Autoimmune Prone Mouse

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The serologic characteristics of these mice are hyper-y-globulinemia, a high titer of antinuclear antibodies, and the presence of anti-double-stranded DNA, anti-single-stranded DNA, and antihapten antibodies, high levels of retroviral gp70, circulating immune complexes, and reduced complement levels. Lupus nephritis, such as pro-teinuria and immune complex glomerulonephritis, is also common in SLE-prone

Table 16.1. Characteristics of systemic lupus erythematosus-prone mouse strains

Table 16.1. Characteristics of systemic lupus erythematosus-prone mouse strains

NZB 0

unknown

NZB 0

unknown

IGs at DEJ, immunoglobulins deposits at the dermoepidermal junction; IC-GN, immune complex glomerulonephritis; ANA, antinuclear antibody.

mice. In addition, thymic atrophy and lymphoid hyperplasia (T cells in MRL/lpr mice and B cells in NZB mice and BXSB mice) are frequently observed (Theofilopoulos and Dixon 1981). Because these lymphocyte subsets are responsible for the development of murine lupus, MRL/lpr mice have been described as T lupus, and NZ and BXSB mice as B lupus. In these mouse models, common genes or genetic pathways may contribute to immune dysregulation and to susceptibility to multiple autoimmune diseases, such as SLE and rheumatoid arthritis (Wandstract and Wakeland 2002). Compared with B-lupus strains, such as NZB, B/W F1, and BXSB mice, the MRL/lpr mouse has some unique features, such as rheumatoid arthritis, inflammatory changes in their salivary glands (e.g., Sjogren's syndrome), and arteritis (Table 16.1). Macroscopic skin lesions are also observed in MRL/lpr mice (Murphy and Roths 1978). A common dermatologic finding in SLE-prone mouse strains is the deposition of immunoglobulins, complement components, or both at the dermoepi-dermal junction (DEJ) (Table 16.1). Immunoglobulin deposits at the DEJ are associated with the occurrence of anti-DNA antibodies and proteinuria (Furukawa et al. 1985a), and eluates from these skin lesions contain the binding ability to DNA components (Furukawa 1986b).

These autoimmune traits are regulated under multigenetic factors (Izui et al. 1994, Table 16.2). Although the precise nature and number of genes involved in the development of SLE remains unclear, several major histocompatibility complex (MHC) and non-MHC genes have been investigated as candidate genes to be implicated in SLE (Wandstract and Wakeland 2002), including immounglobulin variable (V) region genes encoding autoantibodies with pathogenic specificity, T-cell receptor (TCR) genes, and the MHC genes (Wandstract and Wakeland 2002). With respect to skin lesions, the immounglobulin deposition seen in NZB mice and MRL/lpr mice are regulated by the Lbt-1 gene on chromosome 17 (Furukawa et al. 1985b) and Ipr gene on chromosome 19 (Furukawa et al. 1984,1996), respectively.

Table 16.2. Possible genetic factors involved in murine systemic lupus erythematosus3

1. Immunoglobulin variable region genes

2. T-cell receptor genes

3. Major histocompatibility complex class II genes

4. Genes regulating apoptosis:

Fas apoptosis gene: the Ipr mutation gld gene: the Fas ligand

5. Yaa gene

6. Genes for the expression of nephritogenic autoantigens

Genes encoding and/or regulating the expression of serum retroviral gp70 antigen

7. Genes regulating immunoglobulin class switching Genes for cytokines or their receptors xid gene: Bruton's tyrosine kinase a This table is based on the report of Izui et al. 1994.

Ipr, lymphoproliferation; gld, generalized lymphoproliferative disease; Yaa, Y chromosome-linked autoimmune acceleration; xid, X chromosome-linked immunodeficiency.

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