The body’s complement system, which is a vital part of the immune system and particularly important to understanding autoimmune diseases such as cold agglutinin disease (CAD), is almost laughably opaque to lay people in the sense that its name reveals absolutely nothing about the way it functions. 

The immune system is vast and complex, and there is still much we still do not know about it. An oversimplification goes like this: it is the body’s defense against foreign pathogens, keeping us healthy. In reality, the immune system is a web of intricate functions that independently and interdependently fight infection, and just as all roads lead to Rome, a detailed study of the various pathways of human immunity will always lead us back to the complement system. 

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So what is it, and how has our understanding of it evolved? To answer this question, we will turn to the work of Pouw and Ricklin, as well as that of Conigliaro and colleagues. 

An Ancient System, Revisited 

First things first: “The complement system plays an essential role in both innate and adaptive immune responses. A dysfunction in this system in terms of upregulation, down-regulation, or dysregulation can cause a wide range of effects, including disturbance of normal host defense and altered inflammatory response,” Conigliaro et al wrote. 

According to Pouw and Ricklin, the evolutionary origin of the complement system predates antibodies by thousands of years. It has been described in the medical literature as occurring as early as the start of the 20th century. However, it has long been regarded as a “novelty”—complementary, if you will.

A paradigm shift in the way we think about the complement system is unfolding right now. “The shift in the perception of the complement system from auxiliary antimicrobial pathway to decisive pathological contributor and therapeutic target has been a long way coming and has been based on decades of seminal research that shed new light on molecular, functional, and clinical aspects of this fascinating protein cascade,” Pouw and Ricklin wrote. 

Scientists now know that the complement system can sense pathogen- and damage-associated molecular patterns and mark them for elimination. “Even without pattern recognition, the complement system targets surfaces via the spontaneous low-rate activation of its promiscuous alternative pathway,” according to Pouw and Ricklin. (The alternative pathway is one of many pathways that the complement system can trigger). A surface attack by complement may lead to the release of C3a and C5a, which induces shuttling to the lymphatic system, the stimulation of the adaptive immune response, as well as phagocytosis. 

Ditching the prior paradigm of viewing the complement system as responsible for triggering only individual immune pathways, scientists have embraced “a more refined and dynamic picture of complement functions . . . in which the sum of all activating and regulating surface signatures and stimuli shape an overall response that typically involves several pathways and effectors and engages various crosstalk mechanisms,” Pouw and Ricklin wrote. 

When Things Go Wrong 

Unfortunately, the complement system does not function like a well-oiled machine all the time, and defects do occur. Conigliaro and colleagues identified 2 forms of complement system dysfunction: primary and secondary complement system deficiencies. 

Primary complement system deficiencies are rare disorders of complement components that predispose patients to autoimmune diseases (like CAD) and infections. Secondary complement system deficiencies are more common; this involves any pathological process that causes the complement system to enhance infective diseases and trigger autoimmune diseases. 

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Pouw and Ricklin identified the consequences of a defective complement system. On cancer, they wrote, “Whereas insufficient complement regulation is the culprit in many disorders, increased complement-regulatory capacities may unfavorably impact tumor development as many cancer cells were found to express high densities of membrane-bound complement regulators as part of their evasion strategy.” 

On COVID-19 and sepsis, they wrote that a defective complement system can be excessively activated “at such an extent that the fulminant complement activation results in host tissue damage and propagation of a vicious thromboinflammatory cycle.” 

On autoimmune diseases, they commented that the core problem is that the complement system acts in an “appropriate” way—but to an inappropriate target. This can also be observed when the body rejects a transplanted organ; the immune system identifies the new organ as foreign and acutely rejects it. This misdirected activation of the complement system is also clearly seen in autoimmune diseases and age-related disorders. 

When the immune system does not behave in a way that is beneficial to the patient, physicians have to be careful to preserve the useful functions of the immune system while dampening its pathological effects. The success of the drug eculizumab demonstrated that complement inhibition could be a legitimate therapeutic approach. 

However, the story does not end there. According to Pouw and Ricklin, “there are even more candidates in late-stage trials or approval registration that cover various stages of complement activation.” The experimental drugs sutimlimab and narsoplimab are 2 such examples. In the years ahead, we can expect more drugs to be included in our therapeutic arsenal when treating diseases that have a defective complement system among their causes. 


Pouw RB, Ricklin D. Tipping the balance: intricate roles of the complement system in disease and therapy. Semin Immunopathol. Published online October 26, 2021. doi: 10.1007/s00281-021-00892-7

Conigliaro P, Triggianese P, Ballanti E, Perricone C, Perricone R, Chimenti MS. Complement, infection, and autoimmunity. Curr Opin Rheumatol. 2019;31(5):532-541. doi:10.1097/BOR.0000000000000633