Mims pathogenesis of infectious disease - part 4 ppsx

5 The Spread of Microbes through the Body 139 Microorganism Table 5.2. Principal rashes in infectious disease in man Disease Features Measles virus Rubella virus Parvovirus Echoviruses 4, 6, 9, 16 Coxsackie viruses A9, 16, 23 Varicella-zoster virus Coxsackie virus A16 Rickettsia prowazeki and others Rickettsia rickettsiae and others Streptococcus pyogenes Measles German measles 1 Erythema infectiosum Not distinguishable Treponema paUidum Syphilis Treponema pertenue Yaws Salmonella typhi ~ Enteric fever Salmonella paratyphi B J Neisseria meningitidis Spotted fever Blastomyces dermatitidis Blastomycosis Cutaneous leishmaniasis Prodromal rashes Very characteristic maculopapular rash Leishmania tropica Hepatitis B and viral exanthems Dermatophytes (skin fungi) Maculopapular rashes not distinguishable clinically Chickenpox, zoster } Hand, foot and mouth Vesicular rashes disease Typhus } Spotted fever group Macular or haemorrhagic rash of diseases Scarlet fever Erythematous rash caused by toxin Disseminated infectious rash seen in secondary stage, 2-3 months after infection Sparse rose spots containing bacteria Petechial or maculopapular lesions containing bacteria Papule or pustule develops into granuloma; lesions contain organisms Papules, usually ulcerating to form crusted sores; infectious Dermatophytid or allergic rash Streptococcus pyogenes l Impetigo a Staphylococcus pyogenes S Generalised rash due to hypersensitivity to fungal or viral antigens Vesicles, forming crusts, especially in children a These skin lesions are multiple but like those of erysipelas or warts are formed locally at the sites of infection, not after spread through the body. its own immune cells, particularly Langerhans cells (see p. 151), many mast cells (see p. 161), and recirculatory T-cells are always present in the dermis. The skin of man is mostly naked, and is an important thermoregula- tory organ, under finely balanced nervous control. It is a turbulent, highly reactive tissue, and local inflammatory events are common- place. At sites of inflammation, circulating microorganisms readily localise in small blood vessels and pass across the endothelium. The skin of most animals, in contrast, is largely covered with fur. Skin lesions are a feature of many infectious diseases of animals, but these lesions tend to be on exposed hairless areas where the skin has the 140 Mims' Pathogenesis of Infectious Disease human properties of thickness, sensitivity and vascular reactivity. Hence, although virus rashes very occasionally involve the general body surface of animals, it is udders, scrotums, ears, prepuces, teats, noses and paws that are more regular sites of lesions. For instance, the closely related diseases of measles, distemper and rinderpest can be compared. Cattle with rinderpest may show areas of red moist skin with occasional vesiculation on the udder, scrotum and inside the thighs. In dogs with distemper the exanthem often occurs on the abdomen and inner aspect of the thighs. Yet in human measles there is one of the most florid and characteristic rashes known, involving the general body surface. Even in susceptible monkeys, the same virus produces skin lesions sparingly and irregularly. Macules and papules are formed when there is inflammation in the dermis, with or without a significant cellular infiltration, the infection generally being confined to the vascular bed or its immediate vicinity. Immunological factors (see Ch. 8) are often important in the production of inflammation. Measles virus, for instance, localises in skin blood vessels, but the maculopapular rash does not appear unless there is an adequate immune response. Virus by itself does little damage to the blood vessels or the skin, and the interaction of sensitised lymphocytes or antibodies with viral antigen is needed to generate the inflamma- tory response that causes the skin lesion. Rickettsia characteristically localise and grow in the endothelium of small blood vessels, and the striking rashes seen in typhus and Rocky Mountain Spotted Fever are a result of endothelial swelling, thrombosis, small infarcts and haem- orrhages. The immune response adds to the pathological result. Vascular endothelium is an important site of replication and shedding of viruses and rickettsias that are transmitted by blood-sucking arthropods and which must therefore be shed into the blood. After replication in vascular endothelium, they may be shed not only back into the vessel lumen, but also from the external surface of the endothelial cell into extravascular tissues (see also p. 136). Certain arthropod-borne viruses replicate in muscle or other extravascular tissues, and can then reach the blood after passage through the lymphatic system. Circulating immune complexes consisting of antibody plus microbial antigen also localise in dermal blood vessels, accounting for the trichophytid rashes of fungal infections and the prodromal rashes seen at the end of the incubation period in many exanthematous virus diseases. Antibodies to soluble viral antigens appear towards the end of the incubation period in people infected with hepatitis B virus and form soluble immune complexes. These localise in the skin causing fleeting rashes and pruritis, and rarely the more severe vascular lesions of periarteritis nodosa (see Ch. 8). Certain microbial toxins enter the circulation, localise in skin blood vessels, and cause damage and inflammation without the need for an immune response. An erythrogenic toxin is liberated from strains of 5 The Spread of Microbes through the Body 141 Streptococcus pyogenes carrying the bacteriophage ~, and the toxin enters the blood, localises in dermal vessels, and gives rise to the striking rash of scarlet fever. Vesicles and pustules are formed when the microorganism leaves dermal blood vessels and is able to spread to the superficial layers of the skin. Inflammatory fluids accumulate to give vesicles, which are focal blisters of the superficial skin layers. Virus infections with vesi- cles include varicella, herpes simplex and certain coxsackie virus infec- tions. The circulating virus localises in dermal blood vessels, grows through the endothelium (herpes, varicella) and spreads across dermal tissues to infect the epidermis and cause focal necrosis. Only viruses capable of extravascular spread and epidermal infection can cause vesicles. Inevitably there is an immunopathological contribution to the lesion, although a primary destructive action on epidermal cells gives a lesion without the need for the immune response, as with the oral lesions seen in animals as early as 2 days after infection with foot and mouth disease virus. A secondary infiltration of leucocytes into the virus-rich vesicle turns it into a pustule which later bursts, dries, scabs and heals. Such viruses are shed to the exterior from the skin lesion. Certain other microorganisms are shed to the exterior after extravasa- tion from dermal blood vessels. They multiply in extravascular tissues and form inflammatory swellings in the skin, which then break down so that infectious material is discharged to the exterior. This occurs and gives rise to striking skin lesions in the secondary stages of syphilis and yaws (caused by the closely related bacteria Treponema pallidum and pertenue) and is also seen in a systemic fungus infection (blastomycosis) and a protozoal infection (cutaneous leishmaniasis). In patients with leprosy, Mycobacterium leprae circulating in the blood localises and multiplies in the skin, and for unknown reasons superfi- cial peripheral nerves are often involved. The skin lesions do not break down, although large numbers of bacteria are shed from sites of growth on the nasal mucosa. Bacterial growth is favoured by the slightly lower temperature of the skin and nasal mucosa. Almost all the factors that have been discussed in relation to skin localisation and skin lesions apply also to the mucosae of the mouth, throat, bladder, vagina, etc. In these sites the wet surface means that the vesicles will break down and form ulcers earlier than on the dry skin. Hence in measles the foci in the mouth break down and form small visible ulcers (Koplik's spots) a day or so before the skin lesions have appeared (Fig. 5.3). Similar considerations apply to the localisa- tion of microorganisms and their antigens on the other surfaces of the body (see Fig. 2.1). In chickenpox and measles, circulating virus localises in subepithelial vessels in the respiratory tract, and after extravasation there is only a single layer of cells to grow through in the nearby epithelium before the discharge of virus to the exterior. Hence in these infections the secretions from the respiratory tract are infec- tious a few days before the skin rash appears and the disease becomes 142 Mims' Pathogenesis of Infectious Disease recognisable. Much less is known about the localisation of circulating microorganisms in the intestinal tract. Probably localisation here is not often of great importance, but this is a difficult surface of the body to study. In typhoid, secondary intestinal localisation of bacteria takes place following excretion of bacteria in bile, rather than from blood. Virus localisation in the intestinal tract is a feature in rinderpest in cattle but occurs only to a minor extent in measles. When the patient with measles suffers from protein deficiency, however, it is more important and helps cause the diarrhoea that makes measles a life- threatening infection in malnourished children (see p. 378). The foetus The blood-foetal junction in the placenta is an important pathway for infection of the foetus. The number of cells separating maternal from foetal blood depends not only on the species of animal, there being four cell sheets for instance in the horse and only one or two in man, but also on the stage of pregnancy. The junction usually becomes thinner, often with fewer cell layers, in later pregnancy. There are regular mechanical leaks in the placenta late in most human pregnancies, and up to 4.0 ml of blood is transferred across the placenta, but this appears to be principally in one direction, from foetus to mother. There is little evidence for the passive carriage of microorganisms across the placenta, and foetal infection takes place by either of two mechanisms. If a circulating microorganism, free or cell associated, localises in the maternal vessels it can multiply, cause damage, locally interrupt the integrity of the junction and thus infect the foetus. Treponema pallidum and Toxoplasma gondii presumably infect the human foetus in this way. Alternatively, a circulating microorganism can localise and grow across the placental junction. This occurs with rubella and cytomegalovirus infections of the human foetus. In both instances, a placental lesion or focus of infection occurs before foetal invasion. The microorganisms causing foetal damage are listed in Table 5.3 (see also p. 334). These, however, are special cases, and special microorganisms. Nearly always the foetus is protected from microbial as well as from biochemical and physical insults. The factors that localise micro- organisms in the placenta are not understood, but blood flow is slow in placental vessels, as in sinusoids, giving maximal opportunities for localisation. Once microorganisms are arrested in placental vessels, their growth may be favoured by particular substances that are present in the placenta. Erythritol promotes the growth of Brucella abortus, and its presence in the bovine placenta makes this a target organ in infected cows. Susceptibility of infected cattle to abortion thus has a biochemical basis. Microorganisms can damage the foetus without invading foetal tissues. If they localise extensively in placental vessels and cause primarily vascular damage this of course can lead to foetal anoxia, death and abortion. Also the toxic products of microbial 5 The Spread of Microbes through the Body 143 Table 5.3. Principal microorganisms infecting the foetus Microorganisms Species Effect Viruses Rubella virus Cytomegalovirus HIV Hog cholera virus (vaccine strain) Bluetongue virus (vaccine strain) Equine rhinopneumonitis Bovine diarrhoea- mucosal disease virus Malignment catarrh virus Bacteria Treponema pallidum Listeria monocytogenes Vibrio foetus Man Abortion Stillbirth Malformations Man Malformations Man About 1 in 5 infants born to infected mothers are infected in utero Pigs Malformations Sheep Stillbirths, CNS disease Horse Abortion Cow Cerebellar hypoplasia Wildebeest Foetus unharmed Man Stillbirth, malformations Man Meningoencephalitis Sheep, cattle Abortion Protozoa Toxoplasma gondii Man Stillbirth, CNS disease growth in the placenta or elsewhere and probably cytokines can reach the foetus and cause damage. High fever and biochemical disturbances in a pregnant female can adversely affect the foetus. Miscellaneous sites There are certain other sites where circulating microorganisms selec- tively localise. In rats and other animals infected with Leptospira, circulating bacteria localise particularly in capillaries in the kidney and give rise to a chronic local lesion. Infectious bacteria are dis- charged in large numbers into the urine, which is therefore a source of human infection. Microorganisms that are discharged in the saliva (mumps and most herpes-type virus infections in man) must localise and grow in salivary glands. Those that are discharged in milk must localise and grow in mammary glands (the mammary tumour virus in mice and Brucella, tubercle bacilli, and Q fever rickettsia in cows). A few examples, such as Haemophilus suis in pigs, Ross River virus in man (Table A.5), and occasionally rubella virus, localise in joints. Almost any site in the body, from the feather follicles (Marek's disease) to testicles or epididymis (mumps in man, the relevant Brucella species in rams, boars, bulls) can at times be infected. Nothing is known of the mechanism of localisation in these organs. 144 Mims" Pathogenesis of Infectious Disease Spread via other Pathways Cerebrospinal fluid (CSF) Microorganisms in the blood can reach the CSF by traversing the blood-CSF junction in the meninges or choroid plexus. Capillaries in the choroid plexus have fenestrated endothelium and are surrounded by a loose connective tissue stroma (Fig. 3.2). Inert virus-sized particles and bacteriophages leak into the CSF when very large amounts are injected into the blood. It is assumed that the viruses causing aseptic meningitis in man (polio-, echo-, coxsackie, lymphocytic choriomenin- gitis and mumps viruses) enter the CSF by leakage or growth across this junction (Fig. 5.6). Once in the CSF microorganisms are passively carried with the flow of fluid from ventricles to subarachnoid spaces and throughout the neuraxis within a short time. Invasion of the brain itself and spinal cord can now take place across the ependymal lining of the ventricles and spinal canal, or across the pia mater in the subarachnoid spaces. Nonviral microorganisms entering the CSF across the blood-CSF junction include the meningococcus, the tubercle bacillus, Listeria monocytogenes, Haemophilus influenzae, Strepto- coccus pneumoniae, and the fungus Cryptococcus neoformans. Pleural and peritoneal cavities Rapid spread of microorganisms from one visceral organ to another can take place via the peritoneal or pleural cavity. Entry into the peritoneal Fig. 5.6 Routes of microbial invasion of the central nervous system. CSF = cerebrospinal fluid. 5 The Spread of Microbes through the Body cavity takes place from an injury or focus of infection in an abdominal organ. The peritoneal cavity, as if in expectation of such events, is lined by macrophages and contains an antimicrobial armoury, the omentum. The omentum, originating from fused folds of mesentery, contains mast cells and lymphocytes, macrophages and their precursors in a fatty connective tissue matrix. It is movable in the peritoneal cavity and becomes attached at sites of inflammation.* Microorganisms spread rapidly in the peritoneal cavity unless they are taken up and destroyed in macrophages or inflammatory polymorphs. Peritoneal contents drain into lymphatics opening onto the abdominal surface of the diaphragm, so that microorganisms or their toxins are delivered to retrosternal lymph nodes in the thorax, sometimes with slight leakage into the pleural cavity. Inflammatory responses in the peritoneum eventually result in fibrinous exudates and the adherence of neigh- bouring surfaces, which tends to prevent microbial spread. Microbes entering the pleural cavity from chest wounds or from foci of infection in the underlying lung have a similar opportunity to spread rapidly. During pneumonia the overlying pleural surface first becomes inflamed, causing pleurisy, and later often infected. Pleurisy occurs in about 25% of cases ofpneumococcal pneumonia. The pleural cavity, like the peritoneal cavity, is lined by macrophages. 9 145 Nerves For many years peripheral nerves have been recognised as important pathways for the spread of certain viruses and toxins from peripheral parts of the body to the central nervous system (Fig. 5.6). Rabies, herpes simplex and related viruses travel along nerves at up to 10 mm h -1, but the exact pathway in the nerve was for many years a matter of doubt and debate. Herpes simplex virus, following primary infection in the skin or the mouth, enters the sensory nerves and reaches the trigeminal ganglion (see Ch. 10). Here it remains in latent form until it is reactivated in later life by fever, emotional or other factors. The infection then travels down the nerve to reach the region of the mouth, where the skin is once again infected giving rise to a virus- rich cold sore. A similar sequence of events explains the occurrence of zoster long after infection with varicella virus. In cattle or pigs infected with pseudorabies, another herpes virus, the infection also travels up peripheral nerves to reach dorsal root ganglia, causing a spontaneous discharge of nerve impulses from affected sensory neurons, and giving rise to the signs of'mad itch'. Another herpes virus (B virus) is often present in the saliva of apparently healthy rhesus monkeys, and people * Because of its ability to attach to sites of inflammation and infection or to foreign bodies the omentum has been referred to as the 'abdominal policeman'. 146 Mires' Pathogenesis of Infectious Disease bitten by infected monkeys develop a frequently fatal encephalitis, the virus reaching the brain by ascending peripheral nerves from the inoc- ulation site. Rabies virus slowly reaches the CNS along peripheral nerves following a bite delivered by an infected fox, jackal, wolf, raccoon, skunk or vampire bat. It also travels centrifugally from the brain down peripheral nerves to reach the salivary glands and other organs. Poliovirus was long thought to reach the CNS via peripheral nerves, but this was a conclusion from studies with artificially neuro- adapted strains of virus. In natural infections, poliovirus traverses the blood-brain junction (Fig. 3.2). Peripheral nerves are affected in leprosy, the bacteria having a special affinity for Schwann cells, which are unable to control the multiplying bacteria. The molecular basis for this targeting of Schwann cells is being unravelled. This causes a very slow and insidious degeneration of the nerve, but it is certainly not a pathway for the spread of infection. Peripheral nerves are known to transport tetanus toxin to the CNS (see Ch. 8), and also prion agents (scrapie) in experimental infections of mice. Possible pathways along nerves include sequential infection of Schwann cells, transit along the tissue spaces between nerve fibres, and carriage up the axon (Fig. 5.7). The last route is probably an impor- tant one, although at first sight it might seem less likely. There is a small but significant movement of marker proteins up normal axons from the periphery to the CNS, and in experimental herpes simplex and rabies infections virus particles have been seen in axons by elec- tron microscopy. In experimental infections, herpes viruses can also travel in nerves by sequential infection of the Schwann cells associated with myelin sheaths, but this is not a natural route. An alternative neural route of spread to the CNS is by the olfactory nerves. Axons of olfactory neurons terminate on the olfactory mucosa, the dendrites projecting beyond the mucosal surface giving a direct anatomical connection between the exterior and the olfactory bulbs in 1. Perineural~ lymphatic 2. Interspaces in nerve Perineureum 3. Endoneural cell elin (e.g. Schwann ( ;ath 4. Axon Fig. 5.7 Possible pathways of virus spread in peripheral nerves. 5 The Spread of Microbes through the Body 147 the brain. This route of infection, although at one time a popular postu- late, is not often important. Aerosol infection with rabies virus (from the excreta of bats in caves in North America) presumably involves this route. When administered intranasally in experimental infections of mice, Semliki Forest virus rapidly enters the olfactory bulbs and thence into the rest of the brain. Naegleria fowleri, a free-living amoeba that can lurk in the sludge at the bottom of freshwater pools, causes a rare but often fatal meningitis in swimmers after infecting by the olfactory route. The meningococci that live commensally in the nasopharynx of 5-10% of normal people, and occasionally cause menin- gitis, were once thought to spread directly upwards from the nasal mucosa, along the perineural sheaths of the olfactory nerve, and through the cribriform plate to the CSF. More probably, the bacteria invade the blood, sometimes causing petechial rashes ('spotted fever'), and reach the meninges across the blood-CSF junction. In summary, peripheral nerves are important pathways for the spread of tetanus toxin and a few viruses to the CNS, and for the passage of certain herpes viruses between the CNS and the surfaces of the body. Herpes and rabies viruses can travel both up and down peripheral nerves. The neural route is not generally used by bacteria or other microorganisms. References de Voe, I. W. (1982). The meningococcus and mechanisms of patho- genicity. Microbiol. Rev. 46, 162-190. Drutz, D. J. et al. (1972). The continuous bacteraemia of lepromatous leprosy. N. Engl. J. Med. 287, 159-163. Friedman, H. M., Macarek, E. J., MacGregor, R. A. et al. (1981). Virus infection of endothelial cells. J. Infect. Dis. 143, 266. Griffin, J. W. and Watson, D. F. (1988). Axonal transport in neurologic disease. Ann. Neurol. 23, 3-13. Johnson, R. T. (1982). ~Viral Infections of the Nervous System'. Raven Press, New York. Mims, C. A. (1964). Aspects of the pathogenesis of virus diseases. Bact. Rev. 28, 30. Mims, C. A. (1966). The pathogenesis of rashes in virus diseases. Bact. Rev. 30, 739. Mims, C. A. (1968). The pathogenesis of virus infections of the foetus. Prog. Med. Virol. 10, 194. Mims, C. A. (1981). The pathogenetic basis of viral tropism. Am. J. Pathol. 135,447-455. Moxon, R. E. and Murphy, P. A. (1978). Haemophilus influenzae bacteremia and meningitis resulting from survival of a single organism. Proc. Natl Acad. Sci. U.S.A. 75, 1534-1536. 148 Mims' Pathogenesis of Infectious Disease Pearce, J. H. et al. (1962). The chemical basis of the virulence of BruceUa abortus II. Erythritol, a constituent of bovine foetal fluids which stimulates the growth of Br. abortus in bovine phagocytes. Brit. J. Exp. Pathol. 43, 31-37. Quagliarello, V. and Schell, W. M. (1992). Bacterial meningitis; patho- genesis, pathophysiology, and progress. N. Engl. J. Med. 327, 864-872. Rambukkana, A. (2000). How does Mycobacterium leprae target the peripheral nervous system? Trends Microbiol. 8, 23-28. Williams, A. E. and Blakemore, W. F. (1990). Pathogenesis of meningitis caused by Streptococcus suis Type 2. J. Infect. Dis. 162, 474-481. Williams, A. E. and Blakemore, W. F. (1990). Monocyte-mediated entry of pathogens into the central nervous system. Neuropath. Appl. Neurobiol. 16, 377-392. [...]... factor-~ (TGF-~) is a potent inhibitor ofT- and B-cell proliferation Other cytokines such as IFN-y inhibit IL -4 activation of B cells, whereas IL -4 and IL-10 155 156 Mims" Pathogenesis of Infectious Disease inhibit IFN-y activation of macrophages and hence DTH reactions T cells producing these cytokines can therefore be thought of as regulator or suppressor cells Excessive production of any one of these... ~ < ~ ~ _~ ~] ~ ~ ~ ~ m ~ 0 - ~ ~C ~::" ~ ~ CL~ ~ ra0 ~'~.~' ~,.~ _-, m ~g.~ ~ , u I i o ~ r ~ ~ -o: ~ u _ = "= ' = "a b o '-" >, "="d o ,-. , ~ , o ~oa _ :U 9 - (D i._ "~ '~ ~ ~ ~ ' " ~ ~ 9 4 ~ ~ "= ~ o Cl X ,- c -a 0 o~ c ~ ~ ~=._ ,-~ - o ~C~ >.o' ~ ~ - 04 , ~ - , , 0 ~ b _ - ~ c ~o T - ~ e O_ X o ~ c , c -a = ~ o ~ ~ > , 0 C~6 ~ o o" ~ ~r~ r - ~ 0 Do 0 ,_ ~ ~ -o.r 0 ~ ~ or,.) ~ t:~ c 9 ~=... Source IL-1 M Target and action Co-stimulator ofT cells Activates macrophages Inducer of fever IL-2 L Induces proliferation ofT cells and activates natural killer (NK) cells Induces antibody synthesis IL-3 L Growth and differentiation of precursor cells in bone marrow IL -4 L B-cell proliferation and differentiation IL-5 L Induces differentiation of B cells and activates eosinophils IL-6 L,M B- and T-cell... ~D O O O O O O O O O O O O~ O O O O O O O O L~ ~u r r O O CD 0 ~ ~ ~ ~o .~ =LL~ ~ rD O i;z; rD O ~ ~ rD i;z; -I- C o ~ -I- +o ee ~ o ~D O O O O O ~ ~.~ r "~ c~'~ c~ , 4 c~ o c~ c~ c~ i-i c~ r o o r ~ r~ o cD c~ c~ c~ o ,.Q c~ b.O 4- a o 158 Mims' Pathogenesis of Infectious Disease ~ Antigen-binding sites Fab k Hingeregion ~ ss~:I / ain " Heavy chain Fc J Region with variable amino acid sequence in... (this is by a perforin- 171 Mires' Pathogenesis of Infectious Disease 172 Table 6 .4 Detection and assay ofT-cell-mediated immunity Response of sensitised lymphocytes to antigen DNA synthesis and mitosis Liberation of cytokines Cytotoxicity Induction of inflammation and mononuclear infiltration into tissues Antimicrobial activity (attributable to above activities) Clonal analysis ofT-cell responses Test... for T-helper cells in the immune response is summarised in Fig 6.2 T-helper cells can be further subdivided according to their function into two distinct populations of CD4 T cells, T h l and Th2 These cells are distinguished from each other by the type of cytokines produced T h l cells are characterised by the expression of interleukin-2 (IL-2) and interferon-y (IFN-y) and fail to produce IL -4 , IL-5... Incorporation of tritiated thymidine into lymphocyte DNA Measurement of growth and proliferation of specific cytokine-dependent cell lines, e.g IL-2, IL-3 Inhibition of virus replication, e.g IFN Inhibition of cell growth (e.g TGF-~) or cytolytic activity on virus-infected or tumour cells (e.g TNF-a) Capture of cytokines by specific antibodies fixed to plastic surfaces and detection of cytokine binding... influenza viruses often means infection with an antigenically distinct strain of virus, but re-infections with respiratory syncytial virus or with the same strain of parainfluenza virus, for instance, are common Re-infection of the respiratory tract or other mucosal surfaces is more likely to lead to signs of disease, because of the short incubation period of this type of infection After re-infection with... Fc region of IgG (Fc~/RIII or CD16) Antibody-dependent cell cytotoxicity (ADCC) of this type is more efficient per antibody molecule than complement- 165 166 Mims' Pathogenesis of Infectious Disease 7 8 9 10 dependent cell killing and is therefore more likely to be relevant in vivo Antibodies combining with the surface of microorganisms agglutinate them, reducing the n u m b e r of separate infectious. .. by the presence of particular membrane markers The commonest m a r k e r involves different isoforms of CD45 The high molecular weight isoform of CD45, CD45RA, is found on naive T cells and the low molecular weight isoform, CD45RO, is found on memory T cells It is still unclear whether memory cells arise directly from naive cells or whether they arise from effector cells The purpose of immunological . Target and action IL-1 M IL-2 L IL-3 L IL -4 L IL-5 L IL-6 L,M IL-10 L,M IL-12 L,M IL-13 L IL-18 M IFN-y L TNF-a L,M TNF-[~ L TGF-[~ L,M GM-CSF L,M Co-stimulator ofT cells. Activates. expression of interleukin-2 (IL-2) and interferon-y (IFN-y) and fail to produce IL -4 , IL-5 or IL-10. In contrast, Th2 cells produce IL -4 , IL-5 and IL-10, but not IL-2 or IFN-y. In terms of their. inhibitor ofT- and B-cell proliferation. Other cytokines such as IFN-y inhibit IL -4 activation of B cells, whereas IL -4 and IL-10 156 Mims& quot; Pathogenesis of Infectious Disease inhibit IFN-y activation