A Text Book of Immunology

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This is a book of immunology , helpfull for graduation and post graduation's students.
You may contact with me if any query @ aki-d-biotechnologist-mba@hotmail.com

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A Text Book of Immunology

  1. 1. A TexT book of Immunology edITed by ArkAbrATA bAnerjee b.sc bIoTech(h) from The unIversITy of burdwAn & TrAIned In mAgenTA pIgmenT producTIonfrom fungus In lAb. condITIon ,shrm bIoTech kolkATA & mbA from wbuT,AIcTe ……………………1 sT edITIon 2011…………………… IMMUNO BIOLOGY
  2. 2. An immune system is a system of biological structures and processes within an organism that protectsagainst disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents,from viruses to parasitic worms, and needs to distinguish them from the organisms ownhealthy cells and tissues in order to function properly. Detection is complicated as pathogenscan evolve rapidly, producing adaptations that avoid the immune system and allow the pathogens tosuccessfully infect their hosts.Immunity is a biological term that describes a state of having sufficient biological defenses toavoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide rangeof pathogens irrespective of antigenic specificity. Other components of the immune system adaptthemselves to each new disease encountered and are able to generate pathogen-specific immunity.Adaptive immunity is often sub-divided into two major types depending on how the immunity wasintroduced. Naturally acquired immunity occurs through contact with a disease causing agent, when thecontact was not deliberate, whereas artificially acquired immunity develops only through deliberateactions such as vaccination. Both naturally and artificially acquired immunity can be further subdivideddepending on whether immunity is induced in the host or passively transferred from a immunehost. Passive immunity is acquired through transfer of antibodies or activated T-cells from an immunehost, and is short lived -- usually lasting only a few months -- whereas active immunity is induced in thehost itself by antigen, and lasts much longer, sometimes life-long. The diagram below summarizes thesedivisions of immunity.A further subdivision of adaptive immunity is characterized by the cells involved; humoral immunity is theaspect of immunity that is mediated by secreted antibodies, whereas the protection provided by cellmediated immunity involves T-lymphocytes alone. Humoral immunity is active when the organismgenerates its own antibodies, and passive when antibodies are transferred between individuals. Similarly,cell mediated immunity is active when the organisms’ own T-cells are stimulated and passive when Tcells come from another organism.Passive immunityPassive immunity is the transfer of active immunity, in the form of readymade antibodies, from oneindividual to another. Passive immunity can occur naturally, when maternal antibodies are transferred to
  3. 3. the fetus through the placenta, and can also be induced artificially, when high levelsof human (or horse) antibodies specific for a pathogen or toxin are transferred to non-immune individuals.Passive immunization is used when there is a high risk of infection and insufficient time for the body todevelop its own immune response, or to reduce the symptoms of ongoingor immunosuppressive diseases. Passive immunity provides immediate protection, but the body does notdevelop memory, therefore the patient is at risk of being infected by the same pathogen later.Naturally acquired passive immunityMaternal passive immunity is a type of naturally acquired passive immunity, and refers to antibody-mediated immunity conveyed to a fetus by its mother during pregnancy. Maternal antibodies (MatAb) arepassed through the placenta to the fetus by an FcRn receptor on placental cells. This occurs around thethird month of gestation. IgG is the only antibodyisotype that can pass through the placenta. Passiveimmunity is also provided through the transfer of IgA antibodies found in breast milk that are transferred tothe gut of the infant, protecting against bacterial infections, until the newborn can synthesize its ownantibodies.Artificially acquired passive immunityArtificially acquired passive immunity is a short-term immunization induced by the transfer of antibodies,which can be administered in several forms; as human or animal blood plasma, as pooled humanimmunoglobulin for intravenous (IVIG) or intramuscular (IG) use, and in the form of monoclonalantibodies (MAb). Passive transfer is used prophylactically in the case of immunodeficiency diseases,such as hypogammaglobulinemia. It is also used in the treatment of several types of acute infection, andto treat poisoning.Immunity derived from passive immunization lasts for only a short period of time, andthere is also a potential risk for hypersensitivity reactions, and serum sickness, especially from gammaglobulin of non-human origin.The artificial induction of passive immunity has been used for over a century to treat infectious disease,and prior to the advent of antibiotics, was often the only specific treatment for certain infections.Immunoglobulin therapy continued to be a first line therapy in the treatment of severe respiratorydiseases until the 1930’s, even after sulfonamide antibiotics were introduced.Passive transfer of cell-mediated immunityPassive or "adoptive transfer" of cell-mediated immunity, is conferred by the transfer of "sensitized" oractivated T-cells from one individual into another. It is rarely used in humans because itrequires histocompatible (matched) donors, which are often difficult to find. In unmatched donors this typeof transfer carries severe risks of graft versus host disease. It has, however, been used to treat certaindiseases including some types of cancer and immunodeficiency. This type of transfer differs from a bonemarrow transplant, in which (undifferentiated) hematopoietic stem cells are transferred.Active immunity
  4. 4. The time course of an immune response. Due to the formation of immunological memory, reinfection at later time points leads to a rapid increase in antibody production and effector T cell activity. These later infections can be mild or even inapparent.When B cells and T cells are activated by a pathogen, memory B-cells and T- cells develop. Throughoutthe lifetime of an animal these memory cells will “remember” each specific pathogen encountered, andare able to mount a strong response if the pathogen is detected again. This type of immunity isboth active and adaptive because the bodys immune system prepares itself for future challenges. Activeimmunity often involves both the cell-mediated and humoral aspects of immunity as well as input fromthe innate immune system. The innate system is present from birth and protects an individual frompathogens regardless of experiences, whereas adaptive immunity arises only after an infection orimmunization and hence is "acquired" during life.Naturally acquired active immunityNaturally acquired active immunity occurs when a person is exposed to a live pathogen, and develops aprimary immune response, which leads to immunological memory.This type of immunity is “natural”because it is not induced by deliberate exposure. Many disorders of immune system function can affectthe formation of active immunity such asimmunodeficiency (both acquired and congenital forms)and immunosuppression.Artificially acquired active immunityArtificially acquired active immunity can be induced by a vaccine, a substance that contains antigen. Avaccine stimulates a primary response against the antigen without causing symptoms of the disease. Theterm vaccination was coined by Edward Jenner and adapted by Louis Pasteur for his pioneering work invaccination. The method Pasteur used entailed treating the infectious agents for those diseases so theylost the ability to cause serious disease. Pasteur adopted the name vaccine as a generic term in honor ofJenners discovery, which Pasteurs work built upon.Layered defenseThe immune system protects organisms from infection with layered defenses of increasing specificity. Insimple terms, physical barriers prevent pathogens such as bacteria and virusesfrom entering theorganism. If a pathogen breaches these barriers, the innate immune system provides an immediate, butnon-specific response. Innate immune systems are found in all plants and animals. If pathogenssuccessfully evade the innate response, vertebrates possess a third layer of protection, the adaptiveimmune system, which is activated by the innate response. Here, the immune system adapts its responseduring an infection to improve its recognition of the pathogen. This improved response is then retainedafter the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptiveimmune system to mount faster and stronger attacks each time this pathogen is encountered.
  5. 5. Components of the immune system Innate immune system Adaptive immune system Response is non-specific Pathogen and antigen specific response Exposure leads to immediate maximal response Lag time between exposure and maximal response Cell-mediated and humoral components Cell-mediated and humoral components No immunological memory Exposure leads to immunological memory Found in nearly all forms of life Found only in jawed vertebratesBoth innate and adaptive immunity depend on the ability of the immune system to distinguish betweenself and non-self molecules. In immunology, self molecules are those components of an organisms bodythat can be distinguished from foreign substances by the immune system. Conversely, non-self moleculesare those recognized as foreign molecules. One class of non-self molecules are called antigens (shortfor antibody generators) and are defined as substances that bind to specific immune receptors and elicitan immune respons.Surface barriersSeveral barriers protect organisms from infection, including mechanical, chemical, and biological barriers.The waxy cuticle of many leaves, the exoskeleton of insects, the shells and membranes of externallydeposited eggs, and skin are examples of the mechanical barriers that are the first line of defense againstinfection. However, as organisms cannot be completely sealed against their environments, other systemsact to protect body openings such as the lungs, intestines, and the genitourinary tract. In thelungs, coughing and sneezingmechanically eject pathogens and other irritants from the respiratory tract.The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by therespiratory and gastrointestinal tract serves to trap and entangle microorganisms.Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobialpeptides such as the β-defensins. Enzymes such as lysozyme and phospholipase A2 in saliva, tears,and breast milk are also antibacterials. Vaginal secretions serve as a chemical barrierfollowing menarche, when they become slightly acidic, while semencontains defensins and zinc to killpathogens. In the stomach, gastric acid and proteases serve as powerful chemical defenses againstingested pathogens.Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers bycompeting with pathogenic bacteria for food and space and, in some cases, by changing the conditions intheir environment, such as pH or available iron. This reduces the probability that pathogens will be able toreach sufficient numbers to cause illness. However, since most antibiotics non-specifically target bacteria
  6. 6. and do not affect fungi, oral antibiotics can lead to an “overgrowth” of fungi and cause conditions such asa vaginalcandidiasis (a yeast infection). There is good evidence that re-introduction of probiotic flora, suchas pure cultures of the lactobacilli normally found in unpasteurized yoghurt, helps restore a healthybalance of microbial populations in intestinal infections in children and encouraging preliminary data instudies on bacterial gastroenteritis, inflammatory bowel diseases,urinary tract infection and post-surgicalinfections.Innate immune system The innate immune system comprises the cells and mechanisms that defend the host from infection byother organisms, in a non-specific manner. This means that the cells of the innate system recognize andrespond to pathogens in a generic way, but unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host. Innate immune systems provide immediate defense againstinfection, and are found in all classes of plant and animal life.The innate system is thought to constitute an evolutionarily older defense strategy, and is the dominantimmune system found in plants, fungi, insects, and in primitive multicellular organisms.The major functions of the vertebrate innate immune system include: Recruiting immune cells to sites of infection, through the production of chemical factors, including specialized chemical mediators, called cytokines. Activation of the complement cascade to identify bacteria, activate cells and to promote clearance of dead cells or antibody complexes. The identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialized white blood cells. Activation of the adaptive immune system through a process known as antigen presentationCells of the innate immune response(a) LeukocytesWhite blood cells (WBCs), or leukocytes (also spelled "leucocytes"), are cells of the immunesystem involved in defending the body against both infectious disease and foreign materials.Five different and diverse types of leukocytes exist, but they are all produced and derived froma multipotent cell in the bone marrow known as a hematopoietic stem cell. Leukocytes are foundthroughout the body, including the blood andlymphatic system.The number of WBCs in the blood is often an indicator of disease. There are normally between 4×109 and1.1×1010 white blood cells in a litreof blood, making up approximately 1% of blood in a healthy adult. Anincrease in the number of leukocytes over the upper limits is calledleukocytosis, and a decrease belowthe lower limit is called leukopenia. The physical properties of leukocytes, such as volume, conductivity,and granularity, may change due to activation, the presence of immature cells, or the presenceof malignant leukocytes in leukemia.
  7. 7. scanning electron microscope image of normal circulatinghuman blood. In addition to the irregularly shaped leukocytes, both red blood cells and many small disc-shapedplatelets are visible.TypesThere are several different types of white blood cells. They all have many things in common, but are alldistinct in form and function. A major distinguishing feature of some leukocytes is the presenceof granules; white blood cells are often characterized as granulocytes or agranulocytes: Granulocytes (polymorphonuclear leukocytes): leukocytes characterised by the presence of differently staining granules in their cytoplasm when viewed under light microscopy. These granules are membrane-bound enzymes which primarily act in the digestion of endocytosed particles. There are three types of granulocytes: neutrophils, basophils, and eosinophils, which are named according to their staining properties. Agranulocytes (mononuclear leucocytes): leukocytes characterized by the apparent absence of granules in their cytoplasm. Although the name implies a lack of granules these cells do contain non-specific azurophilic granules, which are lysosomes. The cells include lymphocytes, monocytes, and macrophages.1.NeutrophilNeutrophil granulocytes are generally referred to as either neutrophils or polymorphonuclearneutrophils (or PMNs), and are subdivided into segmented neutrophils (or segs) and bandedneutrophils (or bands). Neutrophils are the most abundant type of white blood cells in mammals andform an essential part of the innate immune system. They form part of the polymorphonuclear cell family(PMNs) together withbasophils and eosinophils.Neutrophils are normally found in the blood stream. However, during the beginning (acute) phaseof inflammation, particularly as a result ofbacterial infection and some cancers, neutrophils are one of thefirst-responders of inflammatory cells to migrate toward the site of inflammation, firstly through the bloodvessels, then through interstitial tissue, following chemical signals (such as Interleukin-8 (IL-8) and C5a)in a process called chemotaxis. They are the predominant cells in pus, accounting for its whitish/yellowishappearance.Neutrophils are recruited to the site of injury within minutes following trauma and are the hallmark of acuteinflammation.
  8. 8. A neutrophil, stained with Wrights stain. This cell is approximately 12 µm indiameterWith the eosinophil and the basophil, they form the class of polymorphonuclear cells, named forthe nucleuss characteristic multilobulated shape (as compared to lymphocytes and monocytes, the othertypes of white cells). Neutrophils are the most abundant white blood cells in humans (approximately10^11 are produced daily) ; they account for approximately 70% of all white blood cells (leukocytes).A minor difference is found between the neutrophils from a male subject and a female subject. The cellnucleus of a neutrophil from a female subject shows a small additional X chromosome structure, knownas a "neutrophil drumstick".The average half-life of non-activated neutrophils in the circulation is about 12 hours. Upon activation,they marginate (position themselves adjacent to the blood vessel endothelium), and undergo selectin-dependent capture followed by integrin-dependent adhesion in most cases, after which they migrate intotissues, where they survive for 1–2 days.Neutrophils are much more numerous than the longer-lived monocyte/macrophage phagocytes.A pathogen (disease-causing microorganism or virus) is likely to first encounter a neutrophil. Someexperts hypothesize that the short lifetime of neutrophils is an evolutionary adaptation. The short lifetimeof neutrophils minimizes propagation of those pathogens that parasitize phagocytes because the moretime such parasites spend outside a host cell, the more likely they will be destroyed by some componentof the bodys defenses. Also, because neutrophil antimicrobial products can also damage host tissues,their short life limits damage to the host during inflammation.Neutrophils will often be phagocytosed themselves by macrophages after digestion ofpathogens. PECAM-1 and phosphatidylserine on the cell surface are involved in this process. Neutrophil granulocyte migrates from the blood vessel to the matrix, sensingproteolytic enzymes, in order to determine intercellular connections (to the improvement of its mobility) andenvelop bacteria through phagocytosis
  9. 9. Neutrophils undergo a process called chemotaxis, which allows them to migrate toward sites of infectionor inflammation. Cell surface receptors allow neutrophils to detect chemical gradients of molecules suchas interleukin-8 (IL-8), interferon gamma (IFN-gamma), and C5a, which these cells use to direct the pathof their migration.Anti-microbial functionBeing highly motile, neutrophils quickly congregate at a focus of infection, attractedby cytokines expressed by activated endothelium, mast cells, andmacrophages. Neutrophils express andrelease cytokines, which in turn amplify inflammatory reactions by several other cell types.In addition to recruiting and activating other cells of the immune system, neutrophils play a key role in thefront-line defence against invading pathogens. Neutrophils have three strategies for directly attackingmicro-organisms: phagocytosis (ingestion), release of soluble anti-microbials (including granule proteins)and generation of neutrophil extracellular traps (NETs).PhagocytosisNeutrophils are phagocytes, capable of ingesting microorganisms or particles. They can internalize andkill many microbes, each phagocytic event resulting in the formation of a phagosome into which reactiveoxygen species and hydrolytic enzymes are secreted. The consumption of oxygen during the generationof reactive oxygen species has been termed the "respiratory burst", although unrelated to respiration orenergy production.The respiratory burst involves the activation of the enzyme NADPH oxidase, whichproduces large quantities of superoxide, a reactive oxygen species. Superoxide dismutates,spontaneously or through catalysis via enzymes known as superoxide dismutases (Cu/ZnSOD andMnSOD), to hydrogen peroxide, which is then converted to hypochlorous acid HClO, by the green hemeenzyme myeloperoxidase. It is thought that the bactericidal properties of HClO are enough to kill bacteriaphagocytosed by the neutrophil, but this may instead be step necessary for the activation of proteases.Role in diseaseLow neutrophil counts are termed neutropenia. This can be congenital (genetic disorder) or it can developlater, as in the case of aplastic anemia or some kinds of leukemia. It can also be a side-effect of medication, most prominently chemotherapy. Neutropenia makes an individual highly susceptibleto infections. Neutropenia can be the result of colonization by intracellular neutrophilic parasites.Functional disorders of neutrophils are often hereditary. They are disorders of phagocytosis ordeficiencies in the respiratory burst (as in chronic granulomatous disease, a rare immune deficiency,and myeloperoxidase deficiency).In alpha 1-antitrypsin deficiency, the important neutrophil enzyme elastase is not adequately inhibitedby alpha 1-antitrypsin, leading to excessive tissue damage in the presence of inflammation - mostprominently pulmonary emphysema.In Familial Mediterranean fever (FMF), a mutation in the pyrin (or marenostrin) gene, which is expressedmainly in neutrophil granulocytes, leads to a constitutively active acute phase response and causesattacks of fever, arthralgia, peritonitis, and - eventually - amyloidosisNeutrophil Extracellular Traps(NETs)Zychlinsky and colleagues recently described a new striking observation that activation of neutrophilscauses the release of web-like structures of DNA; this represents a third mechanism for killingbacteria. These neutrophil extracellular traps (NETs) comprise a web of fibers composedof chromatin and serine proteases that trap and kill microbes extracellularly. It is suggested that NETs
  10. 10. provide a high local concentration of antimicrobial components and bind, disarm, and kill microbesindependent of phagocytic uptake. In addition to their possible antimicrobial properties, NETs may serveas a physical barrier that prevents further spread of pathogens. Trapping of bacteria may be a particularlyimportant role for NETs in sepsis, where NET are formed within blood vessels. Recently, NETs have beenshown to play a role in inflammatory diseases, as NETs could be detected in preeclampsia, a pregnancyrelated inflammatory disorder in which neutrophils are known to be activated.2.EosinophilEosinophil granulocytes, usually called eosinophils or eosinophiles (or, less commonly, acidophils),are white blood cells that are one of the immune system components responsible for combatingmulticellular parasites and certain infections in vertebrates. Along withmast cells, they also controlmechanisms associated with allergy and asthma. They are granulocytes that developduring haematopoiesisin the bone marrow before migrating into blood.These cells are eosinophilic or acid-loving as shown by their affinity to coal and tar dyes:Normally transparent, it is this affinity that causes them to appear brick-red after staining with eosin, ared dye, using the Romanowsky method. The staining is concentrated in small granules within thecellular cytoplasm, which contain many chemical mediators, such as histamine and proteins suchas eosinophil peroxidase, ribonuclease (RNase), deoxyribonucleases, lipase, plasminogen, and majorbasic protein. These mediators are released by a process called degranulation following activation of theeosinophil, and are toxic to both parasite and host tissues.In normal individuals, eosinophils make up about 1-6% of white blood cells, and are about12-17 micrometers in size. They are found in the medulla and the junction between the cortex andmedulla of the thymus, and, in the lower gastrointestinal tract, ovary, uterus, spleen, and lymph nodes,but not in the lung, skin, esophagus, or some other internal organs[vague] under normal conditions. Thepresence of eosinophils in these latter organs is associated with disease. Eosinophils persist in thecirculation for 8–12 hours, and can survive in tissue for an additional 8–12 days in the absence ofstimulation. Pioneering work in the 1980s elucidated that eosinophils were unique granulocytes, havingthe capacity to survive for extended periods of time after their maturation as demonstrated by ex-vivoculture experiments.
  11. 11. Eosinophil under the microscope (40x) from a peripheral bloodsmear. Red blood cells surround the eosinophil, two platelets at the top left corner.An increase in eosinophils, i.e., the presence of more than 500 eosinophils/microlitre of blood is calledan eosinophilia, and is typically seen in people with a parasitic infestation of theintestines,a collagen vascular disease (such as rheumatoid arthritis), malignant diseases such as Hodgkinsdisease, extensive skin diseases (such as exfoliative dermatitis), Addisons disease, in the squamousepithelium of the esophagus in the case of reflux esophagitis, eosinophilic esophagitis, and with the useof certain drugs such as penicillin. In 1989, contaminated L-tryptophan supplements caused a deadlyform of eosinophilia known as eosinophilia-myalgia syndrome, which was reminiscent of the Toxic OilSyndrome in Spain in 1981.Eosinophil development, migration and activationEosinophils develop and mature in bone marrow. They differentiate from myeloid precursor cells inresponse to the cytokines interleukin 3 (IL-3), interleukin 5 (IL-5), and granulocyte macrophage colony-stimulating factor (GM-CSF). Eosinophils produce and store many secondary granule proteins prior totheir exit from the bone marrow. After maturation, eosinophils circulate in blood and migrate toinflammatory sites in tissues, or to sites of helminth infection in responseto chemokines like CCL11 (eotaxin-1), CCL24 (eotaxin-2), CCL5 (RANTES), and certain leukotrienes likeleukotriene B4 (LTB4) and MCP1/4. At these infectious sites, eosinophils are activated by Type 2cytokines released from a specific subset ofhelper T cells (Th2); IL-5, GM-CSF, and IL-3 are important foreosinophil activation as well as maturation. There is evidence to suggest that eosinophil granule proteinexpression is regulated by the non-coding RNA EGOT (gene).Eosinophil granule proteinsFollowing activation by an immune stimulus, eosinophils degranulate to release an array of cytotoxicgranule cationic proteins that are capable of inducing tissue damage and dysfunction. These include: major basic protein (MBP) eosinophil cationic protein (ECP) eosinophil peroxidase (EPO) eosinophil-derived neurotoxin (EDN)Major basic protein, eosinophil peroxidase, and eosinophil cationic protein are toxic to manytissues. Eosinophil cationic protein and eosinophil-derived neurotoxinare ribonucleaseswith antiviral activity. Major basic protein induces mast cell and basophil degranulation,
  12. 12. and is implicated in peripheral nerve remodelling. Eosinophil cationic protein creates toxic pores in themembranes of target cells allowing potential entry of other cytotoxic molecules to the cell, caninhibit proliferation of T cells, suppress antibody production by B cells, induce degranulation by mast cells,and stimulate fibroblast cells to secrete mucus and glycosaminoglycan. Eosinophil peroxidaseforms reactive oxygen species and reactive nitrogen intermediates that promote oxidative stress in thetarget, causing cell death by apoptosis and necrosis.Functions of eosinophilsFollowing activation, eosinophils effector functions include production of: cationic granule proteins and their release by degranulation. reactive oxygen species such as superoxide, peroxide, and hypobromite (hypobromous acid, which is preferentially produced by eosinophil peroxidase). lipid mediators like the eicosanoids from the leukotriene (e.g., LTC4, LTD4, LTE4) and prostaglandin (e.g., PGE2) families. enzymes, such as elastase. growth factors such as TGF beta, VEGF, and PDGF. cytokines such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-13, and TNF alpha.In addition, eosinophils play a role in fighting viral infections, which is evident from the abundanceof RNAses they contain within their granules, and in fibrin removal during inflammation.Eosinophils along with basophils and mast cells, are important mediators of allergicresponses and asthma pathogenesis and are associated with disease severity. They alsofighthelminth (worm) colonization and may be slightly elevated in the presence of certain parasites.Eosinophils are also involved in many other biological processes, including postpubertalmammarygland development, oestrus cycling, allograft rejection and neoplasia. They have also recently beenimplicated in antigen presentation to T cells.TreatmentTreatments used to combat autoimmune diseases and conditions caused by eosinophils include: corticosteroids- promote apoptosis. Numbers of eosinophils in blood are rapidly reduced monoclonal antibody therapy- e.g., mepoluzimab or reslizumab against IL-5, prevents eosinophilopoiesis antagonists of leukotriene synthesis or receptors Gleevec (STI571)- inhibits PDGF-BB in hypereosinophilic leukemia3.BasophilBasophil granulocytes, sometimes referred to as basophils, are the least common of the granulocytes,representing about 0.01% to 0.3% of circulatingwhite blood cells.The name comes from the fact that these leukocytes are basophilic, i.e., they are susceptibleto staining by basic dyes, as shown in the picture.Basophils contain large cytoplasmic granules which obscure the cell nucleus under the microscope.However, when unstained, the nucleus is visible and it usually has 2 lobes. The mast cell,
  13. 13. a cell in tissues, has many similar characteristics. For example, both cell types store histamine, achemical that is secreted by the cells when stimulated in certain ways (histamine causes some of thesymptoms of an allergic reaction). Like all circulating granulocytes, basophils can be recruited out ofthe blood into a tissue when needed. Basophil Basophil granulocyteBasophils of mouse and human have consistent immunophenotypes as follows: FcεRI+,CD123, CD49b(DX-5)+, CD69+, Thy-1.2+, 2B4+, CD11bdull, CD117(c- – – – – – – – – – –kit) , CD24 , CD19 , CD80 ,CD14 , CD23 , Ly49c , CD122 , CD11c , Gr-1 , NK1.1–, B220–, CD3–,γδTCR–, αβTCR–, α4 and β4-integrin negative.SecretionsWhen activated, basophils degranulate torelease histamine, proteoglycans (e.g. heparin and chondroitin), and proteolyticenzymes (e.g. elastase and lysophospholipase). They also secrete lipid mediators like leukotrienes, andseveral cytokines. Histamine and proteoglycans are pre-stored in the cells granules while the othersecreted substances are newly generated. Each of these substances contributes to inflammation. Recentevidence suggests that basophils are an important source of the cytokine, interleukin-4, perhaps moreimportant than T cells. Interleukin-4 is considered one of the critical cytokines in the development ofallergies and the production of IgE antibody by the immune system. There are other substances that canactivate basophils to secrete which suggests that these cells have other roles in inflammation.Basopenia (a low basophil count) is difficult to demonstrate as the normal basophil count is so low; it hasbeen reported in association with autoimmune urticaria (a chronic itching condition). Basophilia is alsouncommon but may be seen in some forms of leukaemia or lymphoma.FunctionBasophils appear in many specific kinds of inflammatory reactions, particularly those that cause allergicsymptoms. Basophils contain anticoagulant heparin, which prevents blood from clotting too quickly. Theyalso contain the vasodilator histamine, which promotes blood flow to tissues. They can be found inunusually high numbers at sites of ectoparasite infection, e.g.,ticks. Like eosinophils, basophils play a rolein both parasitic infections and allergies. They are found in tissues where allergic reactions are occurringand probably contribute to the severity of these reactions. Basophils have protein receptors on their cellsurface that bindIgE, an immunoglobulin involved in macroparasite defense and allergy. It is the boundIgE antibody that confers a selective response of these cells to environmental substances, forexample, pollen proteins or helminth antigens. Recent studies in mice suggest that basophils may alsoregulate the behavior of T cells and mediate the magnitude of the secondary immune response.
  14. 14. 4.LymphocytThis is under the adaptive immune system. A stained lymphocyte surrounded byred blood cells viewed using a lightmicroscope. A scanning electron microscope(SEM) image of a single human lymphocyte.A particular class of leukocytes known as lymphocyte mostly carry out the specific acquired immuneresponse.Lymphocytes are much more common in the lymphatic system. Lymphocytes are distinguishedby having a deeply staining nucleus which may be eccentric in location, and a relatively small amount ofcytoplasm.Lymphocytes provide both the specificity and memory which are characteristic of the adaptiveimmune response.DevelopmentMammalian stem cells differentiate into several kinds of blood cell within the bone marrow. This processis calledhaematopoiesis. All lymphocytes originate, during this process, from a common lymphoidprogenitor before differentiating into their distinct lymphocyte types. The differentiation of lymphocytesfollows various pathways in a hierarchical fashion as well as in a more plastic fashion. The formation oflymphocytes is known as lymphopoiesis. B cells mature into B lymphocytes in the bone marrow, while Tcells migrate to and mature in a distinct organ, called the thymus. Following maturation, the lymphocytesenter the circulation and peripheral lymphoid organs (e.g. the spleen and lymph nodes) where theysurvey for invading pathogensand/or tumor cells.The lymphocytes involved in adaptive immunity (i.e. B and T cells) differentiate further after exposure toan antigen; they form effector and memory lymphocytes. Effector lymphocytes function to eliminate theantigen, either by releasing antibodies (in the case of B cells), cytotoxic granules (cytotoxic T cells) or bysignaling to other cells of the immune system (helper T cells).Memory cells remain in the peripheraltissues and circulation for an extended time ready to respond to the same antigen upon future exposure.Characteristics
  15. 15. Microscopically, in a Wrights stained peripheral blood smear, a normal lymphocyte has a large, dark-staining nucleus with little to no eosinophiliccytoplasm. In normal situations, the coarse, dense nucleus ofa lymphocyte is approximately the size of a red blood cell (about 7 micrometres in diameter). Somelymphocytes show a clear perinuclear zone (or halo) around the nucleus or could exhibit a small clearzone to one side of the nucleus. Polyribosomes are a prominent feature in the lymphocytes and can beviewed with an electron microscope. The ribosomes are involved in protein synthesis allowing thegeneration of large quantities of cytokines and immunoglobulins by these cells.It is impossible to distinguish between T cells and B cells in a peripheral blood smear. Normally, flowcytometry testing is used for specific lymphocyte population counts. This can be used to specificallydetermine the percentage of lymphocytes that contain a particular combination of specific cell surfaceproteins, such as immunoglobulins or cluster of differentiation (CD) markers or that produce particularproteins (for example,cytokines using intracellular cytokine staining (ICCS)). In order to study the functionof a lymphocyte by virtue of the proteins it generates, other scientific techniques likethe ELISPOT or secretion assay techniques can be used.Lymphocytes and diseaseA lymphocyte count is usually part of a peripheral complete blood cell count and is expressed aspercentage of lymphocytes to total white blood cells counted.A general increase in the number of lymphocytes is known as lymphocytosis whereas a decreaseis lymphocytopenia.HighAn increase in lymphocyte concentration is usually a sign of a viral infection (in some rarecase, leukemias are found through an abnormally raised lymphocyte count in an otherwise normalperson).LowA low normal to low absolute lymphocyte concentration is associated with increased rates of infectionafter surgery or trauma.One basis for low T cell lymphocytes occurs when the human immunodeficiency virus (HIV) infects anddestroys T cells (specifically, the CD4+ subgroup of T lymphocytes). Without the key defense that these Tcells provide, the body becomes susceptible to opportunistic infections that otherwise would not affecthealthy people. The extent of HIV progression is typically determined by measuring the percentage ofCD4+ T cells in the patients blood. The effects of other viruses or lymphocyte disorders can also often beestimated by counting the numbers of lymphocytes present in the blood.TypesThe blood has three types of lymphocytes: B cells: B cells make antibodies that bind to pathogens to enable their destruction. (B cells not only make antibodies that bind to pathogens, but after an attack, some B cells will retain the ability to produce an antibody to serve as a memory system.) T cells:  CD4+ (helper) T cells co-ordinate the immune response and are important in the defense against intracellular bacteria. In acute HIV infection, these T cells are the main index to identify the
  16. 16. individuals immune system activity. Research has shown that CD8+ cells are also another index to identify humans immune activity.  CD8+ cytotoxic T cells are able to kill virus-infected and tumor cells.  γδ T cells possess an alternative T cell receptor as opposed to CD4+ and CD8+ αβ T cells and share characteristics of helper T cells, cytotoxic T cells and natural killer cells. Natural killer cells: Natural killer cells are able to kill cells of the body which are displaying a signal to kill them, as they have been infected by a virus or have become cancerous.T cell Scanning electron micrograph of T lymphocyte (right), a platelet (center)and ared blood cell (left)T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play acentral role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as Bcells and natural killer cells (NK cells) by the presence of a special receptor on their cell surface called Tcell receptors (TCR). The abbreviation T, in T cell, stands for thymus, since this is the principal organresponsible for the T cells maturation. Several different subsets of T cells have been discovered, eachwith a distinct function.TypesHelperT helper cell (TH cells) assist other white blood cells in immunologic processes, including maturation of Bcells into plasma cells and activation of cytotoxic T cells and macrophages, among other functions. Thesecells are also known as CD4+ T cells because they express the CD4 protein on their surface. Helper Tcells become activated when they are presented with peptide antigens by MHC class II molecules that areexpressed on the surface of Antigen Presenting Cells (APCs). Once activated, they divide rapidly andsecrete small proteins called cytokines that regulate or assist in the active immune response. These cellscan differentiate into one of several subtypes, including TH1, TH2, TH3, TH17, or TFH, which secretedifferent cytokines to facilitate a different type of immune response. The mechanism by which T cells aredirected into a particular subtype is poorly understood, though signalling patterns from the APC arethought to play an important role.CytotoxicCytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicatedin transplant rejection. These cells are also known as CD8+ T cells since they expressthe CD8 glycoprotein at their surface. These cells recognize their targets by binding to antigen associatedwith MHC class I, which is present on the surface of nearly every cell of the body. Through IL-10,
  17. 17. adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to ananergic state, which prevent autoimmune diseases such as experimental autoimmune encephalomyelitis.MemoryMemory T cells are a subset of antigen-specific T cells that persist long-term after an infection hasresolved. They quickly expand to large numbers of effector T cells upon re-exposure to their cognateantigen, thus providing the immune system with "memory" against past infections. Memory T cellscomprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells).Memory cells may be either CD4+ or CD8+. Memory T cells typically express the cell surface proteinCD45RO.RegulatoryRegulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial for the maintenanceof immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end ofan immune reaction and to suppress auto-reactive T cells that escaped the process of negative selectionin the thymus. Two major classes of CD4+ regulatory T cells have been described, including the naturallyoccurring Treg cells and the adaptive Treg cells. Naturally occurring Treg cells (also known asCD4+CD25+FoxP3+ Treg cells) arise in the thymus, whereas the adaptive Treg cells (also known as Tr1 cellsor Th3 cells) may originate during a normal immune response. Naturally occurring Treg cells can bedistinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations ofthe FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX.Natural killerNatural killer T cells (NKT cells) are a special kind of lymphocyte that bridges the adaptive immunesystem with the innate immune system. Unlike conventional T cells that recognize peptide antigenpresented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigenpresented by a molecule called CD1d. Once activated, these cells can perform functions ascribed to bothTh and Tc cells (i.e., cytokine production and release of cytolytic/cell killing molecules). They are also ableto recognize and eliminate some tumor cells and cells infected with herpes viruses.γδγδ T cells (gamma delta T cells) represent a small subset of T cells that possess a distinct T cellreceptor (TCR) on their surface. A majority of T cells have a TCR composed of twoglycoprotein chainscalled α- and β- TCR chains. However, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain.This group of T cells is much less common (2% of total T cells) than the αβ T cells, but are found at theirhighest abundance in the gut mucosa, within a population of lymphocytes known as intraepitheliallymphocytes (IELs). The antigenic molecules that activate γδ T cells are still widely unknown. However,γδ T cells are not MHC restricted and seem to be able to recognize whole proteins rather than requiringpeptides to be presented by MHC molecules on antigen presenting cells. Some murine γδ T cellsrecognize MHC class IB molecules though. Human Vγ9/Vδ2 T cells, which constitute the major γδ T cellpopulation in peripheral blood, are unique in that they specifically and rapidly respond to a set of non-peptidic phosphorylated metabolites precursors of cholesterol, collectively named phosphoantigens.Phosphoantigens are produced by virtually all living cells. The most common phosphoantigens fromanimal and human cells (including cancer cells) are isopentenyl pyrophosphate (IPP) and its isomerdimethylallyl pyrophosphate (DMAPP), while in microbes the most common phosphoantigens areprecursors of eubacterial dimethylallyl pyrophosphate (Hydroxy-DMAPP, also known as HMBPP)andcorresponding mononucleotide conjugates. Plant cells produce both types of phosphoantigens. Drugsactivating human Vγ9/Vδ2 T cells comprise synthetic phosphoantigens and aminobisphosphonates,which respectively mimick natural phosphoantigens and by up-regulating endogenous IPP/DMAPP.
  18. 18. Typical recognition markers for lymphocytes[CLASS FUNCTION PROPORTION PHENOTYPIC MARKER(S) Lysis of virally infected cells and tumourNK cells 7% (2-13%) CD16 CD56 but not CD3 cellsHelper T Release cytokines and growth factors 46% (28-59%) TCRαβ, CD3 and CD4cells that regulate other immune cellsCytotoxic T Lysis of virally infected cells, tumour 19% (13-32%) TCRαβ, CD3 and CD8cells cells and allograftsγδ T cells Immunoregulation and cytotoxicity TCRγδ and CD3B cells Secretion of antibodies 23% (18-47%) MHC class II, CD19 and CD21Development in the thymusAll T cells originate from haematopoietic stem cells in the bone marrow. Haematopoietic progenitorsderived from haematopoietic stem cells populate the thymus and expand by cell division to generate alarge population of immature thymocytes. The earliest thymocytes express neither CD4 nor CD8, and aretherefore classed as double-negative (CD4-CD8-) cells. As they progress through their development theybecome double-positive thymocytes (CD4+CD8+), and finally mature to single-positive (CD4+CD8- or CD4-CD8+) thymocytes that are then released from the thymus to peripheral tissues.About 98% of thymocytes die during the development processes in the thymus by failing either positiveselection or negative selection, whereas the other 2% survive and leave the thymus to become matureimmunocompetent T cells.The thymus contributes more naive T cells at younger ages. As the thymus shrinks by about 3% a yearthroughout middle age, there is a corresponding fall in the thymic production of naive T cells, leavingperipheral T cell expansion to play a greater role in protecting older subjects.Positive selectionPositive selection "selects for" T-cells capable of interacting with MHC. Double-positive thymocytes (CD4+/CD8+) move deep into the thymic cortex where they are presented with self-antigens (i.e., antigens that are derived from molecules belonging to the host of the T cell) complexedwith MHC molecules on the surface of cortical epithelial cells. Only those thymocytes that bind theMHC/antigen complex with adequate affinity will receive a vital "survival signal." The implication of thisbinding is that all T cells must be able to recognize self antigens to a certain degree. Developingthymocytes that do not have adequate affinity cannot serve useful functions in the body (i.e. the cellsmust be able to interact with MHC and peptide complexes in order to effect immune responses). Also, thethymocyte must be able to recognize antigens that are self from non-self.). Because of this,the thymocytes with no affinity for self antigens die by apoptosis and are engulfed by macrophages.A thymocytes fate is also determined during positive selection. Double-positive cells (CD4 +/CD8+) that arepositively selected on MHC class II molecules will eventually become CD4+cells, while cells positivelyselected on MHC class I molecules mature into CD8+ cells. A T cell becomes a CD4+ cell bydownregulating expression of its CD8 cell surface receptors. If the cell does not lose its signal through theITAM pathway, it will continue downregulating CD8 and become a CD4 +, single positive cell. But if there is
  19. 19. signal drop, the cell stops downregulating CD8 and switches over to downregulating CD4 moleculesinstead, eventually becoming a CD8+, single positive cell.This process does not remove thymocytes that may cause autoimmunity. The potentially autoimmunecells are removed by the process of negative selection (discussed below).Negative selectionNegative selection removes thymocytes that are capable of strongly binding with "self" peptidespresented by MHC. Thymocytes that survive positive selection migrate towards the boundary of thethymic cortex and thymic medulla. While in the medulla, they are again presented with self-antigen incomplex with MHC molecules on antigen-presenting cells (APCs) such as dendriticcells and macrophages. Thymocytes that interact too strongly with the antigen receive an apoptotic signalthat leads to cell death. The vast majority of all thymocytes end up dying during this process. Theremaining cells exit the thymus as mature naive T cells. This process is an important componentof immunological tolerance and serves to prevent the formation of self-reactive T cells that are capable ofinducing autoimmune diseases in the host.In summary, positive selection selects for T cells that are capable of recognizing self antigens throughMHC. Negative selection selects for T cells that bind too strongly to self antigens. These two selectionprocesses allow for Tolerance of self by the immune system. They do not necessarily occur in achronological order and can occur simultaneously in the thymus.Maturation paradoxPositive and negative selection should theoretically kill all developing T cells. The first stage of selectionkills all T cells that do not interact with self-MHC, while the second stage selection kills all cells that do.This poses the question: How do we have immunity at all? Currently, two models attempt to explain this: 1. Differential Avidity Hypothesis - the strength of the signal dictates the fate of the T cell.The differential avidity hypothesis (or simply avidity hypothesis) is one of two models that attempt toexplain how humans have immunity despite such aggressive selection (positive and negative) to killdeveloping T cells during their maturation process. The other model is the Differential SignalingHypothesis.The Avidity hypothesis states that the affinity of the T-cell receptor for the MHC:peptide complex alongwith the density of the complex provide different signal strength upon binding which in terms dictate theoutcome: 1. strong signal leads to negative selection and thus apoptosis. 2. weak signal leads to positive selection and thus rescued from apoptosis. 2. Differential Signaling Hypothesis - the signals that are transduced differ at each stage.
  20. 20. The differential avidity hypothesis (or simply avidity hypothesis) is one of two models that attempt toexplain how humans have immunity despite such aggressive selection (positive and negative) to killdeveloping T cells during their maturation process. The other model is the Differential SignalingHypothesis.The Avidity hypothesis states that the affinity of the T-cell receptor for the MHC:peptide complex alongwith the density of the complex provide different signal strength upon binding which in terms dictate theoutcome: 1. strong signal leads to negative selection and thus apoptosis. 2. weak signal leads to positive selection and thus rescued from apoptosis.ActivationAlthough the specific mechanisms of activation vary slightly between different types of T cells, the "two-signal model" in CD4+ T cells holds true for most. Activation of CD4+ T cells occurs through theengagement of both the T cell receptor and CD28 on the T cell by the Major histocompatibilitycomplex peptide and B7 family members on the APC, respectively. Both are required for production of aneffective immune response; in the absence of CD28 co-stimulation, T-cell receptor signalling alone resultsin anergy. The signalling pathways downstream from both CD28 and the T cell receptor involve manyproteins.The first signal is provided by binding of the T cell receptor to a short peptide presented by the majorhistocompatibility complex (MHC) on another cell. This ensures that only a T cell with a TCR specific tothat peptide is activated. The partner cell is usually a professional antigen presenting cell (APC), usuallya dendritic cell in the case of naïve responses, although B cells and macrophages can be importantAPCs. The peptides presented to CD8+ T cells by MHC class I molecules are 8-9 amino acids in length;the peptides presented to CD4+ cells by MHCclass II molecules are longer, as the ends of the bindingcleft of the MHC class II molecule are open.The second signal comes from co-stimulation, in which surface receptors on the APC are induced by arelatively small number of stimuli, usually products of pathogens, but sometimes breakdown products ofcells, such as necrotic-bodies or heat-shock proteins. The only co-stimulatory receptor expressedconstitutively by naïve T cells is CD28, so co-stimulation for these cells comes fromthe CD80 and CD86proteins, which together constitute the B7 protein, (B7.1 and B7.2 respectively) onthe APC. Other receptors are expressed upon activation of the T cell, such as OX40 and ICOS, but theselargely depend upon CD28 for their expression. The second signal licenses the T cell to respond to anantigen. Without it, the T cell becomes anergic, and it becomes more difficult for it to activate in future.This mechanism prevents inappropriate responses to self, as self-peptides will not usually be presentedwith suitable co-stimulation.The T cell receptor exists as a complex of several proteins. The actual T cell receptor is composed of twoseparate peptide chains, which are produced from the independent T cell receptor alpha and beta (TCRαand TCRβ) genes. The other proteins in the complex are the CD3proteins: CD3εγ and CD3εδheterodimers and, most important, a CD3ζ homodimer, which has a total of six ITAM motifs. The ITAMmotifs on the CD3ζ can be phosphorylated by Lck and in turn recruit ZAP-70. Lck and/or ZAP-70 can also
  21. 21. phosphorylate the tyrosines on many other molecules, not least CD28, , LAT and SLP-76, which allowsthe aggregation of signalling complexes around these proteins.Phosphorylated LAT recruits SLP-76 to the membrane, where it can then bring in PLCγ, VAV1, Itk andpotentially PI3K. Both PLCγ and PI3K act on PI(4,5)P2 on the inner leaflet of the membrane to create theactive intermediaries diacylglycerol (DAG), inositol-1,4,5-trisphosphate (IP3), andphosphatidlyinositol-3,4,5-trisphosphate (PIP3). DAG binds and activates some PKCs, most important, inT cells PKCθ, a process important for activating the transcription factors NF-κB and AP-1. IP3 is releasedfrom the membrane by PLCγ and diffuses rapidly to activate receptors on the ER, which induce therelease of calcium. The released calcium then activates calcineurin, and calcineurin activates NFAT,which then translocates to the nucleus. NFAT is a transcription factor, which activates the transcription ofa pleiotropic set of genes, most notable, IL-2, a cytokine
  22. 22. that promotes long term proliferation of activated T cells.T cell activationB cellB cells are lymphocytes that play a large role in the humoral immune response (as opposed to the cell-mediated immune response, which is governed by T cells). The principal functions of B cells are tomake antibodies against antigens, perform the role of antigen-presenting cells(APCs) and eventuallydevelop into memory B cells after activation by antigen interaction. B cells are an essential component ofthe adaptive immune system.
  23. 23. The abbreviation "B", in B cell, comes from the bursa of Fabricius in birds, where they mature. Inmammals, immature B cells are formed in thebone marrow, which is used as a backronym for the cellsname.The cells of the immune system that make antibodies to invading pathogens like viruses. They form memory cellsthat remember the same pathogen for faster antibody production in future infections.B cells exist as clones. All B cells derive from a particular cell, and thus, the antibodies their differentiatedprogenies (see below) produce can recognize and/or bind the same components (epitope) of a givenantigen. Such clonality has important consequences, as immunogenic memory relies on it. The greatdiversity in immune response comes about because there are up to 109 clones with specificities forrecognizing different antigens. A single B cell or a clone of cells with shared specificity upon encounteringits specific antigen divides to produce many B cells. Most of such B cells differentiate into plasma cellsthat secrete antibodies into blood that bind the same epitope that elicited proliferation in the first place. Asmall minority survives as memory cells that can recognize only the same epitope. However, with eachcycle, the number of surviving memory cells increases. The increase is accompanied by affinitymaturation which induces the survival of B cells that bind to the particular antigen with high affinity. Thissubsequent amplification with improved specificity of immune response is known as secondary immuneresponse. B cells that encounter antigen for the first time are known as naive B cells.Development of B cellsImmature B cells are produced in the bone marrow of most mammals. Rabbits are an exception; their Bcells develop in the appendix-sacculus rotundus. After reaching the IgM+ immature stage in the bonemarrow, these immature B cells migrate to the spleen, where they are called transitional B cells, andsome of these cells differentiate into mature B lymphocytes.B cell development occurs through several stages, each stage representing a change in the genomecontent at the antibody loci. An antibody is composed of two identical light (L) and two identical heavy (H)chains, and the genes specifying them are found in the V (Variable) region and the C (Constant) region.In the heavy-chain V region there are three segments; V, D and J, which recombine randomly, in aprocess called VDJ recombination, to produce a unique variable domain in the immunoglobulin of eachindividual B cell. Similar rearrangements occur for light-chain V region except there are only twosegments involved; V and J. The list below describes the process of immunoglobulin formation at thedifferent stages of B cell development.When the B cell fails in any step of the maturation process, it will die by a mechanism called apoptosis,here called clonal deletion. B cells are continuously produced in the bone marrow. When B cell receptorson the surface of the cell matches the detected antigens present in the body, the B cell proliferates and
  24. 24. secretes a free form of those receptors (antibodies) with identical binding sites as the ones on the originalcell surface. After activation, the cell proliferates and B memory cells would form to recognise the sameantigen. This information would then be used as a part of the adaptive immune system for a more efficientand more powerful immune response for future encounters with that antigen.B cell membrane receptors evolve and change throughout the B cell life span. TACI, BCMA and BAFF-R are present on both immature B cells and mature B cells. All of these 3 receptors may be inhibitedby Belimumab. CD20 is expressed on all stages of B cell development except the first and last; it ispresent from pre-pre B cells through memory cells, but not on either pro-B cells or plasma cells.Immune ToleranceLike its fellow lymphocyte, the T cell, immature B cells are tested for auto-reactivity by the immune systembefore leaving the bone marrow. In the bone marrow (the central lymphoid organ), central tolerance isproduced. The immature B cells whose B cell Receptors (BCRs) bind too strongly to self antigens will notbe allowed to mature. If B cells are found to be highly reactive to self, three mechanisms can occur. Clonal deletion: the removal, usually by apoptosis, of B cells of a particular self antigen specificity. Receptor editing: the BCRs of self reactive B cells are given an opportunity to rearrange their conformation. This process occurs via the continued expression of the Recombination activating gene (RAG). Through the help of RAG, receptor editing involves light chain gene rearrangement of the B cell receptor. If receptor editing fails to produce a BCR that is less autoreactive, apoptosis will occur. Note that defects in the RAG-1 and RAG-2 genes are implicated in Severe Combined Immunodeficiency (SCID). The inability to recombine and generate new receptors lead to failure of maturity for both B cells and T cells. Anergy: B cells enter a state of permanent unresponsiveness when they bind with weakly cross- linking self antigens that are small and soluble.FunctionsThe human body makes millions of different types of B cells each day that circulate inthe blood and lymphatic system performing the role of immune surveillance. They do notproduceantibodies until they become fully activated. Each B cell has a unique receptor protein (referred toas the B cell receptor (BCR)) on its surface that will bind to one particular antigen. The BCR is amembrane-bound immunoglobulin, and it is this molecule that allows the distinction of B cells from othertypes of lymphocyte, as well as being the main protein involved in B cell activation. Once a B cellencounters its cognate antigen and receives an additional signal from a T helper cell, it can furtherdifferentiate into one of the two types of B cells listed below (plasma B cells and memory B cells). The Bcell may either become one of these cell types directly or it may undergo an intermediate differentiationstep, the germinal centerreaction, where the B cell will hypermutate the variable region ofits immunoglobulin gene ("somatic hypermutation") and possibly undergo class switching.B cell types . Plasma B cells (also known as plasma cells) are large B cells that have been exposed to antigenand produce and secrete large amounts ofantibodies, which assist in the destruction of microbes bybinding to them and making them easier targets for phagocytes and activation of thecomplement system.They are sometimes referred to as antibody factories. An electron micrograph of these cells reveals largeamounts of rough endoplasmic reticulum, responsible for synthesizing the antibody, in the
  25. 25. cells cytoplasm. These are short lived cells and undergo apoptosis when the inciting agent that inducedimmune response is eliminated. This occurs because of cessation of continuous exposure tovarious colony stimulating factors required for survival. Memory B cells are formed from activated B cells that are specific to the antigen encountered during the primary immune response. These cells are able to live for a long time, and can respond quickly following a second exposure to the same antigen. B-1 cells express IgM in greater quantities than IgG and their receptors show polyspecificity, meaning that they have low affinities for many different antigens, but have a preference for other immunoglobulins, self antigens and common bacterial polysaccharides. B-1 cells are present in low numbers in the lymph nodes and spleen and are instead found predominantly in the peritoneal and pleural cavities. B-2 cells are the conventional B cells.Marginal-zone B cellsMarginal zone B cells are noncirculating mature B cells that segregate anatomically into the marginalzone (MZ) of the spleen. This region contains multiple subtypes ofmacrophages, dendritic cells, and theMZ B cells; it is not fully formed until 2 to 3 weeks after birth in rodents and 1 to 2 years in humans. TheMZ B cells within this region typically express high levels of sIgM, CD21, CD1, CD9 with low to negligiblelevels of sIgD, CD23, CD5, and CD11b that help to distinguish them phenotypically from FO B cells andB1 B cells.Similar to B1 B cells, MZ B cells can be rapidly recruited into the early adaptive immune responses in a Tcell independent manner. The MZ B cells are especially well positioned as a first line of defense againstsystemic blood-borne antigens that enter the circulation and become trapped in the spleen. MZ B cellsalso display a lower activation threshold than their FO B cell counterparts with heightened propensity forPC differentiation that contributes further to the accelerated primary antibody responseFollicular B CellsFollicular B cells (FO B cells) are a type of B cell that reside in primary and secondary lymphoid follicles(containing germinal centers) of secondary and tertiary lymphoid organs, including spleen and lymphnodes.The mature B cells from the spleen can be divided into two main populations: the FO B cells, whichconstitute the majority, and the marginal zone B-cells, lining outside the marginal sinus and border the redpulp. FO B cells express high levels of IgM, IgD, and CD23; lower C21; and no CD1 or CD5, readilydistinguishing this compartment from B1 B cells andmarginal zone B-cells . FO B cells organize into theprimary follicles of B cell zones focused around follicular dendritic cells in the white pulp of the spleen andthe cortical areas of peripheral lymph nodes. Multiphoton-based live imaging of lymph nodes indicatecontinuous movement of FO B cells within these follicular areas at velocites of ~6 µm per min. Recentstudies indicate movement along the processes of FDC as a guidance system for mature resting B cellsin peripheral lymph nodes. Unlike their MZ counterpart, FO B cells freely recirculate, comprising >95% ofthe B cells in peripheral lymph nodes.The BCR repertoire of the follicular B cell compartment also appears under positive selection pressuresduring final maturation in the spleen. However, diversity is substantially broader than B1 B and MZ B cellcompartments. More importantly, FO B cells require CD40-CD40L dependent T cell help to promoteeffective primary immune responses and antibody isotype switch and to establish high-affinity B cellmemory.
  26. 26. Recognition of antigen by B cellsA critical difference between B cells and T cells is how each lymphocyte recognizes its antigen. B cellsrecognize their cognate antigen in its native form. They recognize free (soluble) antigen in the blood orlymph using their BCR or membrane bound-immunoglobulin. In contrast, T cells recognize their cognateantigen in a processed form, as a peptide fragment presented by anantigen presentingcells MHC molecule to the T cell receptor.Activation of B cellsB cell recognition of antigen is not the only element necessary for B cell activation (a combination ofclonal proliferation and terminal differentiation into plasma cells). B cells that have not been exposed toantigen, also known as naïve B cells, can be activated in a T cell-dependent or -independent manner.
  27. 27. B cell activationT cell-dependent activationOnce a pathogen is ingested by an antigen-presenting cell such as a macrophage or dendritic cell, thepathogens proteins are then digested to peptides and attached to a class II MHC protein. This complex isthen moved to the outside of the cell membrane. The macrophage is now activated to deliver multiplesignals to a specific T cell that recognizes the peptide presented. The T cell is then stimulated to produceautocrines (Refer to Autocrine signalling), resulting in the proliferation and differentiation to effector andmemory T cells. Helper T cells (i.e. CD4+ T cells) then activate specific B cells through a phenomenonknown as an Immunological synapse. Activated B cells subsequently produce antibodies which assist ininhibiting pathogens until phagocytes (i.e. macrophages, neutrophils) or the complement system forexample clears the host of the pathogen(s).Most antigens are T-dependent, meaning T cell help is required for maximal antibody production. With aT-dependent antigen, the first signal comes from antigen cross linking the B cell receptor (BCR) and thesecond signal comes from co-stimulation provided by a T cell. T dependent antigens contain proteins thatare presented on B cell Class II MHC to a special subtype of T cell called a Th2 cell. When a B cell
  28. 28. processes and presents the same antigen to the primed Th cell, the T cell secretes cytokines that activatethe B cell. These cytokines trigger B cell proliferation and differentiation into plasma cells. Isotypeswitching to IgG, IgA, and IgE and memory cell generation occur in response to T-dependent antigens.This isotype switching is known as Class Switch Recombination (CSR). Once this switch has occurred,that particular B cell will usually no longer make the earlier isotypes, IgM or IgD.T cell-dependent B cell activation, showing a TH2-cell (left), B cell (right), and several interaction moleculesT cell-independent activationMany antigens are T cell-independent in that they can deliver both of the signals to the Bcell. Mice without a thymus (nude orathymic mice that do not produce any T cells) can respond to Tindependent antigens. Many bacteria have repeating carbohydrate epitopes that stimulate B cells, bycross-linking the IgM antigen receptors in the B cell, responding with IgM synthesis in the absence of Tcell help. There are two types of T cell independent activation; Type 1 T cell-independent(polyclonal)activation, and type 2 T cell-independent activation (in which macrophages present several of the sameantigen in a way that causes cross-linking of antibodies on the surface of B cells).The ancestral roots of B cellsIn an October 2006 issue of Nature Immunology, certain B cells ofbasal vertebrates (like fish and amphibians) were shown to be capable of phagocytosis, a function usuallyassociated with cells of the innate immune system. The authors postulate that these phagocytic B cellsrepresent the ancestral history shared between macrophages and lymphocytes. B cells may haveevolved from macrophage-like cells during the formation of the adaptive immune system.
  29. 29. B cells in humans (and other vertebrates) are nevertheless able to endocytose antibody-fixed pathogens,and it is through this route that MHC Class II presentation by B cells is possible, allowing Th2 help andstimulation of B cell proliferation. This is purely for the benefit of MHC Class II presentation, not as asignificant method of reducing the pathogen load.B cell-related pathologyAberrant antibody production by B cells is implicated in many autoimmune diseases, such as rheumatoidarthritis and systemic lupus erythematosus.5.MonocyteMonocyte is a type of white blood cell, part of the human bodys immune system. Monocytes haveseveral roles in the immune system and this includes: (1) replenish resident macrophages and dendriticcells under normal states, and (2) in response to inflammationsignals, monocytes can move quickly(approx. 8-12 hours) to sites of infection in the tissues and divide/differentiate into macrophages anddendritic cells to elicit an immune response. Half of them are stored in the spleen. Monocytes are usuallyidentified in stained smears by their large bilobate nucleus.Monocytes can be used to generate dendritic cells in vitro by adding cytokines like Granulocyte MonocyteColony Stimulating Factor (GMCSF) and IL-4.MonocytePhysiologyMonocytes are produced by the bone marrow from haematopoietic stem cell precursorscalled monoblasts. Monocytes circulate in the bloodstream for about one to three days and then typicallymove into tissues throughout the body. They constitute between three to eight percent ofthe leukocytes in the blood. Half of them are stored as a reserve in the spleen in clusters in the redpulps Cords of Billroth. In the tissues monocytes mature into different types of macrophages at differentanatomical locations.Monocytes which migrate from the bloodstream to other tissues will then differentiate into tissueresident macrophages or dendritic cells. Macrophages are responsible for protecting tissues from foreignsubstances but are also suspected to be the predominant cells involved in triggering atherosclerosis.They are cells that possess a large smooth nucleus, a large area of cytoplasm and manyinternal vesicles for processing foreign material.Monocytes and their macrophage and dendritic cell progeny serve three main functions in the immunesystem. These are phagocytosis, antigen presentation and cytokine production.Phagocytosis is theprocess of uptake of microbes and particles followed by digestion and destruction of this material.Monocytes can perform phagocytosis using intermediary (opsonising) proteins suchas antibodies or complement that coat the pathogen, as well as by binding to the microbe directly viapattern-recognition receptors that recognize pathogens. Monocytes are also capable of killing infected
  30. 30. host cells via antibody, termed antibody-mediated cellular cytotoxicity. Vacuolization may be present in acell that has recently phagocytized foreign matter.Microbial fragments that remain after such digestion can serve as antigen. The fragments can beincorporated into MHC molecules and then traffic to the cell surface of monocytes (and macrophages anddendritic cells). This process is called antigen presentation and it leads to activation of T lymphocytes,which then mount a specific immune response against the antigen.Other microbial products can directly activate monocytes and this leads to production of pro-inflammatoryand with some delay of anti-inflammatory cytokines. Typical cytokines produced by monocytes areTNF tumor necrosis factor, IL-1 interleukin-1and IL-12 interleukin-12.Monocyte subpopulationsThere are at least three types of monocytes in human blood :a) the classical monocyte is characterized by high level expression of the CD14 cell surface receptor(CD14++ CD16- monocyte)b) the non-classical monocyte shows low level expression of CD14 and with additional co-expression ofthe CD16 receptor (CD14+CD16++ monocyte).c) the intermediate monocyte with high level expression of CD14 and low level expression of CD16(CD14++CD16+ monocytes).There appears to be a developmental relationship in that the classical monocytes develop into theintermediate monocytes to then become the non-classical monocytes CD14+CD16+ monocytes. Hencethe non-classical monocytes may represent a more mature version. After stimulation with microbialproducts the CD14+CD16++ monocytes produce high amounts of pro-inflammatory cytokines like tumornecrosis factor and interleukin-12.Diagnostic useA monocyte count is part of a complete blood count and is expressed either as a ratio of monocytes to thetotal number of white blood cells counted, or by absolute numbers. Both may be useful in determining orrefuting a possible diagnosis.MonocytosisMonocytosis is the state of excess monocytes in the peripheral blood. It may be indicative of variousdisease states. Examples of processes that can increase a monocyte count include: chronic inflammation stress response hyperadrenocorticism immune-mediated disease infectious mononucleosis pyogranulomatous disease necrosis red cell regeneration Viral Fever sarcoidosis
  31. 31. A high count of CD14+CD16+ monocytes is found in severe infection (sepsis) and a very low count ofthese cells is found after therapy with immuno-suppressive glucocorticoidsMonocytopeniaMonocytopenia is a form of leukopenia associated with a deficiency of monocytes.(b) Mast cellA mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules richin histamine andheparin. Although best known for their role in allergy and anaphylaxis, mast cells play animportant protective role as well, being intimately involved in wound healing and defenseagainst pathogens.Mast cellsLocalizationMast cells are found in connective tissues throughout the body,close to blood vessels and particularlyareas of the respiratory ,urogenital and gastrointestinal tracks.It has large characteristic electron-densegranules in their cytoplasm,which are very important for their function.the origin of mast cell is uncertainbut they probably also originate in the bone marrow.ClassificationTwo types of mast cells are recognized, those from connective tissue and a distinct set of mucosal mastcells. The activities of the latter are dependent on T-cells.Mast cells are present in most tissues characteristically surrounding blood vessels and nerves, and areespecially prominent near the boundaries between the outside world and the internal milieu, such asthe skin, mucosa of the lungs and digestive tract, as well as in the mouth, conjunctiva, and nose.Physiology
  32. 32. Mast cells play a key role in the inflammatory process. When activated, a mast cell rapidly releases itscharacteristic granules and various hormonal mediators into the interstitium. Mast cells can be stimulatedto degranulate by direct injury (e.g. physical or chemical [such as opioids, alcohols, and certain antibioticssuch as polymyxins]), cross-linking of Immunoglobulin E (IgE) receptors, or by activated complementproteins.Mast cells express a high-affinity receptor (FcεRI) for the Fc region of IgE, the least-abundant member ofthe antibodies. This receptor is of such high affinity that binding of IgE molecules is essentiallyirreversible. As a result, mast cells are coated with IgE. IgE is produced by Plasma cells (the antibody-producing cells of the immune system). IgE molecules, like all antibodies, are specific to oneparticular antigen. The role of mast cells in the development of allergy.In allergic reactions, mast cells remain inactive until an allergen binds to IgE already in association withthe cell (see above). Other membrane activation events can either prime mast cells for subsequentdegranulation or can act in synergy with FceRI signal transduction. Allergens are
  33. 33. generally proteins or polysaccharides. The allergen binds to the antigen-binding sites, which are situatedon the variable regions of the IgE molecules bound to the mast cell surface. It appears that binding of twoor more IgE molecules (cross-linking) is required to activate the mast cell. The clustering of theintracellular domains of the cell-bound Fc receptors, which are associated with the cross-linked IgEmolecules, causes a complex sequence of reactions inside the mast cell that lead to its activation.Although this reaction is most well understood in terms of allergy, it appears to have evolved as a defensesystem against intestinal worm infestations (tapeworms, etc.).The molecules thus released into the extracellular environment include: preformed mediators (from the granules):  serine proteases, such as tryptase  histamine (2-5 pg/cell)  serotonin  proteoglycans, mainly heparin (active as anticoagulant) newly formed lipid mediators (eicosanoids):  prostaglandin D2  leukotriene C4  platelet-activating factor cytokines  Eosinophil chemotactic factorHistamine dilates post capillary venules, activates the endothelium, and increases blood vesselpermeability. This leads to local edema(swelling), warmth, redness, and the attraction of otherinflammatory cells to the site of release. It also irritates nerve endings (leading to itchingor pain).Cutaneous signs of histamine release are the "flare and wheal"-reaction. The bump and rednessimmediately following a mosquito bite are a good example of this reaction, which occurs seconds afterchallenge of the mast cell by an allergen. Structure of histamineThe other physiologic activities of mast cells are much less well-understood. Several lines of evidencesuggest that mast cells may have a fairly fundamental role in innate immunity – they are capable ofelaborating a vast array of important cytokines and other inflammatory mediators such as TNFa, theyexpress multiple "pattern recognition receptors" thought to be involved in recognizing broad classes ofpathogens, and mice without mast cells seem to be much more susceptible to a variety of infections.[citationneeded]Mast cell granules carry a variety of bioactive chemicals. These granules have been found to betransferred to adjacent cells of the immune system andneurons via transgranulation via their pseudopodiaRole in disease
  34. 34. Allergic diseaseMany forms of cutaneous and mucosal allergy are mediated for a large part by mast cells; they play acentral role in asthma, eczema, itch (from various causes) and allergic rhinitis andallergicconjunctivitis. Antihistamine drugs act by blocking the action of histamine on nerveendings. Cromoglicate-based drugs (sodium cromoglicate, nedocromil) block a calcium channel essentialfor mast cell degranulation, stabilizing the cell and preventing release of histamine and relatedmediators. Leukotriene antagonists (such as montelukast andzafirlukast) block the action of leukotrienemediators, and are being used increasingly in allergic diseases.AnaphylaxisIn anaphylaxis (a severe systemic reaction to allergens, such as nuts, bee stings or drugs), body-widedegranulation of mast cells leads to vasodilation and, if severe, symptoms of life-threatening shock.[citationneeded]AutoimmunityMast cells are implicated in the pathology associated with the autoimmune disorders rheumatoidarthritis, bullous pemphigoid, and multiple sclerosis. They have been shown to be involved in therecruitment of inflammatory cells to the joints (e.g. rheumatoid arthritis) and skin (e.g. bullous pemphigoid)and this activity is dependent on antibodies and complement components.Mast cell disordersMastocytosis is a rare condition featuring proliferation of mast cells. It exists ina cutaneous and systemic form, with the former being limited to the skin and the latter involving multipleorgans. Mast cell tumors are often seen in dogs and cats.(c)PhagocytePhagocytes are the white blood cells that protect the body by ingesting (phagocytosing) harmful foreignparticles, bacteria, and dead or dyingcells. Their name comes from the Greek phagein, "to eat" or"devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They areessential for fighting infections and for subsequent immunity. Phagocytes are important throughout theanimal kingdom and are highly developed within vertebrates. One litre of human blood contains about sixbillion phagocytes. Phagocytes were first discovered in 1882 by Ilya Ilyich Mechnikov while he wasstudying starfish larvae. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for hisdiscovery. Phagocytes occur in many species; some amoebae behave like macrophage phagocytes,which suggests that phagocytes appeared early in the evolution of life.Phagocytes of humans and other animals are called "professional" or "non-professional" depending onhow effective they are atphagocytosis. The professional phagocytes include cellscalled neutrophils, monocytes, macrophages, dendritic cells, and mast cells.The main difference betweenprofessional and non-professional phagocytes is that the professional phagocytes have moleculescalledreceptors on their surfaces that can detect harmful objects, such as bacteria, that are not normallyfound in the body. Phagocytes are crucial in fighting infections, as well as in maintaining healthy tissuesby removing dead and dying cells that have reached the end of their lifespan.During an infection, chemical signals attract phagocytes to places where the pathogen has invaded thebody. These chemicals may come from bacteria or from other phagocytes already present. Thephagocytes move by a method called chemotaxis. When phagocytes come into contact with bacteria, thereceptors on the phagocytes surface will bind to them. This binding will lead to the engulfing of thebacteria by the phagocyte. Some phagocytes kill the ingested pathogen with oxidants and nitricoxide. After phagocytosis, macrophages and dendritic cells can also participate in antigen presentation, a
  35. 35. process in which a phagocyte moves parts of the ingested material back to its surface. This material isthen displayed to other cells of the immune system. Some phagocytes then travel to the bodys lymphnodes and display the material to white blood cells called lymphocytes. This process is important inbuilding immunity. However, many pathogens have evolved methods to evade attacks by phagocytes.Methods of killingThe killing of microbes is a critical function of phagocytes that is either performed within the phagocyte(intracellular killing) or outside of the phagocyte (extracellular killing).Simplified diagram of the phagocytosis and destruction of a bacterial cellOxygen-dependent intracellularWhen a phagocyte ingests bacteria (or any material), its oxygen consumption increases. The increase inoxygen consumption, called arespiratory burst, produces reactive oxygen-containing molecules that areanti-microbial. The oxygen compounds are toxic to both the invader and the cell itself, so they are kept incompartments inside the cell. This method of killing invading microbes by using the reactive oxygen-containing molecules is referred to as oxygen-dependent intracellular killing, of which there are two types.The first type is the oxygen-dependent production of a superoxide, which is an oxygen-rich bacteria-killingsubstance. The superoxide is converted to hydrogen peroxide and singlet oxygen by an enzymecalled superoxide dismutase. Superoxides also react with the hydrogen peroxide to produce hydroxylradicals which assist in killing the invading microbe.The second type involves the use of the enzyme myeloperoxidase from neutrophil granules. Whengranules fuse with a phagosome, myeloperoxidase is released into the phagolysosome, and this enzymeuses hydrogen peroxide and chlorine to create hypochlorite, a substance used in domestic bleach.Hypochlorite is extremely toxic to bacteria.Myeloperoxidase contains a heme pigment, which accounts forthe green color of secretions rich in neutrophils, such as pus and infected sputum.
  36. 36. Oxygen-independent intracellularPhagocytes can also kill microbes by oxygen-independent methods, but these are not as effective as theoxygen-dependent ones. There are four main types. The first uses electrically charged proteins whichdamage the bacteriums membrane. The second type uses lysozymes; these enzymes break down thebacterial cell wall. The third type uses lactoferrins, which are present in neutrophil granules and removeessential iron from bacteria. The fourth type uses proteases and hydrolytic enzymes; these enzymes areused to digest the proteins of destroyed bacteria.ExtracellularInterferon-gamma—which was once called macrophage activating factor—stimulates macrophages toproduce nitric oxide. The source of interferon-gamma can be CD4+ T cells, CD8+ T cells, natural killercells, B cells, natural killer T cells, monocytes, macrophages, or dendritic cells. Nitric oxide is thenreleased from the macrophage and, because of its toxicity, kills microbes near the macrophage. Activatedmacrophages produce and secrete tumor necrosis factor. This cytokine—a class of signaling molecule—kills cancer cells and cells infected by viruses, and helps to activate the other cells of the immune system.In some diseases, e.g., the rare chronic granulomatous disease, the efficiency of phagocytes is impaired,and recurrent bacterial infections are a problem. In this disease there is an abnormality affecting differentelements of oxygen-dependent killing. Other rare congenital abnormalities, such as Chediak-Higashisyndrome, are also associated with defective killing of ingested microbes.Role in apoptosisApoptosis (pronounced /ˌæpəˈtoʊsɪs/ or /ˌæpəpˈtoʊsɪs/) is the process of programmed cell death (PCD)that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes(morphology) and death. These changes include blebbing, loss of cell membrane asymmetry andattachment, cell shrinkage, nuclear fragmentation, chromatin condensation,and chromosomal DNA fragmentation. (See also Apoptosis DNA fragmentation.) Apoptosis differsfrom necrosis, in which the cellular debris can damage the organism.In an animal, cells are constantly dying. A balance between cell division and cell death keeps the numberof cells relatively constant in adults. There are two different ways a cell can die: by necrosis or byapoptosis. In contrast to necrosis, which often results from disease or trauma, apoptosis—or programmedcell death—is a normal healthy function of cells. The body has to rid itself of millions of dead or dying cellsevery day, and phagocytes play a crucial role in this process.Dying cells that undergo the final stages of apoptosis display molecules, such as phosphatidylserine, ontheir cell surface to attract phagocytes. Phosphatidylserine is normally found on the cytosolic surface ofthe plasma membrane, but is redistributed during apoptosis to the extracellular surface by a hypotheticalprotein known as scramblase. These molecules mark the cell for phagocytosis by cells that possess theappropriate receptors, such as macrophages. The removal of dying cells by phagocytes occurs in anorderly manner without eliciting an inflammatory response and is an important function of phagocytes.
  37. 37. Apoptosis—phagocytes clear fragments of dead cells from thebody.Interactions with other cellsPhagocytes are usually not bound to any particular organ but move through the body interacting with theother phagocytic and non-phagocytic cells of the immune system. They can communicate with other cellsby producing chemicals called cytokines, which recruit other phagocytes to the site of infections orstimulate dormant lymphocytes. Phagocytes form part of the innate immune system which animals,including humans, are born with. Innate immunity is very effective but non-specific in that it does notdiscriminate between different sorts of invaders. On the other hand, the adaptive immune system of jawedvertebrates—the basis of acquired immunity—is highly specialized and can protect against almost anytype of invader. The adaptive immune system is dependent on lymphocytes, which are not phagocytesbut produce protective proteins called antibodies which tag invaders for destruction andprevent viruses from infecting cells. Phagocytes, in particular dendritic cells and macrophages, stimulatelymphocytes to produce antibodies by an important process called antigen presentation.What is opsonization?This is the process of making a microbes easier to phagocytose.Opsonization is a process inwhich pathogens are coated with a substance called an opsonin, marking the pathogen out for destructionby the immune system. Once a pathogen has been opsonized, it is killed via one of two mechanisms. Thepathogen may be ingested and killed by an immune cell, or killed directly withoutingestion.
  38. 38. The process of killing and ingesting a pathogen is called phagocytosis. Cells called phagocytes ingest thepathogens and then kill them by exposing them to toxic chemicals. The chemicals are stored in smallmembrane-bound parcels within the phagocytes, and these parcels are triggered to open when aphagocyte ingests a pathogen.Opsonization also leads to pathogen death in a second mechanism called antibody-dependent cellularcytotoxicity, in which immune cells directly kill pathogens without ingesting them. In thisprocess, antibodiesact as opsonins, and then trigger immune cells called granulocytes. These cells thenrelease toxic chemicals into the environment around the pathogens to kill them. In addition to killingpathogens, this process also causes tissue damage via inflammation.There are several different substances which may act as opsonins; all of these are proteins which areactive in the immune system. Two antibody types called IgG and IgA are both opsonins. IgG is active inblood and tissues, and IgA is active in mucosal surfaces such as the airways, urogenital system, and gut.Several proteins which act in the complement system are also opsonins. The complement system is acascade of reactions between a number of different proteins. The end result of the cascadeis opsonization of pathogens, as well as direct pathogen killing via the formation of a protein complexwhich punctures holes in bacterial cell walls.PhagocytosisPhagocytosis (from Greek phago, meaning eating, cyte, meaning vessel, and osis meaning process) isthe cellular process of engulfing solid particles by the cell membrane to form aninternal phagosome by phagocytes and protists. Phagocytosis is a specific form ofendocytosis involvingthe vesicular internalization of solid particles, such as bacteria, and is, therefore, distinct from other formsof endocytosis such as the vesicular internalization of various liquids. Phagocytosis is involved in theacquisition of nutrients for some cells, and, in the immune system, it is a major mechanism used toremove pathogens and cell debris. Bacteria, dead tissue cells, and small mineral particles are allexamples of objects that may be phagocytosed.The process is homologous to eating only at the level of single-celled organisms; in multicellular animals,the process has been adapted to eliminate debris and pathogens, as opposed to taking in fuel for cellularprocesses, except in the case of the Trichoplax.
  39. 39. Phagocytosis in threesteps:1. Unbound phagocyte surface receptors do not trigger phagocytosis.2. Binding of receptors causes them to cluster.3. Phagocytosis is triggered and the particle is taken up by the phagocyte.In immune systemPhagocytosis in mammalian immune cells is activated by attachment to Pathogen-associated molecularpatterns (PAMPS), which leads toNF-κB activation. Opsonins such as C3b and antibodies can act asattachment sites and aid phagocytosis of pathogens.Engulfment of material is facilitated by the actin-myosin contractile system. The phagosome of ingestedmaterial is then fused with the lysosome, leading to degradation.Degradation can be oxygen-dependent or oxygen-independent. Oxygen-dependent degradation depends on NADPH and the production of reactive oxygen species. Hydrogen peroxide andmyeloperoxidase activate a halogenating system, which leads to the destruction of bacteria. Oxygen-independent degradation depends on the release of granules, containing proteolytic enzymes such as defensins, lysozyme, and cationic proteins. Other antimicrobial peptides are present in these granules, including lactoferrin, which sequesters iron to provide unfavourable growth conditions for bacteria.It is possible for cells other than dedicated phagocytes (such as dendritic cells) to engage inphagocytosis.In apoptosisFollowing apoptosis, the dying cells need to be taken up into the surrounding tissues by macrophages ina process called Efferocytosis. One of the features of an apoptotic cell is the presentation of a variety ofintracellular molecules on the cell surface, such as Calreticulin, Phosphatidylserine (From the inner layerof the plasma membrane), Annexin A1, and oxidisedLDL. These molecules are recognised by receptors

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