Immunity and the Allergic Response

B Lymphocytes- Antibodies

*Gamma globulins called Immunoglobins *Composed of light and heavy polypeptides chains with large molecular weights *Each antibody is specific for particular antigen due to structural organization of amino acids *The steric shape allows for rapid and tight binding to antigen *Highly specific- held together by hydrogen hydrophobic, ionic, and van der wall bonds

The Allergic Response: Blocking the Mediator Effects

*H1 blockers- Benadryl (0.5-1mg/kg) *H2 Blockers- Ranitadine (150mg) *Corticosteroids- Hydrocortisone 1-5 mg/kg

Hypersensitivity Reactions: Type II

*Hemolytic transfusion reactions, Autoimmune hemolytic anemia, and Heparin induced thrombocytopenia *Involves the binding of IgG antibody/ Antigen complexes *Activation of complement cascade results in cell lysis

Two types of Immunity

*Innate- results from general processes rather than from processes directed at specific disease organism. *Acquired- specific immunity developed against bacteria, viruses, toxins and foreign tissues. Requires repeat exposure

Diagnosing anaphylaxis- (once pt stable, of course)

*May want to send serum tryptase level to confirm this is anaphylaxis....obviously treat the patient regardless. *Serum level remains elevated for 2 hours after attack- should preferentially send within 20 min of onset of symptoms *Histamine ½ life of several minutes precludes its measurement

Anaphylactic Reaction

*Exaggerated/Severe type I hypersensitivity reaction- IgE mediated *Occurs with in minutes of exposure to allergen *The most important mediators of anaphylaxis are histamine, leukotrienes, platelet activating factor. *Mediators released produce the symptoms of anaphylaxis

ANTIGEN

*Foreign substances (protein or polysaccharide) that can induce an immune response

Acquired Immunity

*Formation of antibodies and/or activated lymphocytes to attack and destroy specific invading organisms *Does not develop until after invasion of foreign organism or toxin *Develops slowly (over days); amplified response after repeated exposure *Two basic types of acquired immunity -Humoral (B-cell) Immunity -Cell mediated (T cell Immunity)

The primary function of antibodies is to...

bind antigen to the surface of B cells, activating them to become either memory B cells or antibody-secreting plasma B cells

Cytotoxic T cells attack and destroy...

cells by releasing cytotoxic chemicals

Helper T cells secrete...

cytokines that activate other lymphocytes

MONOCYTE

from bone marrow, enter tissues within 24 hrs, become macrophages

Left alone, allergens do no damage; it is the...

immune response to allergens that causes damage (ranging from mild tissue damage to fatal reactions)

IgA is also found in...

in external secretions (tears, saliva, intestinal and bronchial mucus, and breast milk)

An allergy is an...

inflammatory immune response to a non-pathogenic antigen (an allergen)

In the thymus, T cell precursors mature into...

one of two types of T cell: helper T cells or cytotoxic T cells

The allergen can be a...

protein, polypeptide, or smaller molecule bound to carrier protein (hapten)

IgD appears on the...

surface of B cells, but the physiological role of this antibody is unclear

IgE is associated with ...

the allergic response- atopy

IgM is associated with ...

the antibodies that react to blood group antigens

LEUKOCYTE

*(white blood cells)- body's mobile units of defense

Preventing Anaphylaxis: Medications

**Histamine (H1) antagonist- *Diphenhydramine (0.5-1 mg/kg IV) **Histamine (H2) antagonists (?) *Cimetidine (150-300 mg IV or PO) *Ranitidine (50 mg IV or 150 mg PO) **Corticosteroids *Prednisone (1mg/kg or 50 mg IV Q 6 hours X4 before exposure)

The Allergic Response: Airway

*100% FIO2 *If not secured- may consider prophylactic intubation to prevent airway obstruction and emergent airway *Beta Adrenergics- Albuterol *Anticholinergics- Atrovent *Delay extubation- swelling may progress for up to 24 hours

Neutrophils

*After engulfing large number of bacteria, neutrophils begin to die off (macrophages too) after several days, a cavity forms in the inflamed tissues consisting of dead neutrophis, macrophages, and necrotic tissue, and tissue fluid- this is called PUS

Drugs Associated with Anaphylaxis: Opioids

*Anaphylactic reactions to opioids very rare *Can have non -IgE mediated histamine release from Morphine and Demerol- *More common with meperidine than any other opiate *There are a few reported IgE mediated reactions to fentanyl

Hypersensitivity Reactions: Type I (immediate)

*Atopy, Urticaria , and Anaphylaxis *Involve antigens that cross link with IgE antibodies *Cause release of inflammatory mediators from mast cells (histamine, prostaglandins, Leukotrienes, heparin, etc.)

Drugs Associated with Anaphylaxis: Induction Agents

*Barbituates- 1in 30000; increased incidence with prioir exposure and female gender *Proprofol- 1 in 60,000 with new formualtion (2, 6 diisopropylphenol) - one study stated 2 .1 % of cases of anaphylaxis due to propofol *Etomidate and ketamine- anaphylaxis to these drugs exceedingly rare

Basophils and Mast Cells

*Basophils in blood are similar to mast cells found in tissues *Mediate immediate hypersensivity reactions (Type 1) *High propensity to attach with IgE antibodies *Release histamine, heparin, bradykinins, leukotrienes, prostaglandins, platelet-activating factor, serotonins, and lysosomal enzymes upon degranulation *Chemical mediators released from these cells responsible for many of symptoms associated with allergic reactions

Anaphylaxis Signs and Symptoms Under GA

*CV: Tachycardia, HOTN, Cardiac Arrhythmias, cardiac arrest *RESP: Wheezing, Increased PIP, Increased ETCO2, decreased oxygen saturation *Renal: Decreased Urine output secondary to ATN *Cutaneous: Flushing, Urticaria, Angioedema

Anaphylaxis Signs and Symptoms

*Cardiovascular: Tachycardia, arrythmias, cardiac arrest *Respiratory: wheezing, larygneal edema, SOB, Respiratory arrest *GI: nausea/vomiting, diarrhea, abdominal cramping *Renal: Decreased Urine output *Cutaneous: flushing, urticaria, angioedema

4 Other functions of antibodies:

*Coating bacteria to facilitate phagocytosis *Activating the complement system *Activating mast cells; triggering inflammation *Binding toxins released by bacteria

Eosinophils

*Constitute approximately 20% of circulating leukocytes *Weak phagocytic activity *Released from bone marrow and migrate to extravascular tissues in about 30 minutes- life span of 8- 12 days *Respond to eosinophil chemotactic factor- migrate toward inflamed tissue. *Special propensity to collect in tissue where allergic reactions occur- peribronchial tissue and skin

Hypersensitivity Reactions: Type IV (Delayed, Cell mediated)

*Contact dermatitis, TB- type hypersensitivity, Chronic hypersensitivity pneumonia *Mediated by CD 4 T Lymphocytes that were sensitized by prior exposure *Lymphocytes produce interleukins- attract inflammatory cells over 48-72 hours

Monocytes and Macrophages

*Enter circulation from bone marrow, after 24 hr enter tissues to become macrophages *Contain bactericidal agents (superoxides, hydrogen peroxide) and lysosomal enzymes, are actively phagocytic *Monocyte and macrophage system known as Reticuloendothelial system *Phagocytize bacteria, RBC's, necrotic tissue, and dead neutrophils *Play a major role in presenting antigens to B and T lymphocytes for activation

3 cells are the primary mediators of the Type 1 hypersensitivity reaction:

*Eosinophils *Basophils *Mast cells **All 3 cell types contain surface receptors for the IgE antibody and multiple cytoplasmic granules containing inflammatory mediators

Drugs Associated with Anaphylaxis

*Most common anesthesia related medications are muscle relaxants *Rocuronium>Succinylcholine>atracurium *1 in 6500 patients *IgE to the two quarternary or tertiary ammonium ions mediate anaphylaxis *Can also cause anaphylactoid reactions *Benzylisoquinolinium> aminosteroids *Latex- 2nd most common cause during anesthesia *Chronic exposure and Atopy increase risk of sensitization *Caution in patients with spina bifida, spinal cord injury, and congenital abnormalities of the GU tract *Seek out history of allergic sx in preop interview *Use all Latex free equipment- remove rubber stoppers from vials

Neutrophils

*Most numerous leukocytes in blood *Contain lysosomes filled with proteolytic enzymes capable of digesting bacteria *Responsible for phagocytosis of bacteria, -1st line of defense against a bacterial infection *Release thromboxanes and leukotrienes, also produce hydrogen peroxide - antibacterial effect *Eventually killed by toxins produced and released by lysosomes

Drugs Associated with Anaphylaxis: Anitbiotics

*Nearly 1/2 of true drug allergies in surgical patients are due to antibiotics, mainly beta-lactams such as PCN and cephalosporins. *1-4% of beta-lactam administrations result in allergic reactions *0.004-0.015% of these reactions lead to anaphylaxis *Cephalosporin cross-sensitivity in patients with PCN allergy is estimated at 2-7%, but this rate increases to 50% in patients w/hx of anaphylaxis to PCN *Vancomycin-Too rapid administration can lead to an anaphylactoid-like reaction called "Red man's syndrome" characterized by intense pruritus, flushing, erythema of the head and upper torso, often with arterial HOTN

Cells of the immune system

*Neutrophils *Eosinophils *Basophils and mast cells *Lymphocytes and plasma cells *Monocytes and macrophages

Anaphylactoid Reaction

*Not an IgE or antigen/antibody mediated reaction *Results from direct mast degranulation or complement cascade *Clinically Indistinguishable from Anaphylaxixs *Equally Life Threatening

B Lymphocytes

*Produce antibodies responsible for humoral immunity- large protein molecules that are capable of binding with and destroying antigens *Large diversity (greater than T cells)- form millions of antibodies each with a specific antigen *After "preprocessing", stored in lymph tissue and await activation by antigen

Cytokines

*Proteins that are synthesized by activated macrophages and lymphocytes *Act as secondary messengers and activate the synthesis and expression of specific adhesion molecules on leukocytes that promote attachment and transmigration of leukocytes *Involved in inflammation and immune response- regulate the magnitude and duration of the response *Initiate action by binding to specific receptors on surface of target cells *Usually act on nearby cells (paracrine), or on the same cell (autocrine), rather than released into circulation to work on a distant target (cell).

Hypersensitivity Reactions: Type III (immune complex)

*Serum sickness, Acute Hypersensitivity pneumonitis *Anitgen-antibody (either IgG or IgM) immune complexes become deposited in tissue *Activated complement cascade causing chemotactic factors to be released- neutrophils are attracted *The activated neutrophils enter tissue, release lysosomal ensymes causing tissue injury

The Allergic Response: Treatment

*Stop the Offending Agent ( if you know what it is) *Notify Surgeon (may need to terminate if no response to therapy) *Three armed approach 1. Oxygenation 2. Blood pressure support 3. Volume Replacement *Early treatment with epinephrine is recommended *Epinephrine- cornerstone in Anaphylaxis **Alpha 1- increase blood pressure via vasoconstriction **Beta 2-bronchodilating effects *Dosing-HOTN-5-10 mcg bolus (0.2mcg/kg) -CV Collapse 0.1-0.5mg bolus *IV Crytslloids- 2-4 liters- compensate for venous dilation

T Lymphocytes

*T lymphocytes (T cells) travel from the bone marrow as immature precursor cells to the thymus gland where they mature. *T cells activity also referred to as Cell-Mediated Immunity *T cell activation occurs only after the T cell makes direct contact with an antigen *Antigen presenting cells (dendritic cells, macrophages) activate T cells *Once activated, T cells attack other cells displaying that particular antigen on its surface

Preventing Anaphylaxis

*Take a careful history *Suspect atopic patients as being at risk for allergic reactions *Avoid known allergens *Consider treating patients with both H1 and H2 antagonist for 16-24 hours before treating with known or suspected allergen (contrast dye) *May want to consider large doses of steroids

The Complement Cascade

*The complement system refers to a group of more than 25 plasma and cell membrane-bound proteins. *Analogous to the coagulation cascade, the complement system has multiple triggers and multiple steps *The ultimate step in the complement cascade is the formation of membrane attack complexes that insert themselves into the cell membrane of pathogens leading to cell lysis

B lymphocytes- activation

*When antigen is presented to stored lymphocyte, the lymphocyte becomes activated- reproduces a large number of duplicate lymphocytes- "clones" *Clones are specific to only one type of antigen-may be several if same stereochemical characteristics *Once presented with antigen by macrophage, the B lymphocytes specific to that antigen enlarge and appear as lymphoblasts *Further differentiation occurs to plasmablasts, which begin to divide about every 10hrs for a total of 9 divisions *Plasma cells produce antibodies (gamma globulins) called Immunoglobulins- these are secreted into lymph and into the circulation- process may last for several weeks *Some lymphoblasts never become plasma cells, but rather distribute throughout the lymph tissue and lie dormant for a repeat exposure- Memory cells allow for greatly amplified response to subsequent exposures

GRANULOCYTE

*a morphological class that includes neutrophils, basophils and eosinophils

PHAGOCYTE

*leukocytes that function primarily by engulfing and ingesting targets

LYMPHOCYTE

*responsible for the specific recognition of an antigen and the immune response to that antigen

AUXILIARY cells

*secrete proinflammatory mediators

The immune response to allergens is called...

Hypersensitivity

IgG makes up ...

75% of the serum antibody in adults