Robbins Essential Pathology PDF, Hypersensitivity Reactions
Document Details
Uploaded by CleanlyBoston
Mansoura
Tags
Summary
This document covers hypersensitivity reactions and associated disorders, including detailed mechanisms and clinical manifestations. It's a helpful resource for medical students interested in the immune system and pathology.
Full Transcript
42 CHAPTER 4 Diseases of the Immune System Table 4.1 Hypersensitivity Reactions Type Immune...
42 CHAPTER 4 Diseases of the Immune System Table 4.1 Hypersensitivity Reactions Type Immune Mechanisms Histopathologic Lesions Prototypical Disorders Immediate (type I) Production of IgE antibody → immediate release Vascular dilation, edema, smooth Anaphylaxis; allergies; bronchial hypersensitivity of histamine and other mediators from mast muscle contraction, mucus asthma (atopic forms) cells; later recruitment of inflammatory cells production, tissue injury, inflammation Antibody-mediated Production of IgG, IgM → binds to antigen on Phagocytosis and lysis of Autoimmune hemolytic anemia; (type II) hypersen- target cell or tissue → phagocytosis or lysis cells; inflammation; in some Goodpasture syndrome sitivity of target cell by activated complement or Fc diseases, functional derange- receptors; recruitment of leukocytes ments without cell or tissue injury Immune complex– Deposition of antigen–antibody complexes Inflammation, necrotizing vascu- Systemic lupus erythematosus; mediated (type III) → complement activation → recruitment of litis (fibrinoid necrosis) some forms of glomerulone- hypersensitivity leukocytes by complement products and Fc phritis; serum sickness; Arthus receptors → release of enzymes and other reaction toxic molecules Cell-mediated (type IV) Activated T lymphocytes → (1) release of Perivascular cellular infiltrates; Contact dermatitis; multiple hypersensitivity cytokines, inflammation and macrophage edema; granuloma formation; sclerosis; type 1 diabetes; activation; (2) T cell–mediated cytotoxicity cell destruction tuberculosis Ig, Immunoglobulin. Immediate (Type I) Hypersensitivity Reactons aganst envronmenta antgens ncude aerg y, wc s an abnorma reacon agans common and normay armess This inammatory reaction, also called allergy, is caused by IgE envronmena subsances, and conac sensvy, wc s a cua- antibodies that recognize environmental antigens and sensitize neous mmune reacon agans cemcas and drugs. mast cells, leading to the release of mediators. E x cessve reac tons aganst mc robes a s o c aus e yp ers ens v - Aerges, e mos common mmunoogc dseases, are reacons o y re ac ons. A oug d eens e aga ns m crob es s e nor ma angens n e envronmen, oods, and nsec venoms, and are mos unc on o e mmune s ysem , n s ome c as es , suc as ub er- requen n urban areas n ndusrazed socees (were suc an- c u oss, e mcrob e s unusu a y p ers sen and e m mune gens are abundan). In mos ndvduas, e mmune sysem does no resp ons e s e b e comes e c aus e o ssue njur y. In am maor y reac agans envronmena angens, bu n some ndvduas, ese b owe ds e as es are oug o be c aus e d by re ac ons ag ans normay armess angens ec srong reacons a can ead o sg- commens a b ac er a, w c may ac v ae mmune ce s w en ncan morbdy and even dea. he propensy o deveop ese nor ma proe c ve me can sms are d ee c ve. reacons s caed atopy. he ypca aergc reacon consss o an he erms ypersenstvty and autommunty are oten used ner- eary (wn mnues) vascuar and smoo musce response, wc cangeaby, bu ey are no synonymous. Hypersensvy reers o an may be oowed by a sower (ae-pase) nlammaor y response over mmunoogcay medaed ssue reacon a s domnaed by nlam- e nex ew ours (Fg. 4.1). maon. I s requeny assocaed w auommuny, bu aso may Pathogeness. Mos mmedae ypersensvy reacons oow a be caused by mcrobes and oer envronmena agens. Conversey, sereoypc sequence o ceuar responses (Fg. 4.2). some auommune reacons do no ave a componen o ypersen- Actvaton of 2 ces and producon of IgE anbody. Aopc nd- svy, suc as depeon o red ces and paees by auoanbodes vduas make srong h2 responses o some angens. h2 ces wou accompanyng nlammaon. secree e cyoknes IL-4, IL-5, and IL-13, wc ac on severa Hypersensitivity reactions are classied into four major types ce ypes w negra roes n mmedae ypersensvy. IL-4 based on the nature of the adaptive immune reaction. smuaes B ces specc or e aergen o produce e IgE mmu- hs casscaon s useu because eac ype as dsnc meca- nogobun soype. IL-5 acvaes eosnops a are recrued o nsms and paoogc and cnca eaures (Tabe 4.1). e reacon, and IL-13 acs on epea ces and smuaes mucus Immedate (type I) ypersenstvty s caused by h2 ces and secreon. mmunogobun E (IgE) anbodes. Inlammaon s rggered S ensz aon of ma s ce s by IgE anbody. Mas ce s express a many by medaors reeased by mas ces. g -a n y re cepor or e Fc p or on o e ε e av y can Antbody-medated (type II) ypersenstvty s caused by anbodes o IgE Te re cepor s a s o expre ss e d on bo o d b as op s, bu a bnd o arge angens on ces or n ssues and desroy ces, b e c aus e a erg c re ac ons o cc ur n ssues and no n e crc u - rgger nlammaon, or nduce uncona abnormaes. a on, s key a mas ce s are e maj or ce yp e nvove d Immune compex–medated (type III) ypersenstvty s caused by n es e re ac ons. Mas ce s b nd Ig E and re an on er sur- compexes o anbodes and angens a become deposed n ves- aces. ses and ssues and ec nlammaon. Acvaon of mas ces and reease of medaors. Wen e angen T ce–medated (type IV) ypersenstvty s caused by CD4+ T s renroduced, bnds o e IgE, us cross-nkng e assocaed ces, wc nduce cronc nlammaon, or CD8+ T ces, wc Fc recepors, wc n urn ransm nraceuar sgnas a ead desroy os ces. o e secreon o medaors rom e mas ces. CHAPTER 4 Diseases of the Immune System 43 Immediate Late- reaction phase reaction Allergen exposure Mast cells snoitatsefinam Vascular Eosinophils lacinilC congestion Edema B C 0 1 4 8 12 16 20 A Hours after allergen exposure Fig. 4.1 Immediate hypersensitivity. (A) Kinetics of the immediate and late-phase reactions. The immedi- ate vascular and smooth muscle reaction to an allergen develops within minutes after challenge (allergen exposure in a previously sensitized individual), and the late-phase reaction develops 2 to 24 hours later. (B) Morphology of the immediate reaction is characterized by vasodilation, congestion, and edema. (C) The late-phase reaction is characterized by an inflammatory infiltrate rich in eosinophils, neutrophils, and T cells. (Micrographs courtesy Dr. Daniel Friend, Department of Pathology, Brigham and Women’s Hospital, Boston.) hree groups o medaors are mporan n mmedae ypersens- Morphology. he soogc appearance o ype I ypersensvy vy reacons: s ypcay unmpressve. C ongeson and excessve secreon o Vasoactve amnes, many stamne, are sored n mas ce gran- mucus rggered by samne may be e ony manesaons. ues and rapdy reeased upon mas ce degranuaon. Hsamne In asma, ere may be sgncan bronca gand yperropy, causes rapd vasodaon and ncreased vascuar permeaby and eosnop-rc nlammaor y nraes n bronca was, and causes smoo musces o conrac. Cemoacc acors and pro- mucous pugs a obsruc e umens (see Caper 10). eases are aso reeased. he aer may damage ssues and aso generae knns and ceave compemen componens o produce addona cemoacc and nlammaor y acors. C ln cal Feature s. Imme d ae yp ers ens v y re a c ons range n Lpd medators, ncudng prostagandns and eukotrenes, are s e ver y rom e m d nus anc e o ve s ( ur c ar a) and ay e ver syneszed rom membrane aracdonc acd and ave mu- (a erg c rn s), o s er ous , s ome me s a a , ac ue anapy a x s and pe acons n nlammaon, descrbed n Caper 2. Prosagan- cronc ds e as es suc as bronc a as ma (Tabe 4.2). Te re ac on dn D (PGD ) s e mos abundan medaor generaed by e 2 2 s o c a ze d w en e an ge n s c on ne d o a p ar c u ar se, suc as cycooxygenase paway n mas ces. I causes nense bronco- e sk n (o ow ng con ac ) or e gas rones na ra c (o ow ng spasm, as we as ncreased mucous secreon. he eukorenes nges on). Sysem c exp o sure o proe n an gens (e. g. , n bee LTC and LTD are e mos poen vasoacve and spasmogenc 4 4 venom) or dr ugs (e.g. , p en c n ) may resu n sy se m c anapy ax s. agens known. In anapy axs, w n m nue s o e exp osure n a s ens ze d os , Cy toknes are sy n esze d and s e cree d o ow ng mas ce ac - cng , ur c ar a, and sk n e r y e ma app e ar, o owe d by proound va on. Tes e ncu d e umor ne c ro ss ac or ( T NF ) and ce mo - respraor y d c u y c aus e d by pu monar y bronco c ons r c on k nes, w c re cr u and a c vae eu ko c yes n e ae-pas e and accenu ae d by e y p e rs e c re on o muc us. L ar y nge a e d ema re ac on, and IL-4 and I L- 5 , w c amp y e T 2 - n ae d may exacerb ae d c u y n bre a ng by c aus ng upp er ar way mmune re ac on. obs r uc on. Te mus c u aure o e e n re g as ro ne s na rac he combned acons o ese medaors accoun or e manes- may be a e c e d, w resu an vom ng , ab d om na cramps , and aons o mmedae ypersensvy. I s no cear wy some nd- d ar re a. W ou mme d ae ne r ven on , ere may be s ysem c vduas deveop njurous reacons o angens a are gnored n vas o d a on w a a n bo o d pre ssu re ( anapy a c c so ck) , and mos peope. he many acors accounng or aopy ncude genec e p a en may prog ress o c rc u aor y c o ap s e and d e a w n suscepby and exposure o angens durng cdood. Tweny mnues. percen o 30% o mmedae ypersensvy reacons, especay Tre a m e n or es e c on d ons re e s on b o c k ng or c ou n e r- asma, are rggered by nonangenc smu, suc as empera- a c ng e a c ons o v ar ou s m e d a or s. C om m on y us e d dr ugs ure exremes and exercse, and do no nvove h2 ces or IgE. I are an s am n e s , c or c o s e ro d s ( o re a n am m a on ) , e p - s beeved a n ese cases (caed nonatopc aerg y), mas ces n e p r n e ( o c or re c e pre c pou s d rop n b o o d pre s s u re n are abnormay sensve o acvaon by varous nonmmune smu. 44 CHAPTER 4 Diseases of the Immune System Allergen (e.g., pollen) Table 4.2 Immediate Hypersensitivity (Allergic) negrella erusopxE Mucosal lining Disorders Clinical Syndrome Clinical and Pathologic Manifestations ot Anaphylaxis (may be Fall in blood pressure (shock) caused by caused by drugs, vascular dilation; airway obstruction due Dendritic cell bee sting, food) to laryngeal edema Bronchial asthma Airway obstruction caused by bronchial Naive smooth muscle hyperactivity; inflamma- T cell tion and tissue injury caused by late- phase reaction Allergic rhinitis, Increased mucus secretion; inflammation of sinusitis (hay upper airways and sinuses Activation of T 2 H fever) cells and IgE class switching T 2 H Food allergies Increased peristalsis due to contraction of B cell in B cells cell intestinal muscles, resulting in vomiting and diarrhea IgE-secreting Production of IgE IgE plasma cell Antibody-Mediated (Type II) Hypersensitivity Antibody-mediated (type II) hypersensitivity disorders are caused by antibodies, usually IgG or IgM autoantibodies, directed against FcεRI target antigens on the surface of cells or other tissue components. Binding of IgE to Mast cell FcεRI on mast cells Pathogeness. he angens may be norma moecues nrnsc o ce membranes or n e exraceuar marx, or ey may be adsorbed exogenous angens (e.g., a drug meaboe). Rarey, anbodes o mcroba or oer angens a cross-reac w os angens may be responsbe. he mecansms o ce njur y n s orm o Repeat exposure ypersensvy are e oowng: to allergen Pagocytoss: Anbodes may coa (opsonze) crcuang ces (suc as red ces or paees) and arge em or pagocyoss or compemen-medaed desrucon. Opsonzed bood eemens are mosy emnaed n e speen, expanng wy spenecomy s o Activation of mast cnca bene n anbody-medaed dseases marked by ow bood cell; release of couns. mediators Inlammaton: Anbodes a are deposed n exraceuar ssues bnd eukocye Fc recepors or acvae compemen (descrbed Mediators aer), bo resung n e recrumen and acvaon o eukocyes (neurops and macropages) and acue nlammaon. Vasoactive amines, Ceuar dysfuncton: Anbodes can aso cause ceuar dysuncon Cytokines lipid mediators wen ey bnd o and acvae or nb recepors on e surace o ces, or bnd o and depee essena moecues, producng unc- ona decences wou ce or ssue njur y. Immediate hypersensitivity Late phase reaction Because compemen proens pay an essena roe n ype II and reaction (minutes after (2–24 hours after repeat III orms o ypersensvy, a bre dscusson o compemen acva- repeat exposure to allergen) exposure to allergen) on and uncon oows. Fig. 4.2 The sequence of events in immediate hypersensitivity. Imme- diate hypersensitivity reactions are initiated by the introduction of an Activation and Functions of Complement allergen, which stimulates Th2 cells and immunoglobulin E (IgE) pro- The complement system consists of several circulating and mem- duction. IgE binds to Fc receptors (Fc εRI) on mast cells, and subse- brane proteins that play important roles in host defense, as well as quent exposure to the allergen activates the mast cells to secrete the in inammation and tissue injury in immunologic diseases. mediators that are responsible for the pathologic reactions of immedi- here are ree paways o compemen acvaon, ony one o ate hypersensitivity. wc nvoves anbodes (Fg. 4.4). he pyogenecay oder ater- an apy a x s , an d o re e ve bron c o s p a s m ) , an d , m ore re c e n y, natve patway s acvaed by mcroba moecues a saby bnd an - Ig E an b o dy o n b e pr m ar y n a or o e a e rg c compemen proens. he cassca patway s acvaed by bndng o re a c on. A n b o d e s a b o ck e c y ok n e s I L- 4 , I L- 5 , an d I L- 1 3 compemen proens o anbodes a are deposed on suraces and or er re c e pors are us e d o re a as ma an d aop c d e r m a - orm compexes w angens. hs s mporan n adapve mmuny s. E ar y c d o o d e x p o s u re o an a e rge n ( e. g. , p e anu exrac) and s e ony paway a parcpaes n e anbody-medaed (ype re du c e s e ncdence o a e rg y o a a ge n a e r n e , a ou g II) and mmune compex–medaed (ype III) orms o ypersensvy. e m e c an s m s n o u n d e rs o o d. he ectn patway s acvaed by a pasma ecn a bnds o mcroba CHAPTER 4 Diseases of the Immune System 45 A Opsonization and phagocytosis Phagocytosed Opsonized cell cell C3b C3b Phagocyte receptor Phagocytosis Complement activation B Complement- and Fc receptor–mediated inflammation Fc receptor Neutrophil Complement enzymes, by products reactive oxygen (C5a, C3a) intermediates Inflammation and tissue injury Tissue antigen Complement activation C Antibody-mediated cellular dysfunction Acetylcholine Antibody Nerve ending (ACh) against TSH TSH receptor receptor Antibody to Thyroid ACh ACh receptor epithelial receptor cell Muscle Thyroid hormones Antibody inhibits binding of Antibody stimulates receptor without hormone neurotransmitter to receptor Fig. 4.3 Mechanisms of antibody-mediated diseases. (A) Opsonization of cells by antibodies and com- plement components and ingestion by phagocytes. (B) Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement breakdown products. (C) Antireceptor antibodies disturb the normal function of receptors. In these examples, antibodies to the acetylcholine (ACh) receptor impair neuromuscular transmission in myasthenia gravis, and antibodies against the thyroid-stimulating hormone (TSH) receptor activate thyroid cells in Graves disease. carboydraes. he uncons o compemen are medaed by varous reguaor caed decay acceeratng factor, wc normay ms e or- proeoyc ceavage producs. A ree paways ead o e ceavage maon o e enzyme a ceaves C3. In e absence o s reguaor, o e mos abundan compemen proen, C3, o generae a ragmen, ere s excessve C3 breakdown and ormaon o e membrane aack C3b, a s deposed on nearby suraces (mcrobes or ses o anbody compex. Red bood ces are especay sensve o compemen-med- bndng). C3b opsonzes ces or pagocyoss by bndng o C3b recep- aed yss because o er n ce was, accounng or urnar y excre- ors a are expressed on pagocyes. C3b aso s a componen o a on o emogobn reeased rom ysed red ces. he suscepby o proease a ceaves aer compemen componens. Among e oer red ces o compemen-medaed yss ncreases wen e pH o e proeoyc producs are C5a and C3a, wc smuae e reease o bood decreases durng seep, ence e nocurna naure o e red ce samne rom mas ces, as we as oer pronlammaor y acves. breakdown. Heredtary angoedema resus rom nered decency he ermna seps n compemen acvaon ead o e ormaon o o C1 nbor, a pasma serne proease nbor a ms e pro- a arge proen canne, e membrane aack compex, wc creaes eoyc acvy o eary compemen proens, many C1. Decency o oes n pd membranes and eads o osmoc yss o ces. s nbor eads o excessve producon o numerous vasoacve pro- Compemen acvaon s conroed by severa ce-assocaed and ens, wc ncrease vascuar permeaby and cause epsodes o lud secreed proens a preven coaera damage o norma ces and accumuaon n e skn, gasronesna rac, and ar ynx (e mos unresraned compemen acvaon durng norma deense. Predc- serous eaure because coud ead o ar way obsrucon). aby, decences o ese compemen reguaors ead o ce njur y and Clncal Features. In many auommune dseases, e cnca nlammaon. Paroxysma nocturna emogobnura (PNH) s caused probems are caused by auoanbodes (Tabe 4.3). he paoog y by an acqured decency o an enzyme nvoved n syness o a may be domnaed by nlammaon (as n anbody-medaed 46 CHAPTER 4 Diseases of the Immune System EFFECTOR FUNCTIONS C5a, C3a: Inflammation Alternative Microbe pathway Recruitment and Destruction of microbes activation of leukocytes by leukocytes C3b: Phagocytosis C3b C3a Classical C3b pathway C3b is deposited Recognition of bound C3b Phagocytosis Antibody on microbe by phagocyte C3b receptor of microbe MAC: Lysis of Lectin microbe pathway Mannose For mation of binding lectin membrane attack complex (MAC) Fig. 4.4 Pathways of complement activation and functions of complement. The activation of the comple- ment system (the early steps) may be initiated by three distinct pathways, all of which lead to the production of C3b. C3b initiates the late steps of complement activation, culminating in the formation of a multipro- tein complex called the membrane attack complex (MAC), which is a transmembrane channel composed of polymerized C9 molecules that causes lysis of thin-walled microbes. Peptide by-products released during complement activation are the inflammation-inducing C3a and C5a. The principal functions of proteins pro- duced at different steps are shown. Table 4.3 Antibody-Mediated Diseases Clinicopathologic Disease Target Antigen Mechanisms of Disease Manifestations Autoimmune hemolytic anemia Red cell membrane proteins Opsonization and phagocytosis of red blood Hemolysis, anemia cells Autoimmune thrombocytopenic Platelet membrane proteins (Gpllb: Opsonization and phagocytosis of platelets Bleeding purpura Illa integrin) Pemphigus vulgaris Proteins in intercellular junctions of Antibody-mediated activation of proteases, Skin vesicles (bullae) epidermal cells (desmogleins) disruption of intercellular adhesions Vasculitis caused by ANCA Neutrophil granule proteins, pre- Neutrophil degranulation and inflammation Vasculitis sumably released from activated neutrophils Goodpasture syndrome Protein in basement membranes of Complement- and Fc receptor–mediated Nephritis, lung hemor- kidney glomeruli and lung alveoli inflammation rhage Acute rheumatic fever Streptococcal cell wall antigen; anti- Inflammation, macrophage activation Myocarditis, arthritis body cross-reacts with myocardial antigen Myasthenia gravis Acetylcholine receptor Antibody inhibits acetylcholine binding, Muscle weakness, down-modulates receptors paralysis Graves disease (hyperthyroid- TSH receptor Antibody-mediated stimulation of TSH Hyperthyroidism ism) receptors Pernicious anemia Intrinsic factor of gastric parietal Neutralization of intrinsic factor, decreased Abnormal erythropoiesis, cells absorption of vitamin B anemia 12 ANCA, Antineutrophil cytoplasmic antibodies; TSH, thyroid-stimulating hormone. CHAPTER 4 Diseases of the Immune System 47 Antigen in Immune Complex Formation Table 4.4 Immune Complex Diseases circulation Clinicopathologic Disease Antigen Involved Manifestations B cell Systemic lupus Nuclear antigens (circu- Nephritis, skin erythematosus lating or “planted” in lesions, arthritis, kidney) others Poststreptococcal Streptococcal cell wall Nephritis Plasma Free glomerulone- antigen(s); may be cell antibody phritis “planted” in glomerular basement membrane Polyarteritis Hepatitis B virus antigens Systemic vasculitis nodosa in some cases Antigen- Reactive arthritis Bacterial antigens (e.g., Acute arthritis Endothelium antibody Yersinia) complex Serum sickness Various proteins (e.g., Arthritis, vasculitis, Immune Complex foreign serum protein, nephritis Deposition such as horse antithy- mocyte globulin) Neutrophil Arthus reaction Various foreign proteins Cutaneous vascu- (experimental) litis Pathogeness. Typcay, paogenc mmune compexes are produced n anbody excess and are o a sze suc a ey avod emnaon by pagocyes bu are capabe o deposng n vesses. Tssue deposon Complement eads o compemen acvaon and acue nlammaon (Fg. 4.5). Antigen- Consumpon o compemen durng e acve pase o e dsease antibody eads o decreased serum eves o C3, wc can be used as a marker complex Immune Complex–Mediated Inflammation and o dsease acvy. Serum sckness s a sysemc mmune compex Tissue Injury dsease n wc a snge arge dose o a oregn angen, suc as an anbody produced n oer speces, s njeced no an ndvdua. Immune compexes orm n e bood, become deposed n ssues, acvae compemen, and nduce nlammaon. he Artus reacton s Platelet an expermena mode o cuaneous vascus a resembes uman aggregation vascudes (Caper 7). Morphology. he prncpa morpoogc manesaon o mmune compex njury s acue vascus, wc may be assocaed w brnod necross o e vesse wa and neuropc nraon. Wen deposed n e kdney, e compexes can be seen Vasculitis on mmunoluorescence mcroscopy as granuar deposs o Neutrophil lysosomal enzymes mmunogobun and compemen and on eecron mcroscopy as Fig. 4.5 Immune complex disease. The sequential phases in the induc- eecron-dense deposs aong e gomeruar basemen membrane. tion of systemic immune complex–mediated diseases (type III hyper- sensitivity). Clncal Features. Many s y se m c m mu n o o g c ds e as es are gomeruoneprs), e secondar y efecs o ce depeon a ss o c ae d w e or m a on an d ssu e d e p o s on o m mu n e (auommune emoyc anema and romboc yopena), or c omp e xe s ( Tab e 4.4). T e p a o o g c p c u re s o a c ue uncona derangemens (myasena gravs and Graves dsease). In n am m a on n e s e s o d e p o s on o c omp e xe s , y p c a y e myasena gravs, anbodes agans aceycone (AC) recepors c ap ar e s o e k dne ys ( c au s ng g om e r u on e p r s ) , s y n ov u m n e moor end paes o skeea musces nb neuromuscuar o j o n s ( ar r s ) , an d b o o d ve ss e s n any ssu e ( v a s c u s ). ransmsson, w resuan musce weakness. Anbodes can aso T e proo y p c u m an m mu n e c omp e x ds e as e s s y se m c upu s smuae excessve ceuar responses: In Graves dsease, anbodes e r y e m ao su s ( SL E ) , a ss o c ae d w p e rs se n an b o dy re sp ons e s agans e yrod-smuang ormone (TSH) recepor smuae o auo an ge ns. yrod epea ces o secree yrod ormones, resung n yperyrodsm. T Cell-Mediated (Type IV) Hypersensitivity Two types of T-cell reactions are capable of causing tissue injury Immune Complex–Mediated (Type III) Hypersensitivity and disease: (1) cytokine-mediated inammation (also called Antigen–antibody (immune) complexes that are formed in the delayed-type hypersensitivity), in which the cytokines are pro- circulation may become deposited in blood vessels and induce duced mainly by CD4+ T cells, and (2) cytotoxicity, mediated by inammation. CD8+ T cells (Fig. 4.6)
