The Role of Complement in Lupus

As described in this overview, the classical pathway has four primary functions, and each of them are activated by different molecules. The pathway is triggered when the C1 complex binds to the Fc section of an antibody that is attached to an antigen on the surface of a pathogen. This activation leads to the cleavage of complement proteins, eventually forming C3 convertase, which is a complex containing C4 and C2. The C3 convertase then produces C3a and C3b. C3b is responsible for binding to the surface of a pathogen to allow for opsonization to occur with the aid of phagocytes

C3a can also be used in combination with C5a to create anaphylatoxins. These cause inflammation and activate mast cells, as well as attracting neutrophils (also known as PMNs) to the infection site. The complex of C5b and proteins C6, C7, C8, and C9 assemble to create the membrane-attack complex (MAC). This complex causes lysis of many different types of microbes and is most effective against extracellular bacteria. The classical pathway is thus especially effective against extracellular pathogens, such as bacteria in the bloodstream that have been marked with antibodies for destruction..

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease in which the immune system produces antibodies against itself, causing inflammation and tissue injury. Abnormalities in the classical complement pathway cause both the development and progression of SLE. Individuals who are deficient in early complement components, like C1q or C4, are more likely to develop Lupus due to impaired elimination of apoptotic cells and immune complexes as they form. This error allows the self-attacking antigens to proliferate and stimulate the production of autoantibodies. These complement deficiencies diminish tolerance, which causes the autoimmune inflammation characteristic of lupus.

During active lupus flares, the same complement system that normally protects the body creates inflammation and damages the organs. Overactivation leads to the formation of abnormal complement products such as iC3b, C3dg, and C4d, which mark immune activation and can be accurately scaled with disease severity. These products promote vascular inflammation, thrombosis, and can damage organs such as the kidneys, joints, and central nervous system. The MAC also forms on host tissues, causing tissue damage through lysis and prolonged inflammation. Through these pathways, complement proteins can cause both the start of SLE by an error in normal production, and their overactivation fuels ongoing cell damage throughout the nervous system and in various organs.

The classical complement proteins found at low levels in Lupus cases are C1q, C4, and C2. These low levels can occur either because of inherited genetic deficiencies or because the proteins are destroyed during ongoing classical pathway activation by overstimulated immune complexes. As described in this article, measuring these proteins helps to assess disease case severity and anticipate potential lupus flare-ups. The MAC contributes to organ injury by directly causing cell lysis. Immune complex deposition through C3b and C4b damages tissues such as the kidneys, joints, and nervous system, as discussed earlier. There are also the anaphylatoxins C3a and C5a (see above), which recruit immune cells and increase vascular permeability, prolonging the disease.

Luckily, new therapies are being developed to target complement activation in lupus. One developing technology uses C5 inhibitors to block the MAC and reduce tissue damage caused during flares of inflammation. Another technique aims to block C3 or parts of the classical pathway to limit inflammation. These treatments try to reduce the harmful effects of complement while keeping its protective functions intact, as that is also a contributing factor for the onset of Lupus. Early studies suggest that these therapies could help manage the symptoms of Lupus in the future.