Case-Study-Superantigens_Solution

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Unformatted text preview: Bauh‘tosleshosltayndroms Flg..'l'.1 Supermligensbhdrirmllyto independen’dytothGmwllmolaedas T-oeflreoeptuaartdflflfinroleoules. artltoT-oellraoeptusblndinplothellp amm-lslntemotwilhhll-mdaull dorrrelnslll‘eT-selreoeptor.swayhomlhe molecules andT-oell reoeptorsia awapthet peptide-birding site. The Tnell receptors isoiledbtlnetlromflrewaythatnomrel drahlsmldlleolhrlrrrohadhblnd'ng paplfle troopers bind aperanllpene olnd superamlgen. clalre Bourbon was a healthy til-yearned with a history oi mlld asthma and allerglo rltlnllls who suddenly beam ill with a lever, general muscle aches. and lizzlneas. She llelt nauseous and vomited. Gtalre's temperature rose to seats and her mother rushed hertotbetamlly physician. En route she briefly lost oorreolouanasssnds ran rash desalopedoearhersnnsand spread rapidlyto moatotlhe body. Upon arrival at the phyaloIan‘s she appeared quite ill and was lmmedlatahr referred totha Emergency Heparbnent. She was alertout listless and heroanerel oondltloo gave cause for eonoat'n. Dtt examination. her tempera'bIre was 313°C, and heart rateand respiration rateware martredlyelewatad. at tee beats per minute and 24 breaths perndnuterespecllwely. Blood preeaurewss maul—mm ermine, llllflfl when seated, and arms when standing—and showed avldeltee at slgnllloant Ilrlllurl'le dapleflon. Abrlghlredrssholllalandralsedleslonswasapparentonhartrunlrand extremities, but there were no peteshlae [entail auburteneous harlomtagee] and no signs or toesllsed attention. Duesllortlngraeaaleddratmalrehsdnottalrenalooholormaaandhad notbeen esposadtoodterllllndmleHarteatman-strualpenod hsdbeeniweeltshefore. andahaheddetlalopedsaglnalbleedingonthedaypreldoustothaonaetothar ilmfihehednflusedatmnponovendghbbuthadhrsenedonematmomlnp, betoteshabeoanralil. Given heroriboal slamsastenshra laboratoryhstewereoarded out. Harwhita blood sell count was raised, at 21.tl.'lll sells pl“. with a pradornlnanoa oi nautrophlls and band tonne [lmmattne neutroshlle]. Irritating harassed rnoblllaatlon ot neutrophtls from the bone marrow. Eamm electrolyte lersla were wlthlrl normal limits. 111a blood cremation tlrne was slightly' prolonged mil serum lranaalnlnasa levels were raised: both otlheseslpnsare oendstenl with annual lleertunetlon. Cerebrosphtal lluld {ESP} was normal and showed no euldenos of Intention. clauses of blood. udna, ESP. and ventral tttad were made and Claire was gleen a oephaloaporin millions {oeilrlalrona} along with 2 liters ot lluld Intravenous”. Her blood pressure Improved andshewas lmn'ledlateljrefinltled totha httansilrra oars tbtit, wheneshe developed peteohlae. Shewee treated with lntraeenousllulds,two anti-staphylococcal snbbiotles {oxaelllln and elindamyoln] as wall as a oephalosporln {ostolaldmel with gradual improvement in has overall condition. Her blood. urlna, and GSF oulturea remalned slants, but her vaginal nature was poallhre for abundant 5. swells. She was subsequently transierred to the register lmpslientwsrd andtreatedlorrdayswlm anfi-slephyloooooal anfltlotles. 11w rash gradualll.t taded. CasehTotdcshocitfiyndrcm Claire suffered from staphylococcal toxic shock syndrome {TESL a striking example of the dramatic physiologic alterations caused by superantigens. T35 is a serious disease characterized hyrapid onset of fever, a rash, organ iaiiure. and shock. The maiority of cases occur in menstruating women, typically in their teenage years. but cases do occur in all age groups. T55 is typically associated with a localized S. omens infection {for example. subcutaneous abscesses. osteomyeiifis. and infected wounds}. staphylococcal food poisoning. or local colonization. as secured in the vagina in this case. When kept in the 1vagina for a long time [:12 hours} tampons soaked with menstrual fluid: can enhance the gromh of the bacteria which are the source of superantigens. it is unlikely that the tampon played a part in Claire's disease as it was inserted less than 6 hours before the onset of symptoms. As well as ‘I‘SST-l, toxigenic strains of S. nut-ens can produce other enterotoxins [such as enterototdn Bl that act as superanfigcns. with similar clinics] consequences. In addition. microorganisms other than S. nurses secrete superantigens that can cause disease (Fig. 12]. ii: _—1 acadat V53. 1lint. tints. antayfltayflac Vflfil “$12. "Il'fi‘l 3.1—2. Vflfltfilsfliifl'll‘drfim mm E Fig. 12 Smartest. lip usage and disease. Casai'floaicfihoolfiyndtotm Fig. 1.3 Expansion In numbers of lip2 T oak In toxic shoelt syndrome {1‘55}. Panel a. FADE analysis. Peripheral blood T cells from a norrnal control {bah} and a patient with aortic T53 [right]. Cells are stained with anti-V32 monoclonal antibody with a iiuoresoein tag. Fig. 7.4 tit-sch analysis oi T-ceil receptor v‘g. mane. Auroradiogams of Tech receptor attain trarsoripis arrplifieti by reverse hareoiption ittliowed by polymerase chain reaction {FIT-PCR]. Tcellsiiora a patient ethiioacshoolt syndrome and a oorthoi individual were stimulated with anli-GDS antibody and lL-2 heiorethe attraction at Filth and generation of cDNA. Each reaction oontah'ted specific oligonuciectide printers to expand the periods: its gene stagnant indicated [tie-attibasepairs]. as well asacugers eegmentispptotetiehpiaeaoontrolto ascertain that equivalent amounts of mFthlii were used. Photograph courtesy at if. (they. a ti all it?! Bill fit 43 g... iii 0 Thereisanirereasedpsrosntapeoingoelslnhieoatisntfio horizontal atria represses the mean fluorescence intensity. Psi-sit. tirnaoourseoipetsistenosoihighnumoersandretimtononnaioi vaTcelishapahantwiti-iTSS. Consistent with the V32 specificity of TSST- l. examination of the circulating lymphocytes from patients in the acute phase ofTSS typically reveals a much higher proportion of circulating “32 T cells compared with cells using other it; segments. is the illness resolves there is a gradual return to near normal proportions. The expansion in the numbers otvpz cells can be measured by examining the surface expression of T—cell receptors containing a V32 region using lmmunofluorescence (Fig. is] or by semiquantltatlve measurement of mlitiilh transcripts encoding V52 T-cell receptor chains using reverse trans- cription and the polymerase chain reaction tiff-PCB} [Fig v.4]. Although all the T cells activated by a given superandgen share a common V3 region. they will diiTer in their specificity for conventional peptide antigens. Sequencing of the T—cell receptor from superantigen-activated T cells reveals a difl‘erent use of El and I gene segments by the [i chains and a wide diversity of or chains. Those receptors will encompass a wide variety of antigen specificitica. In contrast to superantig'en. conventional antigen induces the ctonotypic expansion of T cells. an the T cells in any given clone will have identical D and I gene segments in their B chains and identical o. chains. 1tiecause the pool of Vfirl'ESEl'iCtEd T cells activated by superantigen may contain autoreactive T cells. it has been postulated that superantigcns may trigger autoinunune disease. Marry ofthe manifestations oi'TSS are the result of massive and unregulated cytoltine production triggered by the activation of immme system cells. TEST—1 is more effective than bacterial lipopolysaccharide in inducing the synthesis and secretion of interleulcin [ILi-i and tumor necrosis factor {TNT-“lo by monocytes. 'ISSTvl is also a potent T-oell mitogen for those T cells whose receptors it engages: it also induces them to produce large amounts of cytokines, including 1L-2 and interferon {lFNI-y. IL-i and TNF—ot are critical in the induction of the acutesphase response and induce fever and the production of the. IL-1 and TNF‘I‘I also activate vascular endothelium and, together with IL-2. increase vasctdar permeability with the subsequent leakage of fluid fmm the intravascular space into the perivasculature. It is these effects of the massive overproduction of TNF-ot that result in the toxic shock: edema and intravascular volume depletion leading to hypotension and shock with multiple organ failure. mnTcflcSItc-citeyndtoms Susceptibility to T85 scents to correlate with a poor antibody response to TEST-1. While the majority of healthy individuals have protective antibody titers to 'l‘SST-l. more than 313% of patients with T55 lack anti-TEST—l antibodies during the acute illness. and mostfail to develop anti-TEST-l anti bodies following convalescence. Possible explanations include an inability on the patients part to mount an antibody response against TEST-1 and staphy- lococcal enterotoidns. or a specific inhibition of such a response bythe toxins. El How do you detennine another s protein behaves as a filipfii‘flflfigdfl? Superantigens, but not conventional antigens. can activate naive T cells. Superantigens will thus induce the proliferation of lymphocytes from new- borns and from the thymus. as previous exposure to the antigen and expan- sion of the number of antigen-reactive cells is not required. Superantigens do not require processing by accessory cells and are thus able to induce the proliferation of purified T cells in the presence of parafonnaldehyde-treated monocytes. which lack. the capacity to process antigen. Direct binding of a labeled protein to cells positive for MHC class ll, or its cc-precipitation with MHC class I! molecules. confirms it as a superantigen. Explain the rapid progression of clinical symptoms following introduction of super-antigen conaps-titresr with the noisy in apparent: responses to conventionei antigen. During tlteevolufion of an adaptive immune responseto conventional antigen, a cascade of events must occur over a relatively long period of time. The antigen has to be intemalined. processed, and presented as peptidehiHC complexes by antigen-presenting cells. The complexes are recognized only by those T cells healing a T-cell receptor specific for the antigen-derived peptides— a fraction of a percent {cum} of the entire T—cell pool. These few antigen- specificT coils must then proliferate and bystander cells be recmited before an etfective responsccan be mounted. In contrast. superflutigzeclt—inducod inunune activation is independent of antigen processing. thus bypassing the first step, and immediately activates a sieeable fraction ofT cells. every small number of superantigen molecules is sufiicient to activate a T cell with the appropriate lip region in its receptor {clo molecules per T cell]. Activation results in a massive secretion ofT-cell cytokines. which include lL-2. IFN-y. 'I'NF-rt. and TNF—fl. In addition. superanfigens can directly activate monocytes and dendritic cells by cross-linking their surface MHC class :1 molecules. Erossplinking is efiected by superantigens bound to T-cell receptor fl chains andior because a ntunber oi super-antigens. including 135111. have two distinct binding sites for Milt: class II molecuies. [boss-liming of Milt: class I] molecules causes a rapid and massive release of eymkines such as IL-1. “INF—o. Iirfi. lL—B. anti Ill-12. This is associatedtvith the upreguiation of B? co—su‘mulatory molecules undress cells. which. together 1nith cytoltine action. further amplifies T‘cell activation by superantigen. Thus. minute amounts of super-antigen are sufficient to rapidly activate a large number of T cells and monocytesimacropbages. restdtingin an amplificatory loop and in a massive outpouring of cytokines. which leads to the rapid appearance of clinical symptoms. GushTeuleShocltSyntironw Mist ars the potential mnemonic of fiver injury in T55? liver injury may occur as a result of decreased organ perfusion during hypotension. However. immunologic mechanisms may also contribute to injury. Hepatoqrtes eiqiress Pas. a cell-surface molecule crucial for the induction of apoptosis [programmed cell death]. T-cell activation by superantigens and the massive release of cytolines results in the upreguladon of the natural ligand for Fas—FosL—on the surface of circulatinglytnphocytes. Cross-linking of Fas on hepatocytes by FasL on circulating lymphocytes results in the triggering of apoptosis in hepatocytes. in addition. circulating cytoklnes such as "INF-ct are also capable of triggering cell death and can nesuit in liver iniury. lei flair-e susceptible to another ease of res? Protection against toxic shock is conferred by antibodies against the super— antigen. which neutralize it before it can cause disease. In order to stimulate an andbody response. the superantigen must be recognized. internalized. and processed by superantigemspecific B cells which then present the antigenic peptides to antigen—specific T cells. These are activated to become helper T cells that can in turn stimulate the production of superantlgen- speciflc antibodies on reexposure to the superantigen. Antibodies to other antigens that cross-react IInt-I'itl'i the superantigen may also confer protection. In humans. there is evidence that during and following TEST-associated illness. 1&2 T cells become anergic and thus cannot provide help to superantigen—speclflc B cells. Patients with TBS drerefore fail to develop TSST-l-specific antibody. So Claire is. unfortunately. likely to he at risk of another episode of THE. Hopefully. she will evennrallyr develop anti‘TSST-l antibodies. ...
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