The role of complement in immunity to Nippostrongylus brasiliensis.

i DECLARATION.iii ACKNOWLEDGEMENT OF ANY HELP. iv STATEMENT OF AUTHORSHIP-CHAPTER 2.v STATEMENT OF AUTHORSHIP-CHAPTER 3.vii STATEMENT OF AUTHORSHIP-CHAPTER 4.x ACKNOWLEDGEMENTS.xvi PUBLICATIONS.xviii COMMONLY-USED ABBREVIATIONS.xix CHAPTER 1: INTRODUCTION AND REVIEW OF THE LITERATURE 1.1 HEALTH AND ECONOMIC CONSEQUENCES OF PARASITIC HELMINTH INFECTIONS . 1 1.2 IMMUNE RESPONSES TO HELMINTH INFECTION . 2 1.2.1 Immune recognition and antigen processing . 3 1.2.2 Cytokine responses during helminth infection . 4 1.2.3 Immunological basis of gastrointestinal helminth expulsion . 6 1.3 LEUKOCYTE-MEDIATED KILLING OF HELMINTHS.9 1.3.1 Neutrophils.9 1.3.2 Macrophages.10 1.3.3 Eosinophils.10 1.3.3.1 IL-5 and eosinophils . 11 1.3.3.2 Eosinophil recruitment.12 1.3.3. 3 Eosinophil activation, secretion and degranulation . 13 1.3.3.4 Role of eosinophils in disease.14 1.3.3.5 Role of eosinophils is killing helminths . 15 1.3.3.6 Other roles for eosinophils during helminth infections . 17 1.4 THE COMPLEMENT SYSTEM . 19 1.4.1 Function of the complement system . 19 1.4.2 Pathways to complement activation . 20 1.4. 3 Complement-dependent immunity to pathogens . 21 1.5 ROLE OF COMPLEMENT IN IMMUNITY TO HELMINTHS.23 1.5.1 Complement activation by helminths . 25 1.5.2 Complement-dependent leukocyte-mediated killing of helminths.26 1.5.2.1 Recruitment of effector leukocytes.26 1.5.2.2 Adherence and activation of effector leukocytes.27 1.5. 3 Evasion of complement activation and leukocyte adherence . 27 1.6 NIPPOSTRONGYLUS BRASILIENSIS AS A MODEL FOR STUDYING IMMUNITY TO HELMINTHS.29 1.6. 1 Parasite life cycle . 29 1.6. 2 Immune responses to N. brasiliensis . 30 1.6. 2.1 Cellular inflammatory responses . 30 1.6. 2.2 Cytokine responses . 32 1.6. 2.3 Role for eosinophils . 32 1.7 INTRODUCTION TO THIS STUDY.34 CHAPTER TWO: Quantitation of complement and leukocyte binding to a parasitic helminth species. 36 LINKAGE TO CHAPTER TWO AND ARTICLE. 37 CHAPTER THREE: Loss of complement activation and leukocyte adherence as Nippostrongylus brasiliensis develops within the murine host . 39 LINKAGE TO CHAPTER THREE AND ARTICLE.40 CHAPTER FOUR: The role of complement in innate, adaptive and eosinophil-dependent immunity to the nematode Nippostrongylus brasiliensis.43 LINKAGE TO CHAPTER FOUR AND ARTICLE. 44 CHAPTER FIVE: DISCUSSION AND CONCLUSION 5.1 GENERAL DISCUSSION . 46 5.1.1 Summary of main findings . 46 5.1.2 Complement and eosinophil-dependent immunity to helminths . 47 5.1.2.1 Eosinophil-dependent resistance to helminths.47 5.1.2.2 Role of complement in vivo and in vitro.49 5.1.2.3 Complement-dependent eosinophil recruitment to parasite-infected skin . 51 5.1.2.4 Complement-independent eosinophil recruitment.51 5.1.2.5 Eosinophil versus neutrophil recruitment . 53 5.1.2.6 Complement-independent leukocyte adherence to helminths . 54 5.1.2.7 Eosinophil degranulation . 55 5.1.2.8 Larval aggregation . 57 5.1.3 Evasion of complement activation by helminths.58 5.1.4 Pulmonary cellular responses following helminth infection . 59 5.1.4.1 Restricted early cellular inflammation in the lungs . 59 5.1.4.2 Delayed cellular inflammation in the lungs.60 5.1.5 Secondary immune response to helminth infection.61 5.1.6 Future directions for studies using complement-deficient/IL-5 Tg mice . 62 5.1.7 Issues for design of anthelmintic vaccines . 62 5.2 CONCLUSION.63 REFERENCES.65