The document summarizes basic immunologic principles including the humoral and cellular immune responses, antigen presentation, T and B cell differentiation, antibody structure and function, roles of monocytes/macrophages, neutrophils, eosinophils, basophils and mast cells, cytokines/interleukins, complement proteins, and their involvement in inflammation and allergic responses.

1. Immune Function
and
Allergic Response
Karim Maasri
PGY1
April 30, 2010
Karim Maasri MD-AUBMC

2. Basic Immunologic Principles
HOST
Humoral DEFENSE Cellular
Antibody-Mediated Antigen (1st exposure)
immune response
Engulfed by
Free Antigens Display of Antigens
by infected cells
Activation Macrophage
Activation
Becoming
B Cell Cytotoxic T cell
Giving rise Antigen Presenting Cell
Stimulating
Plasma Cell Helper T Cell
Secretion Memory helper
T Cell
Active Cytotoxic
Antigen T cells
Memory B Cells Karim exposure) Memory T Cells
(2nd Maasri MD-AUBMC
Antibodies

3. The antigen
Molecule stimulating an immune response
Anesthesiologists
Polypeptides Protamine
Use of few
antigens Large macromolecules Dextrans
Other drugs
Simple organic compounds
with low molecular weight
Immunogenic
Stable bond with Hapten-
circulating proteins / macromolecular
tissue micromolecules Karim Maasri MD-AUBMC complex

4. Thymus – Derived (T – Cell) Lymphocytes
Thymus of
Immature Fetus
T-Cells
lymphocytes
Subpopulations No specific
Regulatory
of T cells stimulation
Cells
Suppressor cells Helper cells Killer cells
Destruction of
myobacteria, Transplant
fungi, viruses rejection
 In HIV
infection Defense
against
Cytotoxic cells tumor
Karim Maasri MD-AUBMC cells

5. Bursa – Derived (B – Cell) Lymphocytes
Important in producing
cells responsible for Ab
synthesis
Helper T-cell lymphocytes Suppressor T-cell lymphocytes
Specific Specific
lymphocyte plasma
line cells
Karim Maasri MD-AUBMC

6. Antibodies
Ag binding to Fab
Antigen Binding Sites
Variable region
on heavy chain
Conformational
Light Variable region on
change
Chain light chain
Disulfide
Bridges Constant region on
light chain
Activation of
Fc receptor Heavy Chain Constant region on
heavy chain
Karim Maasri MD-AUBMC

7. Monocytes and Macrohpages
Circulating
monocytes
Confined to
specific organs
(Lungs)
Macrophages
Ingesting Ag
Presenting Ag
Mediator
Inflammatory Synthesis
Tumorocidal Facilitating B-Lymphocyte and
T-Lymphocyte response
Microbicidal
Karim Maasri MD-AUBMC

8. Polymorphonuclear Leukocytes (Neutrophils)
First cells appearing in acute inflammatory reaction
Containing
Activation
Hydrolases
Neutral Proteases
Hydroxyl radicals
Lysosomes
Superoxide
Microbial
Hydrogen peroxide killing
Karim Maasri MD-AUBMC

9. Eosinophils
Function in host defense UNCLEAR
Presence at
Parasitic infections
Tumors
Allergic reactions
Karim Maasri MD-AUBMC

10. Basophils
0.5% - 1% of circulating granulocytes in blood
Surface with IgE receptors
Similar function to those
on mast cells
Karim Maasri MD-AUBMC

11. Mast Cells
Important in immediate hypersensitivity responses
Tissue Fixed
Location in
perivascular space
Skin
Lung
Intestine
Release of active mediators
Surface with IgE receptors Activation important to hypersenitivity
responses
Immune Nonimmune
Stimuli Stimuli
Karim Maasri MD-AUBMC

12. Proteins – Cytokines / Interleukins
Synthesis by macrophages
Activation Endothelial cells
Secondary
messengers White cells
IL-1 Fever
TNF Neuropeptide release
Endothelial cell activation
Increased adhesion molecule expression
Important in infection and
inflammatory responses Neutrophil priming
Hypotension
Myocardial suppression
Catabolic state
Karim Maasri MD-AUBMC

13. Proteins – Cytokines / Interleukins
Activation
Extravasation into
alveolar space
Adherence of
neutrophils to
pulmonary capillaries
IL1, IL8, TNF
Karim Maasri MD-AUBMC

14. Proteins – Complement
Primary humoral response Activation of
to Ag-Ab binding complement system
Important effector system of inflammation
Activated Ab
20 different proteins Binding to Other complement proteins
Cell membranes
Activation of
complement system
Classic Pathway Alternate Pathway
IgG / IgM binding to Ag Endotoxins or drugs
Karim Maasri MD-AUBMC

15. Proteins – Complement
Antigen + C3a + C4A + C5a
Antibody C1 Complex
C2a + C4b fragments Important humoral
and chemotactic
Classic Pathway C3 convertase properties
Alternate
Pathway C3 hydrolysis
C3b + C3a fragments
Recognizing bacteria
C5 cleaved into C5a directly and indirectly
and C5b by attracting
phagocytes
Swelling
of cell C5b + C6 + C7 + C8 + C9
formation of membrane Increasing adhesions
And
attack complex of phagocytes to Ag
busting
Cell Lysis
Karim Maasri MD-AUBMC

16. Proteins – Complement
Regulation of complement system by series of inhibitors
Angioneurotic edema
Hereditary (autosomal dominant)
Acquired (lymphoma, lymphosarcoma, CLL, macroglobulinemia)
C1 esterase deficiency
Recurrent increased
vascular permeability of Trauma Surgery No cause
specific subcutaneous
and serosal tissues
(angioedema) Laryngeal obstruction
Respiratory abnormalities
Cardiovascular abnormalities
Pathologic manifestation of
complement activation
Protamine administration Karim Maasri MD-AUBMC
Acute pulmonary vasoconstriction

17. Effects of Anesthesia on immune system
Transfused
Anesthesia
Depression of blood
+ nonspecific host products
resistance mechanisms
Surgery
Coincident
infections
Immunologic
Direct and effects of
hormonal other drugs
effects of used
anesthetic
drugs
Karim Maasri MD-AUBMC

18. Type I Reactions
Independent of
Complement
Antigen
Binding of IgE Ab
to Fc receptors
+
Antigen
IgE - Ag
Fc receptor
IgE Cross-linking of IgE
Degranulation
Intracellular activation
Mast cell / Release of mediators Anaphylaxis
Basophil cell Extrinsic Asthma
Allergic rhinitis
Karim Maasri MD-AUBMC

19. Type II Reactions
Antigen
Complement
activation and
cell lysis
IgG or IgM Killer T Cell
Fc receptor
Individual ABO – incompatible transfusion reactions
own cell Drug – induced anemia
Heparin – induced thrombocytopenia
Karim Maasri MD-AUBMC

20. Type III Reactions
Antigen
IgG or IgM
Soluble protein
Insoluble Protein
– Ab complex
Complement activation
Recruitment of Inflammatory cells
Tissue Injury Classic Serum sickness after snake antisera
Immune complex vascular injury
? Protamine mediated pulmonary vasoconstruction
Karim Maasri MD-AUBMC

21. Type IV Reactions
Second contact with same antigen
Lymphocyte
Antigen regulation
Macrophage
Lymphokines
activation
Mononuclear
cell infiltration
Delayed
tissue
injury
Sensitized Tissue rejection
T -cell Graft-versus-host reactions
Contact dematitis
Tuberculin immunity
Karim Maasri MD-AUBMC

22. Intraoperative Allergic Reactions
Once in every 5,000 to 25,000 anesthetics Mortality rate of 3.4%
Allergic reactions due to an IV drug
90% Time (minutes)
5
Vasodilation
Most dangerous manifestation Circulatory collapse
 Venous return
May be the only manifestation Refractory hypotension
Karim Maasri MD-AUBMC

23. Recognition of Anaphylaxis during Regional and
General Anesthesia
Respiratory System
Coughing
Dyspnea Wheezing
Chest Discomfort Sneezing
Laryngeal Edema
 Pulmonary Compliance
Fulminant Pulmonary Edema
Acute Respiratory Failure
Karim Maasri MD-AUBMC

24. Recognition of Anaphylaxis during Regional and
General Anesthesia
Cardiovascular System
Disorientation
Diaphoresis
Dizziness
Loss of Consciousness
Malaise Hypotension
Retrosternal Oppression Tachycardia
Dysrhythmias
 SVR
Cardiac Arrest
Pulmonary HTN
Karim Maasri MD-AUBMC

25. Recognition of Anaphylaxis during Regional and
General Anesthesia
Cutaneous System
Urticaria (Hives)
Itching
Flushing
Burning
Periorbital Edema
Tingling
Perioral Edema
Karim Maasri MD-AUBMC

26. Arachidonic Acid Metabolites
Activation
Arachidonic
Mast
Acid
Cell
Metabolism
Lipoxygenase pathway
Cylco-oxygenase pathway
Leukotrienes Prostaglandins
Classic slow
reacting
Substance C4, D4, E4 PG D2
of anaphylaxis
Bronchoconstriction Bronchospasm
 Capillary permeability Vasodilation
TX B2
Vasodilation
Coronary vasoconstriction Pulmonary HTN
Myocardial depression  Capillary permeability Protamine
Karim Maasri MD-AUBMC reactions

27. Kinins
Kinins
Small Peptides
Vasodilation
Mast
Cell  Capillary permeability
Kinins Bronchoconstriction
Basophil
Cell Stimulation of vascular endothelium
Release of vasoactive factors
Prostacyclin
EDRF (NO)
Karim Maasri MD-AUBMC

28. Platelet – Activating Factor
Activation
Mast
Cell
Unstored Lipid
Platelet – Activating Factor
Very potent
?
Aggregation of PAF Physiologic effect
at 10-10 M
Leukocytes’ Platelets’ Activation
Activation
Release of
inflammatory  Capillary permeability
products
Smooth muscle contraction
Intense Wheal and flare response
Karim Maasri MD-AUBMC

29. Non-IgE Mediated Reactions – Complement Activation
Complement Activation
Immunologic pathway: Ab mediated (Classic) Non-immunologic pathway (Alternative)
Multimolecular self assembly proteins
Release of biologically active fragments of C3, C5
C3a, C5a
ANAPHYLATOXINS
Histamine
Smooth Increase in
release from Interleukin
muscle capillary
mast/basophil synthesis
contraction permeability
cells
Karim Maasri MD-AUBMC

30. Non-IgE Mediated Reactions – Complement Activation
Directed against
C5a antigenic determinants IgG
Interaction with high or granulocyte surfaces
affinity receptors on
PMNs and platelets
Leukocyte
Chemotaxis LEUKOAGGLUTININS
Aggregation
Activation
Embolus
Microvascular
occlusion Clinical Expression
Transfusion reaction
Liberation of  Pulmonary vasoconstriction
inflammatory (protamine transfusion)
products  ARDS
 Septic Shock
Karim Maasri MD-AUBMC

31. Non-IgE Mediated Reactions – Non Immunologic Release of Histamine
Molecules administered Histamine release in a
during the dose-dependent,
perioperative period nonimmunologic fashion
Mechanism Not well understood
What is know
Basophils not involved
Only cell population responding
Human cutaneous mast cells to drugs and endogenous stimuli
Equimolar basis Atracurium, d-Tubocurarine, Same ability for
metocurine degranulation
Clinically Newer aminosteroidal agents Minimal effect on
recommended dose (Rocuronium, Rapacuronium)
Karim Maasri MD-AUBMC histamine release

32. Treatment Plan
Anaphylactic Reaction
Vasodilation
Hypotension
 Capillary permeability +
Hypoxia
Bronchospasm
Severe reactions Aggressive therapy
Lower respiratory obstruction
Pulmonary hypertension
Persistent hypotension
Laryngeal obstruction
Persistence of symptoms 5h-32h ICU 24h for observation
Karim Maasri MD-AUBMC

33. Treatment Plan
Airway maintenance
100% Oxygen
Intravascular volume expanders
Epinephrine
Karim Maasri MD-AUBMC

34. Treatment Plan
Airway maintenance + Oxygen Administration
Anaphylactic Reaction Ventilation / Perfusion abnormalities
100% O2 Hypoxemia
Ventilatory Support
Follow Up response with ABGs
Karim Maasri MD-AUBMC

35. Treatment Plan
Discontinuation of all anesthetic drugs
Hypotension induction
Not bronchodilators of choice
Anaphylactic Reaction
Inhalational drugs
Bronchospasm
Hypotension
Interference with body’s
compensatory mechanism
to cardiovascular collapse
Halothane
Stop all
Sensitization of
Inhalational
myocardium to
drugs
epinephrine Karim Maasri MD-AUBMC

36. Treatment Plan
Providing volume expansion
Anaphylactic Reaction
Intravascular space Interstitial space
40%
Quick Process Acute Hypotension
Persistence of Hypotension
No advantage
for any Lactated Ringer’s
Colloid 2L – 4L + 25 ml/kg – 50 ml/kg
Normal Saline
Karim Maasri MD-AUBMC

37. Treatment Plan
Providing volume expansion
Accurate assessment of intravascular volume
TEE
Guidance of intervention
After anaphylaxis
Fulminant noncardiogenic pulmonary edema
+
Loss of intravascular volume
Careful hemodynamic monitoring
while replenishing volume
Karim Maasri MD-AUBMC

38. Treatment Plan
Epinephrine
Drug of choice during resuscitation in anaphylactic shock
-adrenergic effect Vasoconstriction Reversal of hypotension
2 receptor stimulation Bronchodilation
Inhibition of mediator release from mast cells and basophils
Hypotensive
patient
Volume
5g – 10g IV + +
Epinephrine
Cardiovascular collapse 0.1mg – 1 mg IV Epinephrine
Laryngeal edema without hypotension Maasri MD-AUBMC Epinephrine
Karim
S/C

39. Secondary Treatment
Antihistamines
Unclear indication
Diphenhydramine 0.5mg/kg – 1mg/kg
Competing with histamine over receptor
No inhibition of anaphylactic reaction
? antidopaminergic effects
Slow infusion to prevent potential hypotension
Karim Maasri MD-AUBMC

40. Secondary Treatment
Catecholamines
Resuscitation Persistent hypotension
Bronchospasm
Patient with Give
anaphylactic Catecholamine
reaction
Epinephrine Titrate according to response
0.05g/kg/min - 0.1g/kg/min
Norepinephrine Those with refractory hypotension to  SVR
Karim Maasri MD-AUBMC

41. Secondary Treatment
Bronchodilators
Bronchospasm as major feature
Ipratropium Patients receiving -adrenergic blockers
Karim Maasri MD-AUBMC

42. Secondary Treatment
Corticosteroids
Anti-inflammatory effects
Infusion of
corticosteroids
Time (hours)
4 6 12 24
Anaphylactic
Reaction
Benefits of Attenuation of
corticosteroids late phase
reactions
IgE mediated reactions 0.25g - 1g IV methylpredisone
Complement mediated reactions 1g - 2g IV methylpredisone
Catastrophic pulmonary vasoconstriction after protamine transfusion reactions
Karim Maasri MD-AUBMC

43. Secondary Treatment
Bicarbonate
Persistent hypotension
Rapid
Acidosis
Reduction in epinephrine effect
on heart and systemic vasculature
Sodium Bicarbonate
0.5meq/kg – 1 meq/kg
Every 5 minutes according to response
Karim Maasri MD-AUBMC

44. Airway Evaluation
Profound Facial Time for
laryngeal edema extubation
edema
Deflation of
Evaluation Airway ET tube cuff
of trachea edema Reassess
before
extubation
Leak No Leak
WAIT
Extubate Keep
Intubated
Karim Maasri MD-AUBMC

45. Vasopressin
Important drug for refractory shock
Hypotension
Vasodilatory
Shock
 Cardiac Output
Inability of -
Activation of
adrenergic
vasodilatory +
mechanisms to
mechanisms
compensate
Infusion: 0.01units/min
Karim Maasri MD-AUBMC

46. Perioperative management
Allergic Reactions
Drugs: 1% - 3% risk of allergic reaction
6% - 10%
Americans: 5% with allergy to 1 or 2 drugs
Adverse
Reactions Adverse
Reactions
Pharmacological action of drug Opioid
Dose dependant Allergy
Nausea
Predictable
Vomiting
Mild Serious
Local release
Overdose of histamine
Unintentional route
of administration
Karim Maasri MD-AUBMC

47. Perioperative management
Side effects
Most common adverse drug reactions
Undesirable pharmacologic actions
occuring at usual prescribed dose
Morphine
Dilatation of venous capacitance bed
Effect depending
 Heart Rate
 on patient’s
blood volume
 Sympathetic Tone
In depleted
patients
Karim Maasri MD-AUBMC Rapid Hypotension

48. Perioperative management
Drug interactions
Predictable
Dose Dependant
IV Benzodiazepine
IV Fentanyl + HYPOTENSION
Sedative – Hypnotic Drug
Karim Maasri MD-AUBMC

49. Perioperative management
Unpredictable adverse drug reactions
Dose Dependant
Related to Allergic
genetic reactions
differences
Small
percentage
Enzyme
of patients
deficiency
Clinical
manifestations not
Sulfa Drugs in resembling known
G6PD deficient pharmacologic action
patients
TIME SPAN
Exposure to drug Manifestations
Karim Maasri MD-AUBMC

50. Immunologic Mechanisms of Drug mechanism
Different
Any
Immunologic
Antigen
Responses
Different reactions in different patients
Penicillin
Different reactions 1 patient
Type I Type II Type III Type IV
Anaphylaxis Hemolytic Serum Contact
Anemia Sickness Dermatitis
Angio-
Localized
neurotic
Rash
edema
Karim Maasri MD-AUBMC

51. Evaluating a patient with allergic reactions
Hard
Identifying
the
drug Relying on Temporal sequence
circumstantial of drug
evidence administration
Allergic Reaction ANY DRUG
Direct challenge of patient with the drug
Only way to prove an allergic reaction
DANGEROUS NOT REOMMENDED
Karim Maasri MD-AUBMC

52. Agents implicated in Allergic Reactions
Allergy to 1 muscle relaxant
Multiple
Agents
Potential of allergy to other
muscle relaxants
Antibiotics
Cross-reactivity because
Induction Agents
similarity of the active site
Muscle Relaxants
NSAIDs Quaternary ammonium molecule
Protamine
Colloid Volume Expanders
Blood Products
Vecuronium Pancuronium
Karim Maasri MD-AUBMC

53. Latex
Important cause of perioperative anaphylaxis
Derived from the tree Hevea brasiliensis
Preservatives
Milky sap + Accelerators
Antioxidants
Increased risk
Health care workers
Children with spina bifida
Children with urogenital abnormalities Banana
Children with certain food allergies Avocado
Karim Maasri MD-AUBMC Kiwi

54. Latex
Anesthesiologists
24% with irritation / contact dermatitis
Of
those 12.5% with Latex – specific IgE positivity
Pretreatment with antihistamine
No data for prevention
No data for decreasing severity
Karim Maasri MD-AUBMC

55. Muscle Relaxants
62% - 81% of anaphylactic reactions
Unique molecular features Potential allergens
Divalent
More in steroid
derived agents
Capable of cross-linking cell- Cross
surface IgE linking
Muscle
IgE Relaxant
Mediator release from mast
cells / basophils
Mast Cell
No need for haptenating to
large carrier molecules Karim Maasri MD-AUBMC

56. Thank You
Karim Maasri MD-AUBMC