Introduction to immunityImmunity, the state of protection from infectious disease, has been categorized as innate and adaptive immunity (1, 2). The innate immunity which is the less specific, which has been also recognized as lack immunological memory provides the first line of defense against infection while the other arm of immunity, the adaptive one, responds to the challenge with a high degree of specificity and a remarkable property of “memory” (3, 4). In contrast to innate immune system, adaptive immunity does not come into play until there is an antigenic challenge to the organism. Typically, there is an adaptive immune response against an antigen within seven days after the initial exposure to a particular antigen (3). Exposure to the same antigen sometime in the future results in a memory response which occurs more quickly, stronger and often more effective in neutralizing and clearing the pathogen than the first response (3, 5). This immune responses consist of a complex system of cellular and humoral components that recognize self from non self, eliminate the latter, thereby realizing a crucial function of neutralization of invading pathogenic micro-organisms (6). The major agents of adaptive immunity are lymphocytes and the antibodies and other molecules they produce (7). Because adaptive immune responses require some time to organize, innate immunity provides the first line of defense during the critical period just after the host’s exposure to a pathogen (8).

The innate immunity has different components where most of them present before the onset of infection and it has constituted a set of disease-resistance mechanisms that are not specific to a particular pathogen (6).  In general, most of the microorganisms encountered by a healthy individual are readily cleared within a few days by defense mechanisms of the innate immune system before they activate the adaptive immune system (9). Innate immunity has different components such as cellular components like macrophages and neutrophils, physical components such as skin, physiological components and a variety of antimicrobial compounds synthesized by the host all play important roles in innate immunity (10). The innate immunity and its componentsThe innate immunity, as it is said above, it is the first line of defense against infection which has  less specificity and which has been also recognized as lack of immunological memory (3, 4).

This innate immunity comprises four types of defensive barriers: anatomic, physiologic, phagocytic, and inflammatory (9).1.      The Skin and the Mucosal Surfaces: the anatomic barriers This provides protective barriers against infection by preventing the entry of pathogens and these are an organism’s first line of defense against infections (9, 11). The skin consists of two distinct layers: a thinner outer layer—the epidermis—and a thicker layer—the dermis. The epidermis contains several layers of tightly packed epithelial cells.

The outer epidermal layer consists of dead cells and is filled with a waterproofing protein called keratin. The dermis, which is composed of connective tissue, contains blood vessels, hair follicles, sebaceous glands, and sweat glands. The sebaceous glands are associated with the hair follicles and produce an oily secretion called sebum. Sebum consists of lactic acid and fatty acids, which maintain the pH of the skin between 3 and 5; this pH inhibits the growth of most microorganisms.

A few bacteria that metabolize sebum live as commensals on the skin and sometimes cause a severe form of acne. One acne drug, isotretinoin (Accutane), is a vitamin A derivative that prevents the formation of sebum. Breaks in the skin resulting from scratches, wounds, or abrasion are obvious routes of infection.(11, 12).The conjunctivae and the alimentary, respiratory, and urogenital tracts are lined by mucous membranes.

These membranes consist of an outer epithelial layer and an underlying layer of connective tissue (13). Although many pathogens enter the body by binding to and penetrating mucous membranes, a number of nonspecific defense mechanisms tend to prevent this entry. For example, saliva, tears, and mucous secretions act to wash away potential invaders and also contain antibacterial or antiviral substances. The viscous fluid called mucus, which is secreted by epithelial cells of mucous membranes, entraps foreign microorganisms (14) . In the lower respiratory tract, the mucous membrane is covered by cilia, hair like protrusions of the epithelial-cell membranes (9).

The synchronous movement of cilia propels mucus-entrapped microorganisms from these tracts. In addition, nonpathogenic organisms tend to colonize the epithelial cells of mucosal surfaces. These normal floras generally outcompete pathogens for attachment sites on the epithelial cell surface and for necessary nutrients. Some organisms have evolved ways of escaping these defense mechanisms and thus are able to invade the body through mucous membranes. For example, influenza virus (the agent that causes flu) has a surface molecule that enables it to attach firmly to cells in mucous membranes of the respiratory tract, preventing the virus from being swept out by the ciliated epithelial cells. Similarly, the organism that causesgonorrhea has surface projections that allow it to bind to epithelial cells in the mucous membrane of the urogenital tract.

Adherence of bacteria to mucous membranes is due to interactions between hair like protrusions on a bacterium, called fimbriae or pili, and certain glycoproteins or glycolipids that are expressed only by epithelial cells of the mucous membrane of particular tissues. For this reason, some issues are susceptible to bacterial invasion, whereas othersare not.2.      Physiologic Barriers to InfectionThe physiologic barriers that contribute to innate immunity include temperature, pH, and various soluble and cell associated molecules. Many species are not susceptible to certain diseases simply because their normal body temperature inhibits growth of the pathogens (15).

Gastric acidity is an innate physiologic barrier to infection because very few ingested microorganisms can survive the low pH of the stomach contents. One reason newborns are susceptible to some diseases that do not afflict adults is that their stomach contents are less acid than those of adults (9).A variety of soluble factors contribute to innate immunity mainly lysozyme, interferon and complement.

Lysozyme is a hydrolytic enzyme which found in mucous secretions and in tears that able to cleave the peptidoglycan layer of the bacterial cell wall.  The other soluble factor interferon comprises a group of proteins produced by virus-infected cells which has ability to bind to nearby cells and induce a generalized antiviral state (16). The Complement is a group of serum proteins that circulate in an inactive state which are later be activated by a variety of specific and nonspecific immunologic mechanisms with the ability to damage the membranes of pathogenic organisms, either destroying the pathogens or facilitating their clearance. Complement may function as an effector system that is triggered by binding of antibodies to certain cell surfaces, or it may be activated by reactions between complement molecules and certain components of microbial cell walls. Reactions between complement molecules or fragments of complement molecules and cellular receptors trigger activation of cells of the innate or adaptive immune systems (17). Recent studies on collectins indicate that these surfactant proteins may kill certain bacteria directly by disrupting their lipid membranes or, alternatively, by aggregating the bacteria to enhance their susceptibility to phagocytosis (15, 16).Many of the molecules involved in innate immunity have the property of pattern recognition, the ability to recognize a given class of molecules (15).

Because there are certain types of molecules that are unique to microbes and never found in multicellular organisms, the ability to immediately recognize and combat invaders displaying such molecules is a strong feature of innate immunity. Molecules with pattern recognition ability may be soluble, like lysozyme and the complement components described above, or they may be cell-associated receptors (18). Among the class of receptors designated the toll-like receptors (TLRs), TLR2 recognizes the lipopolysaccharide (LPS) found on Gram-negative bacteria.

It has long been recognized that systemic exposure of mammals to relatively small quantities of purified LPS leads to an acute inflammatory response (see below). The mechanism for this response is via a TLR on macrophages that recognizes LPS and elicits a variety of molecules in the inflammatory response upon exposure. When theTLR is exposed to the LPS upon local invasion by a Gram-negative bacterium, the contained response results in elimination of the bacterial challenge(19, 20).3.      Cells That Ingest and Destroy Pathogens: Phagocytic Barrier to InfectionAn intact immune response includes contributions from many subsets of leukocytes.

The different leukocyte subsets can be discriminated morphologically by using a combination of conventional histologic stains and analysis of the spectrum of glycoprotein differentiation antigens that are displayed on their cell membranes (13).The phagocytic barrier of innate defense mechanisms is through phagocytic cells which ingest extracellular particulate materials by phagocytosis. There are different cells which participate in innate defense and the most important of them are macrophage, neutrophils, NK cells and DC cells.

Those cells which mediate phagocytosis are blood monocytes, neutrophils and tissue macrophage (9, 15). While the natural killer (NK) cells kill infected cells and tumor cells, the skin and mucous membrane epithelial cells act as mechanical and chemical defenses. Some cells which are commonly called antigen presenting cells (dendritic cells and macrophages) do have also more activity like presenting antigens after recognition and processing antigens to lymphocytes and initiate adaptive cellular immune response (15).Macrophages: Natural killer cellsDC cellsHistory of immunological memoryThough that time microorganisms were not established as infectious agent, as early as 429 BC, Thucydides (the great historian of the Peloponnesian War) in a plague of Athens observed that “the same man was never attacked twice” probably which is the first description of immunological memory.

Although early societies recognized the phenomenon of immunity, almost two thousand years passed before the concept was successfully converted into medically effective practice.  From the 10th century, the Chinese used to insert cotton with dried matter from smallpox pustules into the nostrils and similar techniques spread from Asia to Africa and Europe by the early 18th century, becoming famous as “variolation”, and reducing death risk to 1–2% as compared to 30% after natural infection (3, 21). Edward Jenner, in 1798, intrigued by the fact that milkmaids who had contracted the mild disease cowpox were subsequently immune to smallpox, which is a disfiguring and often fatal disease, Jenner reasoned that introducing fluid from a cowpox pustule into people (i.e., inoculating them) might protect them from smallpox. To test this idea, he inoculated an eight-year-old boy with fluid from a cowpox pustule and later intentionally infected the child with smallpox.

As predicted, the child did not develop smallpox. Jenner’s technique of inoculating with cowpox to protectagainst smallpox spread quickly throughout Europe. However, for many reasons, including a lack of obvious disease targets and knowledge of their causes, it was nearly a hundred years before this technique was applied to other diseases  (21).Louis Pasteur has introduced the first advanced immunology through the induction immunity to cholera. He injected chickens with fresh cholera bacterium grown on culture and then had shown that chickens developed cholera. After returning from a summer vacation, he injected some chickens with an old culture and this time chickens recovered though they became ill.

Pasteur then grew a fresh culture of the bacterium with the intention of injecting it into some fresh chickens. But, as the story goes, his supply of chickens was limited, and therefore he used the previously injected chickens. Again to his surprise, the chickens were completely protected from the disease (3). Pasteur hypothesized and proved that aging had weakened the virulence of the pathogen and that such an attenuated strain might be administered to protect against the disease. He called this attenuated strain a vaccine (from the Latin vacca, meaning “cow”), in honor of Jenner’s work with cowpox inoculation. Vaccination, often using weakened microorganisms, was then launched against various types of disease, e.g. rabies (by Pasteur in 1885), diphtheria and tetanus (by Behring and Kitasato in 1890) (9).

After the introduction of vaccination, attempts have been made to explain immunological memory were though all were in controversies. Was memory based on “humoral” or a “cellular”? Was the recognition of diverse antigens achieved through the selection of pre-made receptors or through moulding by antigens? Still, until the mid-20th century it remained unclear exactly how immunological memory works. Then, the clonal selection theory by Jerne and Burnet, the description of the structure of antibodies by Porter and Edelman, and the elucidation of the role of major histocompatibility complex (MHC) by Zinkernagel and Doherty formed a basis for modern understanding of immunological memory in the adaptive immune system (3, 9).3.

Brief picture of immunological memoryIn the late 20th century after the clonal selection theory by Jerne and Burnet, the B cells confirmed to have specific memory in the vertebrate adaptive immune system which is mainly based on clonal amplification of cells producing specific antibodies. For establishing B cell memory, interaction of the two types of lymphocytes, the B and T cells, is required (22). Shortly in simplified form, B cell memory can develop as follows (3, 13, 23). B cells carry on their surface attached forms of antibodies which are the B cell receptors (BCRs). These are specific for particular epitopes such as proteins derived from bacteria or virus. Upon binding, the antigen may be pulled into the cell and cut into smaller peptides, which are bound to proteins of the MHC II and presented on the cell surface. The B cell can then interact with a helper T cell carrying a receptor (TCR) that binds to this MHC II-peptide combination. The T cell may now send a stimulatory signal to the B cell, causing its proliferation and then establishing a B cell clone.

Some of the stimulated B cells differentiate into plasma cells which are antibody-producing cells while others migrate along with matching T cells into lymphoid tissues where B cells undergo somatic hypermutation and affinity maturation. During these processes, the specificity of binding between antigen and antibody is refined through a process of selection. Antibody-producing cells themselves have only a relatively short life of several days. To provide long-term memory, part of the B cells remains in an unproductive state and turn into memory B cells.

These long-lived cells seem to persist for several years. Upon re-infection with the same pathogen, they can be rapidly activated into a plasma cell producing specific antibody. Such B cell memory is not the only kind of memory existing in the adaptive immune system. Memory B cells alone can, for example, not provide protection against secondary infection by certain viruses. CD4 “helper” T cells seem to also differentiate into memory cells, which provide stronger stimulation to B cells than do naïve helper T cells. Such cell to cell communication could be an important issue also with regard to the maintenance of B cell memory.

However, memory CD4 T cells are difficult to distinguish from effector CD4 T cells by means of surface markers or cytokine profiles. Finally, cytotoxic CD8 T cell (CTL) memory can lead to faster and more intense secondary CTL responses. CTL memory is, e.g.

crucial for protection against certain viruses (3).The relevance of immunological memoryThe medical importance of immunological memory is simply illustrated by the success of vaccination.  After establishment of the concept immunological memory and the development of vaccine Louis Pasture,  using weakened microorganisms, many vaccines so far has been launched against various types of disease like rabies, diphtheria and tetanus (9). Moreover, if immunological memory is also present in invertebrate species (recently believed they have it) its importance may be extended to fields such as the control of disease vectors and aquaculture. Since decades ago, it has been becoming clear that the degree of immunological memory and specificity influences the evolution of hosts and pathogens and will thus crucially affect disease dynamics.

 Innate immunity immunological memoryAs indicated in the introduction section, for more than half a century immunity has been divided into the innate immunity that is rapid, relatively non-specific and incapable of building immune memory, and the adaptive immunity that takes longer time to develop then act specifically and capable of building long-term immunological memory (1, 2) . However, more recently evidences suggest that adaptive (immune memory) characteristics  are also found in cells of the innate immune system (8, 24-26). The basis for this recent occurrence in field of mammalian immunology is the findings of immunological memory in invertebrates which was believed previously that invertebrates have only innate immunity but no adaptive immunity. Additionally, what has been agreed in innate immunity of invertebrates was no immunological memory however numerous studies have recently demonstrated diverse forms of immune memory in a number of invertebrate species (27, 28). The findings of these studies done on plants and invertebrates derived immunologist to further investigate if mammalian innate immunity has immunological memory. The concept that innate immunity can also adapt and develop memory after challenges leading to increased responses to secondary infections has now been supported with evidences from mammals leading to a paradigm shift in our understanding of host defense (29).Important differences between the cell populations and the molecular mechanisms exist between the adaptive traits of innate host defense on the one hand and immunological memory of adaptive immunity on the other hand.

The lasting state of enhanced innate immunity termed ‘trained immunity’ is mediated by prototypical innate immune cells such as natural killer cells and monocytes/macrophages. Trained immunity provides protection against reinfection in a T- and B-cell-independent manner, with non- specific potentiation of inflammatory reactions and antimicrobial mechanisms playing a central role (30).The discovery of mechanisms of immunological memory within innate host defenses has important implications such as for our understanding of the pathophysiology of infections, possibly other immune-mediated diseases and also for the prevention and treatment of diseases. Additionally, the induction of trained immunity has important beneficial effects for increasing the overall capacity of host defense to respond and eliminate pathogens (14).Of the cells which mediate innate immunity, immunological evidences have been drawn among monocytes/macrophages, DC and NK cells. The myeloid cells, monocytes and macrophages, are crucial cell populations which are mediating the trained immunity and epigenetic reprogramming of them through histone modifications have been proposed as mechanisms mediating innate immune memory (31). Another very important cell population that mediates trained immunity effects are the natural killer (NK) cells and changes at the level of their membrane receptors are believed to be the process of training NK cells (32).

Here below, the training of macrophage, DC and NK cells will be discussed.


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