Development and characterization of murine experimental autoimmune mastitis

Mastitis is a substantial clinical problem in lactating women that may result in severe pain and a failure of offspring to thrive. Many cases appear to involve no known infectious agent and as such may be fundamentally due to autoimmune mediated inflammation of the breast. The purpose of this study is to create a mouse model for autoimmune mastitis which would enable us to study the underlying basis of breast specific autoimmunity. To this end we have selected the milk specific protein, alpha-lactalbumin, as our targeted self antigen and generated recombinant alpha-lactalbumin for use as an immunogen.; Immunization of SWXJ mice with alpha-lactalbumin leads to a Th1/Tc1 proinflammatory response from CD4+/CD8+ T cells, respectively. Immunocytochemical analysis of mammary gland sections taken at various times from alpha-lactalbumin immunized mice show extensive T cell infiltration. Flow cytometry analysis of leukocytes taken from inflamed mammary glands show increased frequencies of CD4+ and CD8+ T cells expressing activated phenotype (CD44hi and CD45hi). In addition, quantitative RT-PCR analysis of breast tissue mRNA from alpha-lactalbumin immunized mice show significantly increased expression of inflammatory mediators including IFNgamma (P=0.010) and TNFalpha (P=0.057) but not IL-10 (P=0.14). Increased mammary mRNA expression of milk specific proteins such as alpha-lactalbumin (P=0.05) and alpha-casein (P=0.021) was also observed in lactating breast of EAM mice.; The phenotype of this targeted breast specific autoimmunity involves decreased ability to nurture offspring as evident from significantly inhibited growth curves (p=0.03) sometimes accompanied by kwashiorkor-like alopecia in litters from alpha-lactalbumin immunized females compared to control immunized females. Our data indicate that a targeted autoimmunity directed against alpha-lactalbumin leads to a breast-specific inflammation that compromises normal breast function and the ability of offspring to thrive. Our experimental model has useful applications for addressing complications in breast feeding as well as nutritionally based failure to thrive issues, and may also serve as a potent target immunogen for therapeutic breast cancer vaccination.*; *This dissertation is a compound document (contains both a paper copy and a CD as part of the dissertation). The CD requires the following system requirements: Adobe Acrobat.