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`ll. Immunologic Diseases 7 Detect or Deception?
`When an Individual develops a disease involving the immune system, it is either because an element or
`component is missing (deficiency) or because the normal control mechanisms of the adaptive response have
`‘misfired”. resulting in the lack of an appropriate immune response or even loo vigorous a response
`(dysregulation). Remember. the immune response is supposed to protect the host. As those of us who care
`tor patients with profound immunodeficiencies can attest, these folks typically die of overwhelming inlections,
`often by intections that are han'nless to those us with Intact Immune systems. In contrast. a normal immune
`response against a specific antigenic entity can produoe reactions de5igned to be protective But actually
`producing disease In the host.
`Ill. Hypersensitivity Disease
`When an Immune response to an antigen Is in itself harmful to the host, it is referred to as a hypersensitivity
`disease. Gel and Coomhs recognized that many such diseases had common mechanisms and classified
`them accordingly.
`Type I reactions occur as a result Of production Di IQE. This immediate hypersensitivity accounts tor the
`classic allergic diseases that we treat (much more about this In More articles].
`Type II reactions occur as a result 0! specific antlbodles that bind to host cells and kill the cell (cytolysisj.
`Such reactions Involve either a series of plasma proteins collectively termed complement that bind to the cell—
`bound antibodies or a specific lymphocyte that binds to the back at the oell.bnund antibodies to cause
`antibody dependent cellular cytotoxicity (ADCC). Type II reactions commonly occur in certain drug reactions,
`particulady those causing a hemolytic anemia, This mechanism is also responsible for the once common
`hemolytic disease of newborns occurring in Rh+ irilarrts born to Rh- mothers
`Type III reactions occur as a result of soluble antigen-antibody complexes that deposit on vanous organ
`surtaces (such as the kidney, hung, synovium. etc) where they activate complement. Theses activated
`complement components, among other things. attract inflammatory cells to the site of the immune complex
`depositions. The inflammatory cells attempt to “swallow’ the tissue and release proteolytic enzymes that
`damage the tissues. Diseases such as rheumatoid arthritis and systemic iupus erythematosus occur as a
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`result of this mechanism
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`Type IV reactions are the only ones not Involving antibodies. Rather, sensitized T cells secrete small peptides
`called cytokines that activate macrophages to form granulornas. apparently to contain the infectious agent,
`Diseases such as tuberculosis, leprosy and sarcoidoeis all occur as a result of this mechanism.
`IV. lgE» The Allergy Antibody
`IgE is one of five classes of antibodies (immunoglobulins) made by humans (the others being IgM, lgG, IgA
`and IgD) and apparently is made as a primary defense against certain parasites. While parasitic disease may
`not be a major clinical issue in most industrialized nations, it is a major public health problem in third world
`countries, The antigen specific lgE acts with mast cells and eosinophils to protect the host against the
`invading parasite. However, the same antibody-cell combination is also responsible for the signs and
`symptoms of allergic diseases.
`V. Mast Cells- The Central Cell of Allergic Reactions
`When lgE is produced, it seeks cells containing receptors for the back of the antibody molecule [called the Fc
`portion). There are two maior types of receptors for lgE on cells. One, called a low affinity receptor, is found
`on a variety of cells Including lymphocytes and eosinophils. The other, a high athhity receptor, is found
`pnmarlly on mast cells. Mast cells are found In or near a variety of organs and tissues Including nose. lungs,
`gut, skin and even blood vessels. They contain large granules which house molecules such as
`histamine serotonin and tryptase. They normally function as pan or the host detense system.
`Once the mast cells are "armed" by the allergen—specific IgE molecules binding to the high affinity receptors,
`the 'Immune gun is cocked". Subsequent exposure to the specific allergen (Le. pollen, dander, etc.) causes
`pairs 0' IgE molecules to become crossllnked. ThIS 'PUIIS the tngger' on the mast cell, causing "S granules [0
`release their contents as well as activating to form new molecules. The histamine causes itching, increase in
`vascular permeability, smooth muscle constriction and reflexes such as sneezing, coughing and
`gastrointestinal motility increases.
`Grosslinking also activates mast cells to begin to synthesize and secrete molecules that can attract
`inflammatory cells (such as eosinophils) and further the allergic reaction itself. One such mechanism is
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`activation of biochemical pathways that metabolize a component of cell membranes called arachidonic acid.
`Arachidonic acid can be metabolized down two major pathways by two diiferent enzyme systems —
`cyclooxygenase and Iipooxygenase. The end products of these pathways are called prostaglandins and
`Ieukotrienes. Both pmstaglandins and leukotrienes are capabte of enhancing the inflammation characteristic
`of this part or the allergic reaction. While the Immediate hypersensitivity of histamine release typically occurs
`In minutes, the Inflammatory response take several hours (3-24) and Is referred to as a late phase allergic
`response. The affected organs detlne the specific signs and symptoms of allergic disease In a particular
`patient. Why all allergic patients do not have rhinitis. asthma. atoplc den'natills and anaphylaxls together Is not
`understood but is the subject of great interest and research.
`VI. Establishing Clinical Allergic Disease
`The major target organs affected by IgE-medlated reactions define the clinical syndrome In a particular
`patient. Diagnosis of allergic disease is a combination or history, physi-I findings and Judiclous use or
`laboratory testing, including aliergy testing. The history is fundamental to any diagnosis of allergic disease.
`What are the symptoms? Do they occur in a cenain piace (Le home, workplace)I time or year, time at day.
`alter ingesting certain things (Le. food, drugs, etc), alter exercise, when stressed. etc. are all vitally important
`questions to be explored with every patient. Fast medical history oi previous allergic (and/or other
`immunologic) conditions can be associated with current illness. Family history of similar reactions as well as
`alopy in general is significant. The incidence of allergic diseases is estimated at about 10—1 5 % ot the
`population (I in Bto 10). If one parent Istruly atopic, the incidenoe ls up to 1 in 4 and lfboth parents are
`aloplc. the incidence rises lo1 in 2.
`Physical examination is important because there are characteristic findings of allergic vs nonallergic
`conditions In a variety of organ systems including nose. eyes. lung and skin. Ruling out other causes for
`symptoms (Le. mechanical obstruction for nasal congestion, pneumonia for shortness of breathI Infection for
`Irritated eyes and nonaloplc Inflammation for a skin rash) typically occur at this point.
`Laboratory evaluation must be directed and cost eflective. There are relatively few indications for obtaining a
`total semm IgE In the evaluation of routine allergic disease. However, directed assessment of allergen»
`specific lgE Is very helpful In differentiating alopic from nonatoplc individuals who have characteristic
`symptoms. Indeed, It Is estimated that up to 50% of Individuals who have nasal symptoms compatible with
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`allergic rhinitis are nonatopic. Management strategies are dependent upon this distinction.
`Allergy testing is commonly done by two methods — skin testan and In vitro determination or allergen specific
`lgE in the blood (RAST). Skin testing takes advantage of the allergen—specific lgE bound to mast cells in the
`skin. For safety, testing usually begins with percutanecus [“prick') testing. The allergen is applied and a
`needle passed through the drop to prick the skin. In highly sensitive individuals, this will result in the formation
`ofa white, raised area (wheel) sunuunded bya red, erylhematous zone (flair) within 15-20 minutes indicative
`of a positive reaction. When indicated, nega‘a've prim tests may be confirmed by injecting a minute amount of
`more dilute allergen into the skin (intradennal) and observing an additional 15-20 minutes for the appearance
`of a wheat and flair.
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`Controls are typically placed in conjunction with the skin tests. Positive control is usually limited to histamine
`which is the major mediator responsible for the wheat and flair. This is to be certain that the skin reaction can
`occur in a partiwlar patient when histamine is released from a degranulated mast cell. Such reactions are
`most commonly suppressed by the recent use ol antihistamines, The negative control (most commonly
`saline) IS used to confirm that the SKI" mast cells do not nonspecifically degranulate from the mechank‘al
`manipulation of the skin (Le. pricking or injecting). This Is called dermatographlsm and is a contraindication to
`allergy sldn testing, at least at that particular time.
`In vitro testing Is indicated when the histamine controls are negative (i.e. recent use or long acting
`antihistamines) or tithe individual has a chronic skin condition that would make proper reading ot skin tests
`impossible (Le. dermatitis. dennatographlsm. etc). The principle is the use of a method that can detect
`allergen-specific lgE molecules in patient blood samples.
`This method, while usefulI has certain drawbacks. FirstI IgE is a very minor mmponent of the circulating
`plasma. Allergenepecific IgE. even in highly atopic individuals, is only a small portion of the total lgE. Thus.
`very sensitive methods must be employed to detect allerfsE specificth in plasma. In contrast, it is estimated
`that as little as 50 crosslinked lgE pairs may be sufficient to activate a mast cell. This results in the sensitivity
`of RAST being only about 70% of skin testing. In addition, the hall life of lgE in the blood is only 2-3 days ,
`making determination of pollen-specific lgE by RAST more difficult out of season since the plasma level goes
`down during that time. In contrast, mast cell hound th is apparently stable for a more prolonged time (up to
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`months). Finally, RAST testing is, on a per allergen basis, considerably more expensive that skin testing.
`Interpretation at positive allergy testing results must be incorporated with historical and physical findings. It is
`only in this context that the diagnosis of allergic disease can be made and specific therapies initiated.
`VII. Specific Allergic Diseases
`In discussing allergic diseases, there are seleded difierencei between organ systems that makes diagnosis
`and management distinctive.
`Allergic rhinitis is the most common of all atopic diseases in the United States, affecting up to 10% of the
`adult population. While no one dies directly as a result of allergic rhinitis, the economic impact is substantial.
`Over $600 million is spent in the USA annually in the management of this disease, This does not include the
`costs ot the 2 million lost workdays _ 3 million lost school days and 28 million days of den-eased productivity
`trorn the symptoms at the disease andlor side effects of the medications used to treat them.
`Clinically, information is gained from a nasal examination which may reveal pale, boggy turbinate as well as
`clear to greenish rhinonhea. when colored nasal secretions are stained and examined, they typically reveal
`large numbers of eosinophlls as the main inflammatory cell. In many instances (panicularly In children)
`complications such as chronic otltls media, rhinoslnusllls and conjunctivitis can be traced to chronic
`obstruction from allergic rhinitis.
`Asthma Is a disease whose Incidence and mortality rate continue to Increase. It Is commonly considered a
`bronchospastlc disease. However, we now know that this Is In fact a chronic disease of the airways
`charactedzed by mucus hypersecretion as well as bronchial InflammationI edema, and hyperresponsiveness
`resulting in increased bronchocorrstrimicn. The end result may he frequent exacerbations and need for
`multiple medications.
`The contibution of lgE to this disease process has long been implicated and more recently estimated. It is
`suggested that up to 95% of children less than 15 are “allergic" tor extrinsic) asthmatics. This number is still
`70% in young adults between 15 and 30. Finally. 50% of asthmatics over the age of 40 have demonstrable
`asthma triggers that are IgE-mediated.
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`Thus history that emphasizes exacerbating (actors. physical examinations that conelated degree of
`breathlessness with wheezing and peak flow measurement and laboratory that at time quantitales Ihe number
`of peripheral blood eosinophils are all important in management.
`Allergic 5K1" dlseases including urticaria and angioedema as well as atopic dermatitis are less clearly defined
`as a true allergic disease, Unicaria and angloedema are both due to excessive mast cell activity in the skin.
`Chronic urticaria and angioedema rs seldom due to a definable lgE mechanism but , when determined, is due
`to a drug. food orfood additive.
`Alupic dermatitis is associatm with high serum 39E levels as well as a history of atopic disease (rhinitis,
`asthma. etc). Unfortunately. management is most difficult since the medications ctassically associated with
`treatment of allergic diseases (is. antihistamines) have little etfect in these patients.
`VIII. The Reasons We Use Specific Drugs 10f Treating Allergic Diseases
`Antlhlstamines
`When mast cell-bound lgE ls crossllnked, the mast cell membrane becomes activated. This ‘destabllizes" the
`membrane, resulting in the release at mediators from me large bmphillc granules in the mast cell (a process
`called degranuiatlon). The major constituent of the large granules is histamine. Histamine has many effects
`including itching, sneezing, bronchospasm and increased vascular permeability that can result In loss a!
`intravascular volume (anaphylaxis) andlur extravasation of plasma into skin (wheal), lat layers (angioedema),
`nose or lung, Most histamine-induced effects occur when histamine binds to target tissue via histamine
`receptors. There are three distinct type at histamine receptors [H1,H2 and H3). Most allergic reactions are via
`H1 receptor binding.
`The major therapy for most allergic diseases is the use of antihistamines which are H1 receptor blockers.
`They do NOT stop histamine release from mast cells, rather they compete with histamine for the H1 receptor
`on target cells. It then follows that antihistamines are less eflective after histamine has been released than if
`they block the receptor priorto mast cell degranulation.
`Mast Getl Stabilizers (Cromolyn, Nedocromil)
`It would be even more desirable to stop histamine from being released at all. One way would be to stop
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`crosslinklng ot lgE Dy allergen (dismissed below). Another way would be to stop mast cells trom
`degranulating even If lgE was crosslinked. Several drugs have this property. Cromolyn Is the llrst drug
`licensed as a mast cell stabilizer, that is Inhibit degranulatlon and activation. it Is available for use in the nose,
`lungs and GI tract. Its major limitation is a short duration of action (approx. 6 hours) and lack of available
`systemic preparation. Recently, a related compound called Nedocromil has been released in the US for use
`in asthmatics. It appears to have a longer duration of action and may have more anti-inflammatory properties
`than Cromolyn.
`Alter histamine is released. other mediators are also released, the impedance at which is not fully
`understood. Such mediators include TAME esterase. tryptase, serotonin and various cytokines. Research is
`underway to evaluate the clinical potential for drugs that antagonize the release andlor activity at many of
`these agents.
`As the mast cell is activated, several other events occur that contribute to the pathophysiology ot allergic
`diseases. One such event is the activation of a membrane enzyme called phospholipase A2 , which breaks
`down membrane components to arachioonic acid, a 20 carbon fatty acid. Nachidonic acid is lurther
`metabolized by one or two enzyme pathways Into various prostaglandlns ( by cyclooxygenase) or
`leukotrlenes (by llpooxygenase). Both prostaglandlns and leukotrlenes are highly prolnflammatary,
`bronchospastlc and vasodllatory.
`In addition, other mediators are synthesized that act as chemotaxlns to attract inflammatory cells to the
`activated mast cell environment. The major Inflammatory cell in allergic reactions Is the eosinophll. other
`inflammatory cells found in allergic reactions include basophils, lymphocytes, monocytesi‘rnacrophagES and
`neutrophils. But it is the eosinopnil that appears to have the most harmful potential.
`As the eosinophll is drawn to the inueasiugiy Inflammatory milieu, It becomes activated by a variety ur the
`mediators present. Its large granules release their contents (such as major basic protein, eosinophilic cationic
`protein, various cytokines, etc.) which can further promote inflammation and direct tissue toxicity. Research is
`currently underway to evaluate drugs that antagonize me activity or these eoslnophll-derlved mediators.
`Since the process of mast cell activation, mediator production and chemotaxis takes longer than mast cell
`deuranulation. allercrio reactions otten have two distinct phases — the first or earlv phase occurs in minutes
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`uegiailurauuu, allergic Ieacuuila uric“ nave Mu uisuiiui phases 7 the mar ui early phase occurs In minutes
`and is primarily from the preformed granularcontents. The second or late phase occurs some 13—12 hours
`later and is an inflammatory reaction from the above mentioned mast cell and eosinophil products.
`Antihistamines have no eflect on late phase reactions while corticosteroids have little direct reflect on early
`phase reactions. Cromolyn and Nedocrorriil appear to be active against both.
`CorticostercldS
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`The discussion of the pharmacothelapy of allergic diseases would be incomplete without mentioning the most
`commonly used class of medications 7 corticosteroids. These agents are antl-int'lamrnatories 7 that lsI they
`Inhibit late phase alferglc reactions.
`This occurs via a variety of mechanisms including decreasing the density of mast cells along mucosai
`surtaces, decreasing chemotaxis and activation of eosinophils. decreasing cytokine production by
`lymphocytes, monocytes, mast cells and eosinophils, inhibiting the metabolism of arachidonic acid and other
`mechanisms.
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`But tor the side effects. corticosteroids would likely be the only dmg needed for treating allergic reactions.
`Much eftort is underway to develop safer corticosteroids including topical application and modifying the
`molecules to preserve the anti-inflammatory properties while minimizing the undesirable side effects.
`IX. Allergen Immunotherapy
`Finally, a word should be said about allergen immunotherapy or allergy shots, They are still the only attempt
`at definitive therapy for lgE-mcdiatcd diseases. Through the parenteral administration of these allergens.
`clinical sensitivity to allergen-mediated reactions gradually diminishes.
`Multiple theories have been advanced to explain the mechanism at action of allergen immunotherapy. Mast
`researchers agree that three major events commonly occur in patients who receive a course of allergen
`immunotherapy 7 first. the production and release oi many of the proinfiammatory mediators [particularly
`cytokines) are diminished. This may be via a direct effect on mast cells and eosinophils or an
`Immunoregulatory efl‘ect mediated by specific populations of lymphocytes.
`Second, it is common to find increasrng amounts of allergen-specific lgG cinallating in the plasma of patients
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`receiving allergen immunotherapy. Such lgG could also bind to the speci‘lic allergen and prevents its
`intemction with mast cell-bound lgE.
`Finally‘ it can be demonstrated that, after an initial rise, allergen-specific IgE levels in the plasma fall wiltl
`allergen immunothempy. This is thought to be due to active immunoregulatory medianisms that alter how a
`specific individual responds to a particular allergen.
`Not all mechanisms are likely to be active in every treated patient. Many researchers are trying to determine
`exactly which mechanisms) is(are) active in a specific patient 50 allergen immunctherapy can be better
`tailored to the individual. Also work Is ongoing to better chemically define the treating allergens. make
`allergen immunotheiapy safer and even safely Increase the interval between Inlectlons.
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