CD59: A Critical Regulator of Complement-Mediated Cell Defence

Structure and Molecular Characteristics

CD59, which is also referred to as protectin or membrane attack complex inhibitory factor (MACIF) is a small protein that is glycosylated and phosphorylated to attach to the glycosylphosphatidylinositol (GPI) cell anchor. The protein becomes matured to a membrane protein which is quite small, comprised of 77 amino acids, and has a specific structure in which the hydrophobic core is surrounded by five disulfide bonds which are essential for the proper functioning of the protein. It has a highly conserved topography with many cysteine residues that are involved in creation of specific architecture that is crucial for binding with complement proteins. The glycosylphosphatidylinositol (GPI) anchor is a post translational modification which allows CD59 to be anchored to the external face of the cell membrane and enables the CD59 to move within the membrane and shield the cell from complement mediated lysis.

Expression and Distribution

CD59 is a protein which is synthesized in virtually every cell of the human body, and this shows how crucial this protein is in protection of the cells. It is detected on almost all blood cells for instance the erythrocytes, leukocytes and the platelets as well as endothelial and epithelial cells in other tissues also. The amount of CD59 varies depending on the type of cell and it can also be up regulated and down regulated according to a number of conditions including cytokines, growth factors and cellular stress. This pattern is important as it provides protection to all the body parts from complement system activation. For instance, CD59 is expressed at high levels in areas of the body that are prone to complement deposition including the blood brain barrier and the glomerular basement membrane of the kidney.

Function in Complement Regulation

The main role of CD59 is to avoid the formation of the membrane attack complex (MAC) also known as the terminal complement complex (C5b-9). This is done in that it interacts with C8α that is found in the C5b-8 complex and thus prevents polymerization of C9 that is required for formation of the membrane damaging pore. This control mechanism is very important in order to prevent the destruction of the host cells by complement mediated lysis. Besides its function in MAC inhibition CD59 has been found to be involved in cellular signalling for instance it may regulate cellular activation, proliferation and survival. The mobility of the protein makes it easy for it to reach any part of the membrane where complement has been activated hence effective protection against complement induced injury.

Role in Disease and Pathology

Defects or dysregulation of CD59 can cause various disorders. The best known is paroxysmal nocturnal hemoglobinuria (PNH), which is an autosomal dominant disorder that results in the deficiency of GPI-anchored proteins such as CD59 on the cell surface. This deficiency makes the cells susceptible to complement mediated lysis especially during sleep hence the name paroxysmal nocturnal hemoglobinuria. CD59 dysfunction has also been associated with other diseases such as autoimmune diseases, neurodegenerative diseases, and certain types of cancer. In some cancers CD59 can be up regulated which may provide protection for the malignant cells from complement mediated lysis thus promoting tumor growth and spread. On the other hand, in some inflammatory conditions, down regulation of CD59 or its functional defects may enhance the tissue injury by increasing the complement activation.

Therapeutic Applications and Future Perspectives

In PNH treatment, elcuizumab and other complement inhibitors have completely changed the management of the patient by preventing complement induced hemolysis. Ongoing research is also being made to identify and develop new therapeutic options that either affect CD59 or its control mechanisms. These are creation of recombinant CD59 proteins for therapeutic purposes, altering CD59 expression in certain diseases and the use of CD59 in targeted therapy for cancer. Also, the protective function of CD59 in tissue during ischemia/reperfusion injury and other inflammatory diseases is also being considered for therapeutic use.

The development related of disorders, new the strategies creation for of managing new CD59 diagnostic methods according to the CD59 expression profiles and the investigation of the possible uses of CD59 in cancer and inflammatory disease treatment. It is expected that as the knowledge on CD59 biology increases then there will be new targets for therapeutic intervention thus giving rise to better treatments for various complement related disorders.

Suitable ELISA Kits

• • CD59 ELISA Kit