OVERVIEW OF THE HUMAN IMMUNE SYSTEM
Ageneral overview of the immune system is provided so that anappreciation can be gained of how biological molecules from certainmushrooms may modulate the immune response and tackle cancer cells.Immunology is the study of the methods by which the body defends itselffrom infectious agents and other foreign substances in its environment.The immune system is a remarkably adaptive defence system that hasevolved in humans to protect against invading pathogenic microorganismsand evidence is accumulating that the immune system can provideprotection against some tumours (Wood, 2001). An infectious organismthat causes a disease is called a pathogen and the individual (personor animal) that is infected by a pathogen is called the host. There arethousands of components to the immune system and it would appear thatthe immune system is far more complicated than necessary for achievingwhat is, on the surface, a simple task of eliminating a pathogenicorganism or abnormal ‘self’ cells. However there are a number ofreasons for this complexity, including the desirability of eliminatingpathogens without causing damage to the host.
Getting rid of a pathogen or dead host cells istheoretically easy, but eliminating these without damaging the host ismuch more complicated. The immune system must be able to distinguishbetween pathogens or abnormal cells and healthy host cells so that itcan direct its destructive powers towards their elimination. As aconsequence of this dynamic complexity, the immune system is able togenerate a tremendous variety of cells and molecules capable ofspecifically recognising and eliminating an apparently limitlessvariety of foreign invaders, in addition to the recognition anddestruction of abnormal cells. Furthermore, these host cells andmolecules act together in an exquisitely adaptable dynamic manner.
Functionally,an immune response can be divided into the interrelated activities ofrecognition and response. The immune system is remarkably specific asit is able to recognise subtle chemical differences that distinguishforeign or ‘non-self’ cells from healthy self-cells. At the same time,the system is able to discriminate between foreign molecules and thebody’s own cells and proteins. Once a foreign protein, microorganism(e.g., bacterium, fungus or virus) or abnormal cell is recognised, theimmune system enlists the participation of a variety of cells andmolecules to mount an appropriate effector response to eliminate orneutralise them. Later exposure to the same foreign organism (e.g., avirus that may have the potential to transform normal healthy cellsinto tumour cells) induces a memory response, characterised by aheightened immune reactivity, which serves to eliminate the microbialpathogen, prevent disease and protect against the development of sometumour cells (Wood, 2001).
Immunity - the state of protection from infectiousdisease, has both non-specific and specific components. Innate, ornon-specific immunity refers to the basic resistance to disease that anindividual is born with. Acquired or specific immunity requiresactivity of a functional immune system, involving cells calledlymphocytes and their products. Innate defence mechanisms provide thefirst line of host defence against invading microbial pathogens andalso provides protection against some tumour cells until an acquiredimmune response develops. In general, most of the foreign molecules ormicrobial cells encountered by a healthy individual are readily clearedwithin a few days by non-specific defence mechanisms without enlistinga specific immune response. When the non-specific defences fail toeliminate foreign invaders or abnormal cells, a specific or humoralimmune response is then enlisted.
Because immunity was shownto be mediated by molecules known as antibodies that were contained inbody fluids (known in earlier times as humors), it was known as humoralimmunity (Wood, 2001). An antibody is a protein or immunoglobulin thatrecognises a particular epitope or site on an antigen, which is anysubstance that binds specifically to an antibody or T-lymphocytereceptor, and facilitates clearance of that antigen. The other arm ofthe specific immune response is cell-mediated immunity or CMI. CMIresponse refers to host defences that are mediated by antigen-specificT lymphocyte cells (i.e., leukocytes) and various non-specific cells ofthe immune system. It protects against intracellular bacteria, virusesand cancer and is responsible for graft rejection. Acquired immunitydoes not operate independently of innate immunity; rather, the specificimmune response supplements and augments the non-specific defencemechanisms, producing a more effective total response (Wood, 2001).
Innate (non-specific) immunity
Innateimmunity can be envisioned as comprising four types of defensivebarriers: anatomic, physiologic, endocytic and phagocytic, andinflammatory. Tissue damage and infection induce leakage of vascularfluid, containing serum with antimicrobial activity, and influx ofphagocytic cells into the affected area. While physical and anatomicbarriers, such as skin and the surface of mucous membranes, prevent theentry of pathogenic microorganisms and are the body’s first line ofdefence, this component of innate immunity will not be developed anyfurther as it has no bearing on immuno-modulation or anti-tumourresponses.
The physiologic barriers that contribute to innateimmunity include elevated temperature (e.g., fever), pH (e.g., acidityproduced in stomach and within macrophages), oxygen tension, andvarious soluble factors (Kuby, 1997). Among these soluble proteins arelysozyme (a hydrolytic enzyme found in mucous secretions that killsbacteria), interferons (INF) and other cytokines (chemical messengers),and complement (plasma proteins that participate in a controlledenzymatic cascade which results in damage to the membranes ofpathogenic organisms or abnormal cells, either destroying orfacilitating their clearance), markedly influence immunomodulation andregulation, in addition to the prevention of some tumour cells (Kuby,1997).
Cytokines: the chemical messengers
Theterm cytokine covers a variety of small proteins less than 20 kDa(usually) that serve a hormone-like function in enabling cells tocommunicate with each other (Wood, 2001). There are many cytokines andthey can be divided into families (Table 2). The main families ofcytokines are the interleukins (ILs), colony-stimulating factors (CSF),interferons (INFs), tumour necrosis factors (TNFs), chemokines andgrowth factors. The functions of cytokines will be described in detailat the appropriate times when particular immunological mechanisms arebeing explained. Cells in the body are never exposed to singlecytokines – they will be exposed to a number of different cytokines,probably produced by a number of different cell types (Wood, 2001).Different cytokines can either act cooperatively in promoting aresponse, or act antagonistically in inhibiting each other’s actions(Kuby, 1997, Wood, 2001).
| Family | Members | Comments |
| Interleukin (IL) | IL-1 to IL-22 | Different IL have different functions and are secreted by different cells |
| Interferon (IFN) | IFNa IFNb IFNg | Leucocyte IFN. Inhibits viral replication Fibroblast IFN. Inhibits viral replication Secreted by T lymphocytes and NK cells. Many immunoregulatory functions |
| Tumour necrosis Factor (TNF) | TNFa TNFb | Secreted by monocytes and other cells. Factor activates macrophages and endothelial cells. Secreted by T cells. Similar activity to TNFa |
| Colony-stimulating Factors (CSF) | G-CSF, M-CSF, GM-CSF and others | Originally identified by ability to make bone- marrowcells differentiate into particular cell type, e.g. neutrophil. Alsohave effects on mature cells of same lineage, e.g. monocytes,macrophages and neutrophils |
| Chemokine | MCP, Ecotaxin and others | Very important in controlling the migration of cells between and within tissues. Also influence function of many cells |
* Source: Wood, 2001
Macrophages and phagocytosis
Otherimportant components of innate immunity are phagocytic cells(macrophages, neutrophils) and other lymphocytes such as natural killer(NK) cells that do not require activation but can lyse certain infectedor abnormal cells. Macrophages are large leukocytes (any blood cellthat is not an erythrocyte; white blood cell) derived from monocytesthat functions in phagocytosis, antigen processing and presentation,secretion of cytokines, and antibody-dependent cell-mediatedcytotoxicity (ADCC). While explained in more detail later, ADCC is acell-mediated reaction in which non-specific cytotoxic cells thatexpress Fc receptors, such as neutrophils, macrophages, NK cells,recognise bound antibody on a target cell and subsequently causes lysis(destruction) of the target cell. Phagocytosis is a process by whichcertain cells (phagocytes) engulf microorganisms, other cells, andforeign particles (Figure 1).
Figure 1 - Recognition by phagocytes.Phagocytes must distinguish microbes and dead host cells from healthyhost cells so that healthy host cells are not phagocytosed. Phagocyteshave receptors on their surface that recognise sugars present onmicrobes or sugars that are newly expressed on dead or damaged hostcells. These sugars are not present on healthy host cells and thereforethe host cells are not phagocytosed (Source: Wood, 2001).
Natural Killer (NK) cells
Anotherpopulation of cells that form part of the innate immune system arenatural killer cells (NK) cells. NK cells are large, granularlymphocytes that are capable of lysing or killing infected or tumourcells without overt antigenic stimulation (recruiting specific immuneresponse). NK cells osmotically lyse target cells and induce apoptoticcell death. Apoptosis is known as programmed cell death that ischaracterised by morphologic changes including nuclear fragmentation,blebbing, and release of apoptotic bodies, which are phagocytosed. Incontrast to necrosis, it does not result in damage to surrounding cells(Kuby, 1997). NK cells lack the T lymphocyte receptor for antigenrecognition. Another important role for NK cells is in the inflammatoryresponse (discussed in more detail later). NK cells enter sites ofinflammation where they can be stimulated by a cytokine called IL-12that is produced by activated macrophages. The NK cells are stimulatedby IL-12 to produce IFN-g that is a powerful activator of macrophages(Wood, 2001). The cellular origin of natural killer cells is unknown.
Complement system
Target cellscan also be destroyed through the activation of complement which is acomplex series of interrelated proteins present in normal serum.Components of the complement system (i.e., activated components C3a,C3b through to C9) mediate and amplify immune reactions. Following therelease of chemotactic factors and histamine C3a this inducesconsiderable inflammation and tissue damage at the sites of reactionswith antibodies. Residual C3b component bound to the antigen-antibodycomplexes attaches to C3b receptors present on macrophages and thusacts as an opsonin, promoting enhanced phagocytosis.
Whereantibody has reacted with the surface of virus-infected or transformedcells, the complement system is activated to form a membrane attackcomplex resulting in cell lysis. The latter processes are known asantibody-dependent cellular cytotoxicity (ADCC). As with the effectorresponse to unwanted or ‘non-self’ antigen-presenting cells, awell-orchestrated in vivo system regulates the overproduction ofspecialised B and T lymphocytes (discussed in more depth later). Forexample, transforming growth factor (TGF)-ß inhibits B and T cellproliferation; INF-g inhibits IL-4 activation of B cells; and IL-4 /IL-10 inhibit INF-g activation of macrophages.
Inflammatory and acute phase responses
Usuallythere are not enough macrophages or monocytes present in tissue tophagocytose and remove all invading pathogens and therefore the tissuemacrophages must initiate a response that will bring additionalphagocytes, together with a variety of host proteins (cytokines) andcells (lymphocytes), to the site of infection from the bloodstream(Kuby, 1997). This response is known as the inflammatory response andin addition to removing pathogens it also eliminates dead or abnormalhost cells. Figure 2 illustrates the four main events occurring in aninflammatory response that are:
1. Vasodilation – causes increased blood flow to the area, increasing the supply of cells and factors
2.Activation of endothelial cells – lining the blood vessels makes themmore ‘sticky’ to white blood cells so that the blood cells can adheremore strongly to the endothelium
3. Increased vascular permeability– makes it easier for cells and proteins to pass through the bloodvessel walls and enter the tissue
4. Chemotactic factors are produced – these are molecules that attract cells into the tissue from the blood (Wood, 2001).
The first stage of the inflammatory response isrecognition of the pathogen and activation of tissue macrophages thaton stimulation, produce a number of factors including prostaglandins(small biologically active lipid molecules), platelet-activating factor(PAF) and cytokines (of particular importance are interleukin–2 andIL-8, and tumour necrosis factor-a or TNF-a ).
These cytokines act directly on the endothelium toincrease vascular permeability and PAF also causes platelets to releasehistamine (another agent that increases vascular permeability). IL-1and TNF-a activate endothelial cells lining the blood vessels at thesite of infection that causes these cells to express surface moleculesthat neutrophils in the bloodstream can bind to, enabling theneutrophils to leave the bloodstream and enter the tissue. Neutrophils(also promoted by IL-8) and macrophages eliminate pathogens by theprocess of phagocytosis (Wood, 2001).
Other cell types and biochemical pathways can also beactivated during an inflammatory response that can result in theaccumulation and activation of granulocytes and monocytes resulting inthe removal of pathogenic microorganisms by phagocytosis. Activation ofthe complement and clotting systems is also important for theinflammatory response. The complement system is made up of a number ofdifferent plasma proteins that participate in a controlled enzymaticcascade that results in damage to membranes of pathogenic organisms orabnormal cells, either destroying or facilitating their clearance. Theroles of activated complement components in eliminating pathogens andabnormal cells will be addressed later. The clotting system leads tothe cleavage of fibrinogen to generate fibrin threads that form bloodclots and fibrinopeptides with are chemotactic for phagocytes (Wood,2001).
If the pathogen is not eliminated the continuedrecruitment and stimulation of macrophages will lead to a rise in theconcentration of macrophage-derived cytokines in the plasma (Wood,2001). These cytokines can affect organs such as the brain and liver,that causes a systemic response known as an acute phase response. Ofparticular importance is the production of a series of proteins calledacute phase proteins (APPs) such as, fribrinogen (involved in theclotting and generation of fibrinopeptides), heptoglobulin (binds ironwhereby limiting bacterial growth), complement component C3 (itscleavage to C3a - activates mast cells that contain large granules ofhistamine, heparin and proteolytic enzymes (protein attacking), and C3b- helps phagocytes recognise pathogens), and proteins such asC-reactive and mannose binding proteins that target specific receptorson invading microorganisms facilitating their elimination byphagocytosis. Because the cells and proteins of the inflammatory andacute phase responses are pre-existing, they provide an immediateresponse to tissue damage and infection (Wood, 2001).
Acquired (non-specific) immunity
Acquired,or specific, immunity reflects the presence of a functional immunesystem that is capable of specifically recognising and selectivelyeliminating foreign microorganisms and molecules (i.e. foreignantigens). Unlike innate immune responses, acquired immune responsesare adaptive and display the following characteristics:
1. Antigenic specificity – permits the immune responseto distinguish subtle differences among antigens. Antibodies candifferentiate between two molecules that differ by a single amino acid(building block of proteins).
2. Diversity – it is capable of generating tremendousdiversity in its recognition molecules, allow it to specificallyrecognise billions of uniquely different structures on foreignantigens.
3. Immunologic memory – once the immune system hasrecognised and responded to an antigen, a second encounter with thesame antigen induces a heightened state of immune reactivity.
4. Self/nonself recognition - the immune systemnormally responds only to foreign antigens indicating that it iscapable of self/nonself recognition. The ability of the immune systemto distinguish self from nonself and respond only to nonself-moleculesis essential, for the outcome of an appropriate response toself-molecules can be a fatal autoimmune disease (Kuby, 1997).
Acquired immunity does not occur independently ofinnate immunity. The phagocytic cells (NK cells, neutrophils,macrophages) crucial for non-specific immunity are intimately involvedin the activation of the specific immune response. Conversely, varioussoluble factors produced during a specific immune response, have beenshown to augment the activity of these phagocytic cells. Thus, throughthe carefully orchestrated interplay of acquired and innate immunity,the two systems work in tandum to eliminate a foreign invader orabnormal cells (Kuby, 1997). Generation of an effective immune responseinvolves two major groups of cells: lymphocytes and antigen-presentingcells (APCs). Lymphocytes are one of the many types of white bloodcells produced in the bone marrow during the process known ashematopoiesis.
There are three general classes of cellsproduced from hematopoietic stem cells, (1) red blood cells(erythrocytes) that are responsible for oxygen transport, (2) plateletsthat are responsible for the control of bleeding, and (3) white bloodcells (lymphocytes), the vast majority of which are involved in hostimmunity. Lymphocytes leave the bone marrow, circulate in the blood andlymph system, and reside in various lymphoid organs (Kuby, 1997).Lymphocytes possess antigen-binding cell-surface receptors, mediate thedefining immunologic attributes of specificity, diversity, memory, andself/nonself recognition. There are two major populations oflymphocytes – B lymphocytes (B cells) and T lymphocytes (T cells)(Kuby, 1997).
B lymphocytes
B lymphocytesmature within the bone marrow and leave the marrow expressing a uniqueantigen-binding receptor on their membrane. The B cell receptor is amembrane-bound antibody molecule. Upon activation, B cells specific forthe antigen (usually foreign) proliferate and become antibody secretingor plasma cells. Antibodies are complex molecules (glycoproteins) thathave the property of combining specifically to the antigen that inducedits formation. The resulting antibodies bind to the invading pathogen,marking it for destruction by killer T-lymphocytes by a process calledantibody dependent cell cytotoxicity (ADCC).
Antibodies alsomark cells for phagocytosis by neutrophils and other phagocytic cellsby a process called opsonisation. Most of the daughter cells producedby B cell activation die within a few weeks but a proportion of themrecirculate in the body for many years as memory cells. If they arereintroduced to the same antigen that elicited an initial response,they rapidly become reactivated and produce antigen-specific antibody.This function provides the basis for vaccination. It is estimated thata single antibody secreting or plasma cell can produce more that 2000molecules of antibody per second (Kuby, 1997). Secreted antibodies arethe major effector molecules of humoral immunity
T lymphocytes
T-lymphocytes (Tcells) also arise from hematopoietic stem cells in the bone marrow.Unlike B cells, which mature within bone marrow, T cells migrate to thethymus gland to mature. During its maturation within the thymus, the Tcell comes to express a unique antigen-binding receptor on itsmembrane, called the T cell receptor (TCR). Unlike membrane boundantibodies on B cells, which can recognise antigen alone,
TCRs canonly recognise antigen that is associated with cell membrane proteinsknown as major histocompatability complex (MHC) molecules (Kuby, 1997).When a naïve T cell encounters antigen associated with a MHC moleculeon a cell, the T cell proliferates (clones) and differentiates intomemory T cells and various effector T cells.
There are twowell-defined subpopulations of T cells: T helper (TH) and T cytotoxic(TC) cells. T helper and T cytotoxic cells can be distinguished fromone another by the presence of either membrane glycoproteins CD4+ orCD8+ on their surfaces. T cells displaying CD4+ generally function asTH cells, whereas those displaying CD8+ function as TC cells. After aTH cell recognises and interacts with an antigen-MHC II moleculecomplex, the cell is activated and becomes an effector cell thatsecretes various cytokines. These secreted cytokines play an importantrole in activating B cells, TC cells, macrophages, and various other Tcells, and initiate the delayed type hypersensitivity (DTH) response.
TheDTH reaction promotes local inflammation resulting in the recruitmentof more lymphocytes and activated macrophages (i.e., convertedmonocytes from the bloodstream) to target cells. Under the influence ofTH-derived cytokines, a TC cell that recognises an antigen-MHC Imolecule complex proliferates and differentiates into an effector cellcalled a cytotoxic T lymphocyte (CTL). In contrast to the TH cell, theCTL generally does not secrete many cytokines and instead exhibitscytotoxic activity (Kuby, 1997). The CTL has a vital function inmonitoring the cells of the body and eliminating any that displayantigen, such as infected or tumour cells. Figure 3 illustrates keycellular interactions involved in induction of acquired immuneresponses.
Thus, acquired immunity is composed of activatedCD4 (TH) and CD8 (TC) cellular responses. Furthermore, TH cellsrecognise foreign proteins or antigens that have been processed throughan exogenous pathway by antigen-presenting cells such as dendriticcells in lymph nodes, macrophages or B cells expressing majorhistocompatability complex (MHC) class II molecules (Fig. 4). This MHCII mediated-recognition of foreign antigens causes TH cells to becomeactivated, whereupon differentiation occurs into functional subsetstermed T helper 1 or (TH1)-type and T helper 2 or (TH2)-type cells.Activation of TH cells is central to cellular immunity and isfacilitated through the action of IL-1 and INF-g secreted byantigen-presenting cells.
Cytokines such as INF-g and certain interleukins(including IL-2, IL-4, IL-5, IL-8, IL-10 and IL-12) assist TH cells inthe activation, proliferation and clonal expansion of effectorlymphocytes such as NK cells, TC cells and B cells. Additional factorsproduced by antigen-presenting cells, e.g., IL-1 and IL-6 act asco-stimulators of T cell activation.
Cytotoxic T lymphocytes(termed TC cells) recognise antigens that are processed through anendogenous pathway and presented by infected or transformed cellsexpressing MHC I class molecules (Fig. 4). TC cells also mediate theireffector function through the production of cytokines such as INF-g andtumour necrosis factor (TNF)-a and/or through a direct cytotoxicmechanism. The mechanism of cytotoxic killing can be mediated by therelease of granule contents such as perforin and granzyme from TC cellsresulting in irreparable pore formation in the cell membrane andapoptosis (i.e., programmed cell death). In addition, TC cells candestroy cells by a process of Fas-mediated lysis.
Antigen-presenting cells (APCs)
Activationof both humoral (antibody-generating) and cell-mediated (T-lymphocytes)branches of the immune system requires cytokines produced by TH cells(Kuby, 1997). It is essential that activation of TH cells be carefullyregulated as an inappropriate TH-cell response to self components canhave fatal autoimmune consequences. To ensure carefully regulatedactivation of TH cells, they only recognise antigen that is displayedtogether with class MHC II molecules on the surface ofantigen-presenting cells (APCs).
These specialised cells,which include macrophages, B lymphocytes, and dendritic cells, aredistinguished by two properties: (1) they express class II MHCmolecules on their membrane, and (2) they are able to deliver aco-stimulatory signal that is necessary for TH-cell activation (Kuby,1997). Dendritic cells are professional antigen-presenting cells thathave long membrane processes. They are found in the lymph nodes, andthymus (follicular and interdigitating dendritic cells); skin(Langerhans cells); and other tissues (interstitial dendritic cells)(Kuby, 1997). Indeed, dendritic cell ability to prime naïve CD4+ or THcells is a unique and critical function both in vitro and in vivo.
In the presence of soluble antigen, TH cells primed bydendritic cells can interact with B cells and stimulateantigen-specific antibody production. Dendritic cells are equallyimportant in priming CD8+ or TC cells. Interestingly, dendritic cellscan directly induce cytotoxic TC cell proliferation with help from THcells. It remains to be determined if the unique ability of dendriticcells to prime T lymphocytes results from the expression of uniquedendritic cells, or if it results from the high density of moleculesinvolved in dentritic cell (DC)/Tcell interactions. However, a crucialfactor for sustaining this DC/T cell interaction is the interaction ofco-stimulatory molecules on dendritic cells (CD40, CD83, CD86) andtheir ligands (i.e., any molecule recognised by a receptor) on the Tcells (Young and Steinman, 1990).
Therefore, as antigen-presenting cells (APC) they canalso elicit a local rapid reaction or cascade of events that triggersthe specific-immune responses. While APCs can be simply described asany cell that alters the immune system to respond to foreign invadersand cancer cells by presenting non-self molecules (or antigens) thatare associated with these infected or abnormal cells. Specifically,APCs are any cells that can process and present antigenic peptides(usually foreign) in association with class II MHC molecules(heterodimeric membrane proteins that function in antigen presentationto TH cells) on the surface of antigen-presenting cells or alteredself-cells. [for references, please see Chapter 6]
출처: http://blog.naver.com/hwanzzang78?Redirect=Log&logNo=80009127125
Posted by gwlee
