Innate or Natural Immunity

Whereas the adaptive immune system arose in evolution less than 500 million years ago and is confined to vertebrates, innate immune responses have been found among both vertebrates and invertebrates, as well as in plants. Unlike adaptive immunity, innate immunity begins very soon after an infection begins and it does not depend on a host's prior exposure to the pathogen. Innate immune responses are also activated mainly at sites of infections, whereas adaptive immune responses are activated in peripheral lymphoid organs.

The Russian biologist IIya Mechnikov is credited with discovering innate immunity in the early 1880s when he plucked some thorns from a tangerine tree and poke them into a starfish larva. The next morning he saw that the thorns were surrounded by mobile cells, which he surmised were in the process of engulfing bacterail. He then discovered that water fleas exposed to fungal spores mount a similar response.

The innate system traditionally includes phagocytoic cells, natural killer (NK) cells, complement, and interferons (IFNs). Recently dendritic cells have also been added as effectors of innate immunity against tumoral cells and viruses.  Innate immune systems use proteins encoded in the germ line to identify potentially noxious substances. There proteins usually recognize carbohydrate structures. For example, macrophages endocytose particles or soluble glycoconjugates that are bound by the mannose receptor, a C-type lectin with broad carboyhydrate specificty. Macrophages also have a receptor for LPS.

When a pathogen invades a tissue, it typically elicits an inflammatory response characterized by pain, redness, heat and swelling. This inflammatory response is mediated by a variety of signaling molecules. Activation of TLRs (discussed below) results in the production of signaling molecules such as cytokines. Some of the cytokines produced by activated macrophages are chemoattractants called chemokines. Some of these attract neutrophils which are the first cells recruited in large numbers to the site of the new infection. Others later attract monocytes and dendritic cells. Other cytokines trigger fever which makes bacterial and viral growth less desirable. The proteolytic release of complement fragments (discussed below) also contributes to the inflammatory response.

Some cells of the innate immune system directly present microbial antigens to T cells to initiate an adaptive immune response. Thus there is a high degree of cooperativity between the innate and adaptive responses.  For example, dendritic cells recognize and phagocytose invading microbes and then migrate to peripheral lymphoid organs where they act as antigen presenting cells which activate T cells to respond to the microbial antigens. Once activated, some of the T cells migrate to the site of infection, where they help other phagocytic cells, mainly macrophages, destroy the microbes. Other activated T cells remain in the lymphoid organ and help B cells respond to the microbial antigens. The activated B cells secrete antibodies that circulate in the body and coat the microbes, targeting them for efficient phagoyctosis.

Effectors of  Innate Immunity

Barriers to Infection: Various epithelial surfaces such as the following provide a physical barrier between the inside of the body and the outside world:

• skin is an important epithelial barrier against pathogens. The skin contains an outer layer called the epidermis, which is packed with epithelial cells. The outer layer of cells is dead and filled with a protein called keratin. Beneath the epidermis is a thicker layer called the dermis which is composed of connective tissue and contains blood vessels, hair follicles and glands. The dermis produces an oily secretion ("sebum") which maintains the pH of the skin between 3-5 which can inhibit the growth of most microorganisms. A few bacteria that metabolize sebum can cause a severe form of acne. One drug (Accutane) is a vitamin A derivative that prevents the formation of sebum.

• mucusa on interior epithelial surfaces such as the respiratory, GU, and GI tracts. Mucous membranes are composed of epithelial cells which secrete mucus and can have cilia which act to mechanically remove microbes. In addition, these cells can secrete degradative enzymes like lysozyme which degrades bacterial peptidoglycan which makes up bacterial cell walls. They can also secrete defensins which constitute a diverse family with a broad spectrum of antimicrobial activity including the ability to kill bacteria, fungi and even HIV. Mucus membranes can also have lactoferrin which binds iron to keep it from being used by harmful microbes as well as lactoperoxidase which geenrates toxic superoxide anion radicals which kill infectious microbes. Mucous membranes are not fullproof. Pathogens like the influenza virus (flu) has a surface molecule that enables it to attach to cells in the mucous membrane. Gonorrhea has surface projections that allow it to bind to mucous membrane epithelial cells in the urogenital tract.

Cellular Components: In addition to epithelial cells, various leukocytes are associated with the innate immune response. These leukocytes include the following:

• phagocytes such as neutrophils and macrophages. Phagocytosis or the ingestion of foreign material can be either 1) immune mediated where the uptaken particles are opsinized with either IgG or complement (C3b) or it can be 2) non-immune mediated. In the immune mediated phagocytosis, specific receptors on macrophages and neutrophils bind to the tail region of an IgG molecule which has coated a bacterium. The binding of the antibody coated bacterium to these F_c receptors activates the phagocytic process. Once the pathogen has been phagocytosed, the phagosome is acidified and fuses with lysosomes which contain lyszyme and acid hydrolases. Lysosomes also contain defensins (particularly neutrophils). In addition, the phagocytes assemble an NADPH oxidase complex on the phagosomal membrane that catalyzes the production of a series of highly toxic oxygen derived compounds, including superoxide (O₂^-), hypochlorite (HOCl) which is the active ingredient in bleach, hydrogen peroxide, hydroxyl radicals, and nitric oxide (NO). The production of these toxic compounds is accompanied by a transient increase in oxygen consumption called the oxidative burst. Whereas macrophages will generally survive this degradation process and go on to participate in antigen processing/presentation (adaptive response), PMNs usually undergo cell death. Failure of neturophils to undergo oxidative bust results in chronic granulomatous disease and the inability to kill certain types of bacteria and fungi. Other phagocytosis defects can cause other diseases like Chediak-Higashi syndrome which is often fatal in childhood and is due to disordered assembly of microtubules resulting in impaired migration lysosomal degradation.

Although dendritic cells are another type of phaygocytic cell, their primary function is to process antigen for presentation to T cells and to elicit an adaptive immune response.

• natural killer (NK) cells are another type of leukocytes associated with innate immune responses, particularly with respect to viral infection. NK cells also function in anti-tumor immunity. Killing occurs via release of cytotoxic molecules like perforin which is a pore forming protein and granzyme which activates a caspase cascade inducing apoptosis.

• eosinophils are associated with innate immune responses against parasitic infection.

Toll Like Receptors: and other pattern recognition receptors (PRRs)

Complement System:

Cytokines: are low molecular weight glycosylated proteins which are mediators of not only innate but also adaptive immunity. The innate imune response is mediated by expression of a variety of cytokines exemplified by TNFα and IL-1β. Without cytokines would not have proper functioning of adaptive immunity. One must have key cytokines made by innate immunity for adaptive immunity.

IFNs are triggered by virus replication products (ds RNA, viral proteins?). IFN can be experimentally induced with poly I:C (TLR-3). IFNS, both type I (alpha/beta) which is produced by many cells and Type II (IFNy) produced by lymphocytes and some NK cells induce a signal transduction cascade, leading to an antiviral state. IFN cascade leads to induction of cellular proteins with antiviral activity. For example, PKR blocks new translation of proteins, RNase L degrades viral (and host) RNAs and Mx inhibits influenza replication in nucleus. Many viruses have devised strategies to block IFN.