Hypersensitivity ppt Microbiology for Pharm D.pptx

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1. Dr. Anam Zamin HYPERSENSITIVITY

2. INTRODUCTION Hypers e nsitivity i s the te r m used when an im m une re s ponse re s ults in exaggerated or inappropriate reactions harmful to the host. The term allergy is often equated with hypersensitivity but more accurately should be limited to the IgE–mediated reaction. The clinical manifestations of these reactions are typical in a given individual and occur on contact with the specific antigen to which the in d iv i dual i s h ypersen s iti v e . The first contact of the individual with the antigen sensitizes (i.e., induces the antibody), and the subsequent contacts elicit the allergic response. Hypersensitivity reactions can b e s ubd i vided int o f our ma i n t ype s . Types I, II, and III are antibody-mediated, whereas type IV is cell- mediated. Type I reactions are mediated by IgE, whereas types II and III are mediated by IgG.

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4. TYPE I : IM M ED I A TE (AN A PHYL A CT I C) HYPERSENSITIVITY An immediate hypersensitivity reaction occurs when an antigen (allergen) binds to IgE on the surface of mast cells with the c o ns e qu e nt release of se v e r al mediato r . The process begins when an antigen induces the formation of IgE antibody, which binds firmly by its Fc portion to receptors on the surface of basophils and mast cells. Reexposure to the same antigen results in cross-linking of the c e ll - bou n d Ig E , deg r anulatio n, and rel e ase of pharmacologically active mediators within minutes (immediate phase). Symptoms such as edema and erythema (“wheal and flare”) and itching appear rapidly because these mediators (e.g., histamine) are preformed.

5. Immediate (anaphylactic) hypersensitivity

6. The lat e phase of Ig E - mediated inflammatio n occurs a pp r o ximately 6 hours a f ter e xpo s ure to the an t i g en and is due to mediators (e.g., leukotrienes) that are synthesized after the cell degranulates. These mediators cause an influx of inflammatory cells, such as neutrophils and eosinophils, and symptoms such as erythema occur.

7. Note that the allergens involved in hypersensitivity reactions are s u bstanc e s , su c h as polle n s , animal dander s , f o o ds (n u t s , shellfish), and various drugs, to which most people do not exhibit clinical symptoms. H o w e v e r , some individual s res p ond to th o se substanc e s b y producing large amounts of IgE and, as a result, manifest various allergic symptoms. Nonallergic individuals respond to the same antigen by producing IgG, which does not cause the release of mediators f r om mast c e ll s a nd basophil s . There is a genetic predisposition to immediate hypersensitivity reactions

8. The clinical manifestations of type I hypersensitivity can appear in various forms (e.g., urticaria [also known as hives], eczema, rhinitis and conjunctivitis [also known as hay fever], and asthma). T h e most se v ere f o r m of type I h ypers e nsitivity i s s y s t em i c anaphylaxis, in which severe bronchoconstriction and h ypo te n sion (sh o c k) can be lif e - thr e ate n in g . The most common causes of anaphylaxis are foods such as peanuts and shellfish, bee venom, and drugs such as penicillin M a jo r manifestatio n s of anap h ylaxis o c c u r wh e n lar g e amo u nts of mediators are suddenly released as a result of a massive dose of antigen abruptly combining with IgE on many mast cells. This is systemic anaphylaxis, which is potentially fatal.

9. Important mediators Histamine causes vasodilation, increased capillary permeability, and smooth muscle contraction. Clinically, disorders such as allergic rhinitis (hay fever), urticaria, and angioedema can o c cu r . Leukotrienes cause increased vascular permeability and smooth muscle contraction. They are the principal mediators in the bronchoconstriction of asthma. Prostaglandins and thromboxanes Serotonin causes capillary dilation, increased vascular pe r meabilit y , and smooth m uscle cont r action.

10. Desensitization Desensitization can prevent systemic anaphylaxis. Acute desensitization involves the administration of very small amounts of antigen at 15-minute intervals. Antigen–IgE complexes form on a small scale, and not enough mediator is released to produce a major reaction. This permits the administration of a drug or foreign protein to a hypersensitive person. Chronic desensitization involves the long-term weekly ad m inist r ation of the anti g en to whi c h the person is hypersensitive. This stimulates the production of IgA and IgG-blocking antibodies, which can prevent subsequent antigen from reaching IgE on mast cells, thus preventing a reaction.

11. T r e a tment & P r e v ention T rea t me n t of anap h ylact i c r eactions inclu d es d r ugs to counteract the action of mediators, maintenance of an airway, and support of respiratory and cardiac function. Epinephrine, antihistamines, corticosteroids, or cromolyn sodium, either singly or in combination, should be given. There are several approaches to the treatment of asthma . Inhaled β -adrenergic bronchodilators, such as albuterol, a r e com m only use d . Co r ticoste r oid s , su c h as p r edni s on e , are also effective. Aminophylline, a bronchodilator, is effecti v e but not co m mo n ly used.

12. A monoclonal anti-IgE antibody (omalizumab) is indicated for patients with severe asthma whose symptoms are not controlled by corticosteroids. For the prevention of asthma, leukotriene receptor inhibitors, such as montelukast, and cromolyn sodium are effective. The treatment of allergic rhinitis typically involves antihistamines along with nasal decongestants. For allergic conjunctivitis, eye drops containing antihistamines or v aso c o n strict o rs are e ffe c ti v e . Avoidance of the inciting allergens, such as pollens, is helpful in prophylaxis. Des e nsitization can also be helpful.

13. TYPE I I : CY T O T O X I C HYPERSENSITIV I TY Cyt o t o xic h ypers e nsitivity o c curs when anti b o d y direct e d at anti g e n s of the c e l l memb r ane acti v ates c omplem e nt . This generates a membrane attack complex, which damages the cell membrane. The antibody (IgG or IgM) attaches to the antigen via its Fab region and acts as a br i d g e to c o mpleme n t via it s F c r e gio n . As a result, th e re i s complemen t - medi a ted lysi s as i n h emolytic anemias, ABO transfusion reactions, or Rh hemolytic disease. In addition to causing lysis, complement activation attracts phago c yt e s to t h e sit e , w i th c o ns e qu e nt release of e n z y mes that damage cell membranes.

14. Figure: Cytotoxic hypersensitivity. RBC, red blood cell.

15. D r ugs ( e . g . , penicillin s , phenace tin, quinidine ) can atta c h to surface proteins on red blood cells and initiate antibody formation. Such autoimmune antibodies (IgG) then interact with the red blood cell surface and result in hemolysis. Other d r ugs ( e . g . , q uinine) can a tta c h to pla tel e ts and in d uce autoantibodies that lyse the platelets, producing th r omb o c yt o p e nia an d , a s a c o ns e qu e nc e , a bl e e d ing tendency.

16. TYPE II I : IMMUNE COMPLEX HYPERSENSITIVITY Immune complex hypersensitivity occurs when antigen–antibody complexes induce an inflammatory response in tissues. Normally, immune complexes are promptly removed by the reticuloendothelial system, but occasionally they persist and are deposited in tissues, resulting in several disorders. In persistent microbial or viral infections, immune complexes may be deposited in organs (e.g., the kidneys), resulting in damage. In autoimmune disorders, “self” antigens may elicit antibodies that bind to organ antigens or deposit in organs as complexes, especially in joints (arthritis), kidneys (nephritis), or blood vessels (vasculitis). Wherever immune complexes are deposited, they activate the complement system. Polymorphonuclear cells are attracted to the site, and inflammation and tissue injury occur.

17. Two typical type III hypersensitivity reactions are the Arthus reaction and se r um si c knes s . A r thus R eaction Arthus reaction is the name given to the inflammation caused by the deposition of im m une compl e x es at a local i zed sit e . I t i s na m ed f or D r . A r thu s , who first described the infl a mm a tor y response that occurs under the following conditions. Antigen, antibody, and complement are deposited in vessel walls; polymorphonuclear cell infiltration and intravascular clumping of platelets then occur. These reactions can lead to vascular occlusion and necrosis.

18. Se r um Sickness In contrast to the Arthus reaction, which is localized inflammation, serum sickness is a systemic inflammatory response to the presence of immune complexes deposited in many areas of the body. It leads to the formation of immune complexes, which may circulate or be deposited at various sites. Typical serum sickness results in fever, urticaria, arthralgia, lymphadenopathy, splenomegaly, and eosinophilia a few days to 2 w eeks after in j ection of the f oreign se r um or d r u g . Nowadays, serum sickness is caused more commonly by drugs (e.g., penicillin).

19. Imm u ne Co m pl e x D i se a ses S y stemic L u p u s E r yt h em a to s us Systemic lupus erythematosus is a chronic inflammatory autoimmune disease that affects several organs, especially the skin of the face, the joints, and the kidneys. Antibodies are formed against DNA and other components of the nucleus of cell s . These antibodies form immune complexes that activate complement. Complement acti v a t io n p r oduces C5a, whi c h a t t r acts neutrophils that release enzymes, thereby damaging tissue

20. TYPE I V : DEL A YE D (CEL L - MEDI A TED) HYPERSENSITIVITY Del a y ed h ypersensitivity i s a function of T lymp h oc y te s , n o t anti b o d y . The response is “delayed” (i.e., it starts hours [or days] af t er contact with the anti g en and often last s f or d a ys). In certain contact hypersensitivities, such as poison oak, the pruritic, vesicular skin rash is caused by CD8-positive cytotoxic T cells that attack skin cells that display the plant oil as a f orei g n an t i g en. In the tuberculin skin test, the indurated skin rash is caused by CD4-positive helper T cells and macrophages that are attracted to the injection site.

21. FIGURE: Delayed (cel l - medi a ted) hypersensitivity

22. Clinic a lly Impo r ta n t Del a yed Hypersensitivity R eactions C o ntact Hy p erse n siti v ity This manifestation of cell-mediated hypersensitivity occurs after sensitization with simple chemicals (e.g., nickel, formaldehyde), plant materials (e.g., poison ivy, poison oak), topically applied drugs (e.g., sulfonamides, neomycin), some cosmetics, soaps, and other substances. Neomycin is a very common ca u s e . In all cases, the small molecules acting as haptens enter the skin, attach to body proteins, and become complete antigens. Cell-mediated hypersensitivity is induced, particularly in the skin. Upon a later skin contact with the offending agent, the sensitized person develops contact dermatitis characterized by erythema, itching, vesicles, eczema, or necrosis of skin within 12 to 48 hours caused by the attack of c y t o t o xic T cell s .

23. Drug alle r gy A d r ug al l er g y i s an aller g y to a d r u g , most co m mo n ly a medication. Drugs often contain many different substances, including dyes, which could cause allergic reactions. This can cause an allergic reaction on the first a d minist r ation of a d r u g . F or e xampl e , a pers on who developed an allergy to a red dye will be allergic to any n e w d r ug whi c h cont a in s th a t red d y e . When a medication causes an allergic reaction, it is called an allergen.

24. Mechanism Drug allergies are attributed to "drug hypersensitivity," initiated by exposure to a drug at a dose normally toler a t ed b y no n - h ype r sen s iti v e pe r son s . There are two mechanisms for a drug allergy to occur: Ig E or no n - Ig E m edi ate d . I n Ig E - media t ed re a ction s , al s o kn o w as Im m unoglo b ulin E mediated reaction s , d r ug aller g ens bind to Ig E an t ibodie s , which are attached to mast cells and basophils, resulting in IgE cross-linking, cell activation and release of preformed and newly formed mediators

25. Drug Hyper s en s iti v ity Drugs, particularly antimicrobial agents such as penicillin, are n o w among t h e most c omm o n causes of h ype rse n sitivity reactions. Usually it i s n o t the intac t d r ug that indu c es a n tibo d y formation. Rather, a metabolic product of the drug, which acts as a hapten and binds to a bo d y p r ot e in , do e s s o . The resulting antibody can react with the hapten or the intact drug to give rise to type I hypersensitivity. When reexposed to the drug, the person may exhibit a drug rash, fever, or local or systemic anaphylaxis of variable severity.

26. In non –IgE-mediated drug allergy, the mechanisms include cytotoxic/cytolytic reactions involving the interaction of IgG or IgM antibodies and complement with a drug aller g en as s ociat e d with cell m emb r anes ( e . g . , im m une hemolytic anemia, thrombocytopenia), drug immune complex reactions and T-cell–mediated reactions. Drug allergy, occurs in 1% to 2% of all admissions and 3% to 5% of hospitalized patients, respectively but the t r ue incidenc e of d r ug alle r g y i n the com m unit y , and among c hild r en and a d ult s , i s unkn o wn.

27. Symptoms Identifying a drug allergy can sometimes be the hardest part. Sometimes drug allergies are confused with Nonallergic drug reactions because they both cause somewhat similar reactions. Symptoms of a drug allergy can include, but are not limited to, the following list. Hives Itching Rash Fever Facial swelling S h o r tn e ss of breath Anaphylaxis, a life threatening drug reaction (produces most of these symptoms as well as low blood pressure)

28. D R UGS Antibiotics 🞑 Penicillin 🞑 Sulfa drugs 🞑 Tetracycline Analgesics 🞑 Codeine 🞑 Non-steroidal anti-inflammatory drugs (NSAIDs) Antiseizure 🞑 Phenytoin 🞑 Carbamazepine