Complement regulators in human disease: lessons from modern genetics

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• The complement system is a crucial part of the humoral immune system, originating over a billion years ago.
• It comprises nearly 60 proteins functioning through three activation pathways and a common terminal cytolytic pathway.
• Initially identified in the 19th century for its role in bacterial lysis, it acts as a complement to antibodies.

Purpose of the Study:

• To elucidate the structure and function of complement system components using modern molecular biology and genetics.
• To identify genetic variations, including rare variants and common polymorphisms, that influence complement system function.
• To understand how these genetic factors predispose individuals to human diseases characterized by 'hyperinflammatory complement phenotypes' (complementopathies).

Main Methods:

• Utilizing modern molecular biology techniques to study the structure of complement system proteins.
• Employing genetic analysis to identify variants and polymorphisms in complement regulators, particularly within the alternative pathway.
• Investigating the functional consequences of these genetic alterations on complement system activity and disease predisposition.

Main Results:

• Detailed elucidation of the structure of numerous complement system components.
• Identification of function-altering rare variants and common polymorphisms, especially in regulators of the alternative pathway.
• Demonstration that these genetic variations can lead to 'hyperinflammatory complement phenotypes', increasing susceptibility to certain diseases.

Conclusions:

• The complement system's complexity and genetic underpinnings are increasingly understood.
• Genetic variations in the complement system are significant contributors to human inflammatory diseases.
• Targeted therapies, such as monoclonal antibodies against C5, are emerging for treating 'complementopathies'.