Development of Autoimmunity in IL-14α-Transgenic Mice

Abstract

Multiple genetic loci contribute to the development of systemic lupus erythematosus (SLE). In murine models for SLE, various genes on chromosome four have been implicated. IL-14 is a cytokine originally identified as a B cell growth factor. The il14 gene is located on chromosome 4. IL-14α is a cytokine encoded by the plus strand of the IL-14 gene using exons 3–10. The expression of IL-14α is increased in (NZB × NZW)F1 mice. In this study, we produced IL-14α-transgenic mice to study the role of IL-14α in the development of autoimmunity. At age 3–9 mo, IL-14α-transgenic mice demonstrate increased numbers of B1 cells in the peritoneum, increased serum IgM, IgG, and IgG 2a and show enhanced responses to T-dependent and T-independent Ags compared with littermate controls. At age 9–17 mo, IL-14α-transgenic mice develop autoantibodies, sialadenitis, as in Sjögren’s syndrome, and immune complex-mediated nephritis, as in World Health Organization class II SLE nephritis. Between the ages 14–18 mo, 95% of IL-14α-transgenic mice developed CD5+ B cell lymphomas, consistent with the lymphomas seen in elderly patients with Sjögren’s syndrome and SLE. These data support a role for IL-14α in the development of both autoimmunity and lymphomagenesis. These studies may provide a genetic link between these often related disorders.

A Role for Lymphotoxin in Primary Sjögren’s Disease

“…In previous studies, we demonstrated that transgenic mice expressing the B cell growth factor IL-14a develop a disease that reproduces the clinical and immunological changes characteristic of Sjögren's disease. Moreover, these pathological changes occur in IL-14a transgenic (IL14aTG) mice in the same temporal sequence as observed in patients with Sjögren's disease (3)(4)(5)(6). Confirming previous observations in human disease, we demonstrated that in IL-14a mice, the loss of salivary gland secretion precedes lymphocytic infiltration of the salivary glands (4,7,8).…”

“…LTA has been shown to induce the production of type 1 IFNs (29,61). We have observed production of IFN-a in IL14aTG mice (3). Increased levels of IFN-a have also been observed in the sera of patients with both systemic lupus erythematosus and Sjögren's disease (62).…”

“…We focused on LTA and IFN-a in these studies because microarray studies identified them and their signatures in both IL14aTG mice and patients with Sjögren's disease (33). Previous studies had implicated IFN-a in Sjögren's disease, and we identified IFN-a in the sera of IL14aTG mice (3,10,30).…”

“…The structure of salivary gland tissues was evaluated by standard histological techniques using H&E staining as previously described (3,4). Immunofluorescence studies were performed as previously described using Abs to mouse IgA, IgG, and IgM from Sigma (St. Louis, MO) (4).…”

Development of a murine model for blastoid variant mantle-cell lymphoma

“…Transgenic mice expressing IL4A constructed with the pESR vector develop autoimmunity and large B-cell lymphomas by 18 months of age. 38 The expression of IL-14␣ mRNA has been identified in high-grade B-cell tumors in vivo, and IL-14 antisense oligonucleotides inhibit these tumors in vitro. 39 We describe here the development of lymphoid malignancies closely resembling the blastoid variant of MCL (MCL-BV) in IL-14␣ ϫ c-Myc double-transgenic mice (DTG), each produced using the vector pESR that directs transgene expression in the B-cell compartment.…”