Drivers and regulators of humoral innate immune responses to infection and cancer

Abstract

The complement cascade consists of cell bound and serum proteins acting together to protect the host from pathogens, remove cancerous cells and effectively links innate and adaptive immune responses. Despite its usefulness in microbial neutralization and clearance of cancerous cells, excessive complement activation causes an immune imbalance and tissue damage in the host. Hence, a series of complement regulatory proteins present at a higher concentration in blood plasma and on cell surfaces tightly regulate the cascade. The complement cascade can be initiated by B-1 B cell production of natural antibodies. Natural antibodies arise spontaneously without any known exogenous antigenic or microbial stimulus and protect against invading pathogens, clear apoptotic cells, provide tissue homeostasis, and modulate adaptive immune functions. Natural IgM antibodies recognize microbial and cancer antigens and serve as an activator of complement mediated lysis. This review will discuss advances in complement activation and regulation in bacterial and viral infections, and cancer. We will also explore the crosstalk of natural antibodies with bacterial populations and cancer.

Keywords: B-1 B cells; Bacteria; Cancer; Complement; Natural antibodies; Virus.

Figure 1:. Complement activation pathways and viral evasion of the complement cascade.

Activation of complement cascade by the classical, lectin and alternative pathway leads to the formation of membrane attack complexes (MAC). Viruses use specific mechanisms to evade hosts complement mediated destruction. Some viruses express structural and functional homologs of hosts complement regulatory proteins. These homologs mimic the role of host complement regulators. Another mechanism of viral evasion is by recruitment of host complement regulatory proteins (CD55, CD59) into their virions.

Figure2:. Complement and natural antibodies in bacterial infections.

Bacteria utilize multiple methods to prevent complement-mediated lysis, including direct inhibition by preventing complement components from binding the bacterial surface and preventing recognition of opsonized bacteria, producing complement inhibitors, proteolytically cleaving complement components, and recruiting the host complement inhibitors to the bacterial surface. B. nIgM provides protection against invading bacteria by activation of classical complement pathway via C1q, increased opsonization and phagocytosis by innate like dendritic cells and macrophages, transport of antigens to secondary lymphoid organs and activation of adaptive immune responses, and clearance of DAMPs (e.g. dsDNA) minimizing the autoimmune responses. C. nIgG mediates the pathogen recognition and phagocytosis by acting as a bridge between Ficolins/MBL and FcγR1 receptors on phagocytes.

Figure 3:. Role of B-1 B cells and natural antibodies in influenza infections

B-1 B cell derived nIgM confers influenza-specific protective in a stepwise manner. 1. Mice are infected with influenza. 2. Type I interferon signaling activates CD11b on pleural B-1a B cells to induce migration to the mediastinal lymph nodes. 3. Following cell migration, the expression of CD5 is lost and the secretion of IL-17a is quickly upregulated. IL-17a results in the activation of NF-κB and Blimp-1, subsequently stimulating B-1 B cells to become high rate nIgM producers. 4. Influenza virus-binding nIgM targets and reduces the influenza virus burden prior to the initiation of adaptive immune responses. The increased levels of natural influenza-binding IgM only occur local to the infection.

Figure 4:. Role of humoral innate immunity in cancer

B-1 B cell derived natural antibodies confer both anti- and pro-tumor roles. Natural antibodies recognize tumor specific antigen and activate complement mediated killing of tumor cells. Natural antibodies upregulate and recruit myeloid-derived suppressor cells, leading to the inhibition of immune cell mediated killing of tumor cells. In order to combat complement mediated killing, cancer cells upregulate both membrane-bound and soluble complement regulators. This upregulation inhibits the complement pathway and promote tumor growth and treatment resistance.