Which innate defense mechanism initiates a cascade effect

When bacteria, such as Neisseria meningitidis, invade the body, they are attacked by immune proteins called complement proteins. Complement proteins assist in bacterial killing via three pathways, the classical complement pathway, the alternative complement pathway or the lectin pathway.

The first steps of the classical complement pathway require the binding of antibodies to the surface of the target bacterium. The antibodies then become targets for one particular complement protein complex, known as C1 – C1 binds to the tail (known as Fc region) of the antibody. Once bound, C1 initiates a cascade of cleavage and reforming of complement complexes that ends in the binding of several complement proteins to the surface of the bacterium in the form of a membrane attack complex (MAC) (Figure 1), or can generate opsonins that label a bacterium for destruction. MAC can insert into the cell membrane of Gram-negative, but not Gram-positive, bacteria. There, it produces pores that allow the entry of membrane damaging molecules, such as lysozyme, and makes the bacterium susceptible to osmotic lysis.

The alternative complement pathway does not require antibody to initiate the lysis of bacteria. In this pathway, complement proteins from a complex known as C3 directly bind to bacteria and activate downstream components in the complement cascade, once again ending in formation of MAC that causes lysis of the bacterium.

During the lectin pathway, mannan-binding lectin (MBL) binds to proteins containing mannose residues that are found in some types of bacteria (such as Salmonella spp.). Once bound, MBL forms a complex with an enzyme called MBL-activated serine protease (MASP). In this form, this enzyme activates C3 convertase (by cleaving C2 and C4 complement components) that participates in forming MAC.

Via phagocytosis

Bacteria may also be killed by phagocytes. Immune proteins like acute phase proteins (like complement) and antibodies bind to the surface of bacteria by a process called opsonisation. Opsonised bacteria are, therefore, coated with molecules that phagocytic cells recognise and respond to. Activated phagocytes engulf and destroy opsonised bacteria by a process called phagocytosis. Complement C3b is a particularly important opsonisation protein for controlling bacterial infections by this mechanism. Opsonisation allows killing of Gram-positive bacteria (e.g. Staphylococcus spp.) that are resistant to killing by MAC.

After bacteria are ingested by phagocytosis (Figure 2), they are killed by various processes that occur inside the cell, and broken into small fragments by enzymes. Phagocytes present the fragments on their surface via class II major histocompatibility (MHC class II) molecules.

Circulating helper T cells recognise these bacterial fragments and begin to produce proteins called cytokines. Two major groups of helper T cells are known as Th1 and Th2 cells. These cell types differ in the types of cytokine they secrete. Th1 cells predominantly produce interferon-g (IFN-g), which promotes cell-mediated immune mechanisms (see below). Th2 cells produce mostly interleukin-4 (IL-4), which promotes humoral immunity by activating B cells. B cells make antibodies that stick to extracellular bacteria and prevent their growth and survival.

Via cell-mediated immunity

Some bacteria engulfed during phagocytosis avoid the killing mechanisms of the phagocyte to survive inside cells. Macrophages are a common targets for intracellular bacteria (e.g. Salmonella spp.) that live inside cell compartments. These bacteria cannot be detected by complement or antibody but, instead, are eliminated using a cell-mediated response. Infected macrophages present bacterial peptides on their cell surface using MHC class II molecules. This mechanism is called antigen presentation.

A helper T cell surveys MHC class II molecules with its T-cell receptor (TCR) to observe the peptides they hold. If a bacterial peptide is presented, the Th1 cell releases IFN-g. This cytokine stimulates killing mechanisms, (such as production of lysozyme) inside the infected macrophage to digest and destroy the invading bacterium. IFN-g also increases antigen presentation by cells, making the bacterium more visible to the immune system and more prone to attack (Figure 3).

© The copyright for this work resides with the author

The immune system refers to a collection of cells, chemicals and processes that function to protect the skin, respiratory passages, intestinal tract and other areas from foreign antigens, such as microbes (organisms such as bacteria, fungi, and parasites), viruses, cancer cells, and toxins. Beyond, the structural and chemical barriers which protect us from infection, the immune system can be simplistically viewed as having two “lines of defense”: innate immunity and adaptive immunity. Innate immunity represents the first line of defense to an intruding pathogen. It is an antigen-independent (non-specific) defense mechanism that is used by the host immediately or within hours of encountering an antigen. The innate immune response has no immunologic memory and, therefore, it is unable to recognize or “memorize” the same pathogen should the body be exposed to it in the future. Adaptive immunity, on the other hand, is antigen-dependent and antigen-specific and, therefore, involves a lag time between exposure to the antigen and maximal response. The hallmark of adaptive immunity is the capacity for memory which enables the host to mount a more rapid and efficient immune response upon subsequent exposure to the antigen. Innate and adaptive immunity are not mutually exclusive mechanisms of host defense, but rather are complementary, with defects in either system resulting in host vulnerability or inappropriate responses [1,2,3].

Innate immunity

Innate immunity can be viewed as comprising four types of defensive barriers: anatomic (skin and mucous membrane), physiologic (temperature, low pH and chemical mediators), endocytic and phagocytic, and inflammatory. Table 1 summarizes the non-specific host-defense mechanisms for each of these barriers. Cells and processes that are critical for effective innate immunity to pathogens that evade the anatomic barriers have been widely studied. Innate immunity to pathogens relies on pattern recognition receptors (PRRs) which allow a limited range of immune cells to detect and respond rapidly to a wide range of pathogens that share common structures, known as pathogen associated molecular patterns (PAMPs). Examples of these include bacterial cell wall components such as lipopolysaccharides (LPS) and double-stranded ribonucleic acid (RNA) produced during viral infection.

An important function of innate immunity is the rapid recruitment of immune cells to sites of infection and inflammation through the production of cytokines and chemokines (small proteins involved in cell–cell communication and recruitment). Cytokine production during innate immunity mobilizes many defense mechanisms throughout the body while also activating local cellular responses to infection or injury. Key inflammatory cytokines released during the early response to bacterial infection are: tumour necrosis factor (TNF), interleukin 1 (IL-1) and interleukin 6 (IL-6). These cytokines are critical for initiating cell recruitment and the local inflammation which is essential for clearance of many pathogens. They also contribute to the development of fever. Dysregulated production of such inflammatory cytokines is often associated with inflammatory or autoimmune disease, making them important therapeutic targets.

The complement system is a biochemical cascade that functions to identify and opsonize (coat) bacteria and other pathogens. It renders pathogens susceptible to phagocytosis, a process by which immune cells engulf microbes and remove cell debris, and also kills some pathogens and infected cells directly. The phagocytic action of the innate immune response promotes clearance of dead cells or antibody complexes and removes foreign substances present in organs, tissues, blood and lymph. It can also activate the adaptive immune response through the mobilization and activation of antigen-presenting cells (APCs) (discussed later) [1, 3].

Numerous cells are involved in the innate immune response such as phagocytes (macrophages and neutrophils), dendritic cells, mast cells, basophils, eosinophils, natural killer (NK) cells and innate lymphoid cells. Phagocytes are sub-divided into two main cell types: neutrophils and macrophages. Both of these cells share a similar function: to engulf (phagocytose) microbes and kill them through multiple bactericidal pathways. In addition to their phagocytic properties, neutrophils contain granules and enzyme pathways that assist in the elimination of pathogenic microbes. Unlike neutrophils (which are short-lived cells), macrophages are long-lived cells that not only play a role in phagocytosis, but are also involved in antigen presentation to T cells (see Fig. 1) [1].

Characteristics and function of cells involved in innate immunity [1, 3, 4]. *Dust cells (within pulmonary alveolus), histiocytes (connective tissue), Kupffer cells (liver), microglial cells (neural tissue), epithelioid cells (granulomas), osteoclasts (bone), mesangial cells (kidney)

Dendritic cells also phagocytose and function as APCs, initiating the acquired immune response and acting as important messengers between innate and adaptive immunity. Mast cells and basophils share many salient features with each other, and both are instrumental in the initiation of acute inflammatory responses, such as those seen in allergy and asthma. Mast cells also have important functions as immune “sentinel cells” and are early producers of cytokines in response to infection or injury. Unlike mast cells, which generally reside in the connective tissue surrounding blood vessels and are particularly common at mucosal surfaces, basophils reside in the circulation. Eosinophils are granulocytes that possess phagocytic properties and play an important role in the destruction of parasites that are often too large to be phagocytosed. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma. Natural killer (NK) cells play a major role in the rejection of tumours and the destruction of cells infected by viruses. Destruction of infected cells is achieved through the release of perforins and granzymes (proteins that cause lysis of target cells) from NK-cell granules which induce apoptosis (programmed cell death) [4]. NK cells are also an important source of another cytokine, interferon-gamma (IFN-γ), which helps to mobilize APCs and promote the development of effective anti-viral immunity. Innate lymphoid cells (ILCs) play a more regulatory role. Depending on their type (i.e., ILC-1, ILC-2, ILC-3), they selectively produce cytokines such as IL-4, IFN-γ and IL-17 that help to direct the appropriate immune response to specific pathogens and contribute to immune regulation in that tissue.

The main characteristics and functions of the cells involved in the innate immune response are summarized in Fig. 1.

Adaptive immunity

The development of adaptive immunity is aided by the actions of the innate immune system, and is critical when innate immunity is ineffective in eliminating infectious agents. The primary functions of the adaptive immune response are: the recognition of specific “non-self” antigens, distinguishing them from “self” antigens; the generation of pathogen-specific immunologic effector pathways that eliminate specific pathogens or pathogen-infected cells; and the development of an immunologic memory that can quickly eliminate a specific pathogen should subsequent infections occur [2]. Adaptive immune responses are the basis for effective immunization against infectious diseases. The cells of the adaptive immune system include: antigen-specific T cells, which are activated to proliferate through the action of APCs, and B cells which differentiate into plasma cells to produce antibodies.

T cells and APCs

T cells derive from hematopoietic stem cells in bone marrow and, following migration, mature in the thymus. These cells express a series of unique antigen-binding receptors on their membrane, known as the T-cell receptor (TCR). Each T cell expresses a single type of TCR and has the capacity to rapidly proliferate and differentiate if it receives the appropriate signals. As previously mentioned, T cells require the action of APCs (usually dendritic cells, but also macrophages, B cells, fibroblasts and epithelial cells) to recognize a specific antigen.

The surfaces of APCs express a group of proteins known as the major histocompatibility complex (MHC). MHC are classified as either class I (also termed human leukocyte antigen [HLA] A, B and C) which are found on all nucleated cells, or class II (also termed HLA DP, DQ and DR) which are found only on certain cells of the immune system, including macrophages, dendritic cells and B cells. Class I MHC molecules present endogenous (intracellular) peptides, while class II molecules on APCs present exogenous (extracellular) peptides to T cells. The MHC protein displays fragments of antigens (peptides) when a cell is infected with an intracellular pathogen, such as a virus, or has phagocytosed foreign proteins or organisms [2, 3].

T cells have a wide range of unique TCRs which can bind to specific foreign peptides. During the development of the immune system, T cells that would react to antigens normally found in our body are largely eliminated. T cells are activated when they encounter an APC that has digested an antigen and is displaying the correct antigen fragments (peptides) bound to its MHC molecules. The opportunities for the right T cells to be in contact with an APC carrying the appropriate peptide MHC complex are increased by the circulation of T cells throughout the body (via the lymphatic system and blood stream) and their accumulation (together with APCs) in lymph nodes. The MHC-antigen complex activates the TCR and the T cell secretes cytokines which further control the immune response. This antigen presentation process stimulates T cells to differentiate primarily into either cytotoxic T cells (CD8+ cells) or T-helper (Th) cells (CD4+ cells) (see Fig. 2). CD8+ cytotoxic T cells are primarily involved in the destruction of cells infected by foreign agents, such as viruses, and the killing of tumour cells expressing appropriate antigens. They are activated by the interaction of their TCR with peptide bound to MHC class I molecules. Clonal expansion of cytotoxic T cells produces effector cells which release substances that induce apoptosis of target cells. Upon resolution of the infection, most effector cells die and are cleared by phagocytes. However, a few of these cells are retained as memory cells that can quickly differentiate into effector cells upon subsequent encounters with the same antigen [2, 3].

Adaptive immunity: T-cell and B-cell activation and function. APC antigen-presenting cell, TCR T-cell receptor, MHC major histocompatibility complex

CD4+ Th cells play an important role in establishing and maximizing the immune response. These cells have no cytotoxic or phagocytic activity, and cannot directly kill infected cells or clear pathogens. However, they “mediate” the immune response by directing other cells to perform these tasks and regulate the type of immune response that develops. Th cells are activated through TCR recognition of antigen bound to class II MHC molecules. Once activated, Th cells release cytokines that influence the activity of many cell types, including the APCs that activate them.

Several types of Th cell responses can be induced by an APC, with Th1, Th2 and Th17 being the most frequent. The Th1 response is characterized by the production of IFN-γ which activates the bactericidal activities of macrophages and enhances anti-viral immunity as well as immunity to other intracellular pathogens. Th1-derived cytokines also contribute to the differentiation of B cells to make opsonizing antibodies that enhance the efficiency of phagocytes. An inappropriate Th1 response is associated with certain autoimmune diseases.

The Th2 response is characterized by the release of cytokines (IL-4, 5 and 13) which are involved in the development of immunoglobulin E (IgE) antibody-producing B cells, as well as the development and recruitment of mast cells and eosinophils that are essential for effective responses against many parasites. In addition, they enhance the production of certain forms of IgG that aid in combatting bacterial infection. As mentioned earlier, mast cells and eosinophils are instrumental in the initiation of acute inflammatory responses, such as those seen in allergy and asthma. IgE antibodies are also associated with allergic reactions (see Table 2). Therefore, an imbalance of Th2 cytokine production is associated with the development of atopic (allergic) conditions. Th17 cells have been more recently described. They are characterized by the production of cytokines of the IL-17 family, and are associated with ongoing inflammatory responses, particularly in chronic infection and disease. Like cytotoxic T cells, most Th cells will die upon resolution of infection, with a few remaining as Th memory cells [2, 3].

A subset of the CD4+ T cell, known as the regulatory T cell (T reg), also plays a role in the immune response. T reg cells limit and suppress immune responses and, thereby, may function to control aberrant responses to self-antigens and the development of autoimmune disease. T reg cells may also help in the resolution of normal immune responses, as pathogens or antigens are eliminated. These cells also play a critical role in the development of “immune tolerance” to certain foreign antigens, such as those found in food.

B cells

B cells arise from hematopoietic stem cells in the bone marrow and, following maturation, leave the marrow expressing a unique antigen-binding receptor on their membrane. Unlike T cells, B cells can recognize antigens directly, without the need for APCs, through unique antibodies expressed on their cell surface. The principal function of B cells is the production of antibodies against foreign antigens which requires their further differentiation [2, 3]. Under certain circumstances, B cells can also act as APCs.

When activated by foreign antigens to which they have an appropriate antigen specific receptor, B cells undergo proliferation and differentiate into antibody-secreting plasma cells or memory B cells (see Fig. 2). Memory B cells are “long-lived” survivors of past infection and continue to express antigen-binding receptors. These cells can be called upon to respond quickly by producing antibodies and eliminating an antigen upon re-exposure. Plasma cells, on the other hand, are relatively short-lived cells that often undergo apoptosis when the inciting agent that induced the immune response is eliminated. However, these cells produce large amounts of antibody that enter the circulation and tissues providing effective protection against pathogens.

Given their function in antibody production, B cells play a major role in the humoral or antibody-mediated immune response (as opposed to the cell-mediated immune response, which is governed primarily by T cells) [2, 3].

Page 2