in fsn/fsn mice is abnormal and that large numbers of T cells in these mice are activated.…”