Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)


Microbiology and Immunology


College of Graduate Studies

First Advisor

Carl Atkinson

Second Advisor

Stephen Tomlinson

Third Advisor

Chenthamarakshan Vasu

Fourth Advisor

Azizul Haque

Fifth Advisor

Charlie Strange


Emphysema is a complex inflammatory condition of the respiratory tract with an incompletely elucidated pathogenesis. Due to the complexity of the disease, treatment options are limited for patients and have poor efficacy. Therefore a greater understanding of disease pathogenesis is imperative to expand therapeutic strategies. Central to disease development is the activation of the innate and adaptive immune system, however, targeting blockade of only one side of the immune response, has shown little clinical benefit. The complement system, while regarded as an innate immune mechanism, can modulate both innate and adaptive immune responses. Given these dual modulatory effects, the complement system may be an ideal target for the management of emphysema. Complement activation has been reported in emphysema patients, demonstrated by increased plasma C3 concentrations, increased BAL complement cleavage fragments, and complement deposition within the emphysematous lungs. Therefore we hypothesize that by targeting the complement cascade we can modulate innate and adaptive immunity, and subsequently rescue lungs from the chronic inflammatory response that persists in emphysema. We demonstrate that deficiency in key complement components, C3, C5 and fB, provides protection from emphysema development. To test the therapeutic significance of these findings, we designed, established and characterized a novel rodent model of smoking cessation, and demonstrate that post smoking cessation modulation of the complement system, with CR2-fH or anti-C5 mAb, significantly reduced inflammation, lung destruction, and improved lung function. Together our multiple mouse models demonstrate that blocking complement protects against lung injury, inflammation, and T cell activation. Further we demonstrate reduced B cell infiltration and circulating autoantibody levels in our complement deficient active smoking models, but that autoantibody levels were unaltered in smoking cessation therapeutic studies. Whether these antibodies are biomarkers of disease or pathogenically contribute to disease development has yet to be elucidated. Using an elastin immunization model we show that increased anti-elastin autoantibodies are associated with exacerbated emphysema disease, thus demonstrating that these antibodies have pathogenic significance. In conclusion, these studies delineate a role for the complement system in the development, and persistence of emphysema, and further highlight the potential clinical benefits for utilization of targeted complement therapeutics for the management of emphysema.


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