[Frontiers in Bioscience 16, 2921-2960, June 1, 2011]

Complement in Neurobiology

Lawrence L. Horstman1, Wenche Jy1, Yeon S. Ahn1, Amir H. Maghzi2, Masoud Etemadifar2, J. Steven Alexander3, Jeanie C. McGee4, Alireza Minagar5

1Wallace Coulter Platelet Laboratory, Division of Hematology and Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, USA, 2 Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran, 3 Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA, 4Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA, 5Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Outline of the complement system
3.1. The classical complement pathway
3.2. The alternative complement pathway
3.3. The Lectin pathway
3.4. The extrinsic complement pathway
4. Regulatory factors of the complement system
4.1. Early or general regulators
4.2. Modulators of the Alternative Pathway
4.3. The Complement Receptors
4.4. Membrane-bound self-cell protecting proteins
4.5. Anaphylatoxins and their receptors
4.6. Additional pathogen recognition factors
4.7. Additional complement modulators
4.7.1. Clusterin
4.7.2. Osteopontin
4.7.3. S protein also vitronectin
4.7.4. Phospholipase A2
4.7.5. Note on acute phase reactants
4.7.6. Alpha-2 Macroglobulin
4.7.7. The A2M receptor
4.7.8. Others
4.8. Note on mouse models of C-mediated disorders
5. Other roles, other systems
5.1. Neuroprotective roles of C
5.2. Role in autoimmunity
5.3. Role in adaptive immunity
5.4. Links to coagulation
5.5. CNS influence, and roles in lipid traffic
5.6. Links to other arms of innate immunity
6. Complement-mediated diseases.
6.1. CNS infections and relation to autoimmune disease
6.2. Age-related macular degeneration
6.3. Myasthenia gravis
6.4. Alzheimer's disease
6.5. Prion diseases
6.6. Amyotrophic lateral sclerosis
6.7. Multiple sclerosis
6.8. Hereditary angioedema
6.9. Ischemia reperfusion injury
6.10. Paroxysmal nocturnal hemoglobinuria
6.11. Traumatic brain and spinal cord injuries
6.12. Atypical hemolytic uremic syndrome
6.13. Thrombotic thrombocytopenic purpura
6.14. Systemic lupus erythematosus
6.15. Antiphospholipid syndrome and antibodies
6.16. Immune thrombocytopenia
6.17. Note on detection of C deposition
6.17. Progress in gene association studies
7. Anti-complement therapies, old and new
7. 1. Recently approved, in trials, or in pipe-line
7.2. Previously established complement-targeting therapies
7.3. Insights from pathogen evasion strategies
7.4. Vitamin D and the complement system
7.5. Heparin and "heparinoids"
7.6. Intravenous immunoglobulins
7.7. Intravenous IgM and the idiotype hypothesis introduced
8. Natural antibodies, complement, and autoimmunity
8.1. Introduction
8.2. Background on natural auto-antibodies
8.3. The complement connection
8.4. Remyelination mediated by complement and natural antibodies
8.5. Natural antibodies and ischemia / reperfusion (I/R) injury
8.6. Natural antibodies, complement, and adaptive immunity
8.7. Concepts of anti-idiotypes
8.8. More roles of natural antibodies
9. Summary and perspective
10. Acknowledgments
11. References

1. ABSTRACT

The complement (C) system is a vital arm of innate immunity with many roles, including control of inflammation. This article examines the (C) system with emphasis on recent developments on complement relevant to neurobiology, in particular regarding our understanding and treatment of immune-mediated diseases. We will briefly outline the C system, and provide an updated review of its many receptors and regulatory factors. This section concludes with a listing of important roles of the C system, from recruitment of neural stem/progenitor cells, to its' relation to coagulation and adaptive immunity, and its lesser-known but beneficial roles in physiology. We also review evidence for C-mediated diseases, which include multiple sclerosis and Alzheimer's disease. Therapeutic approaches for C-mediated diseases, considers emphasizing modulators of the C system including several less widely studied approaches such as heparinoids, vitamin D, and intravenous IgM. Finally, we summarize cutting-edge work on the role of C-mediated natural antibodies in autoimmunity and treatment strategies based on those findings, e.g., for remyelination and post-ischemic stroke repair. Improved understanding of the C system may hold great promise for the treatment of neurodegenerative diseases.