HYPERSENSITIVITY REACTIONS

SRSA: “slow reacting substance” A – Mixture of Leukotrienes (LTC4, LTD4, LTE4)
ECFA: Eosinophil chemotactic factor of anaphylaxis
NCF: Neutrophil chemotactic factor of anaphylaxis

Key Points:

• “Anaphylaxis” may be:
  • True anaphylaxis: a symptoms complex following exposure of a sensitised individual to an antigen, produced by a type I hypersensitivity reaction, associated with IgE mediated mast cell degranulation
  • Anaphylactoid reactions: Indistinguishable from true anaphylaxis, however the immune nature of the reaction is either unknown, or not due to a type I hypersensitivity reaction, immediate generalised reaction is a better term.

Gladwin / Mooney 2016

2015A 15: 79 % of candidates passed this question.
This question can be answered in tabular form and details have been described in a previous exam report (2007). Details of each of the four main types were expected. A description of the timing of reactions was also expected.

2013A 16:
Overall, this question was well answered. Candidates were expected to classify the hypersensitivity reactions into their typical groups (Type I – IV) and to describe the mechanisms within each group. Similar such questions have been asked in previous exams. Again, those candidates who could provide some structure to their answer tended to score well.

2008B 07: 3 (60%) candidates passed this question
A tabular format is a very desirable format for a response to this question. Again candidates who struggled to provide an organised response also failed to provide sufficient and succinct detail in their answer. A good answer would have included the following features.
Syllabus: M2g
Reference Text: Goodman and Gillman Chp 64

2007B 09: 2 candidates (28%) passed this question

Key Points:

• “Anaphylaxis” may be:
  • True anaphylaxis: a symptoms complex following exposure of a sensitised individual to an antigen, produced by a type I hypersensitivity reaction, associated with IgE mediated mast cell degranulation
  • Anaphylactoid reactions: Indistinguishable from true anaphylaxis, however the immune nature of the reaction is either unknown, or not due to a type I hypersensitivity reaction, immediate generalised reaction is a better term. i End-organ effects, e.g. H₁ and H₂ receptors

Anaphylaxis

• acute severe type I hypersensitivity reaction affecting multiple organ systems
• most common triggers:
  • Food, Environmental
  • Drugs: antibiotics, muscle relaxants
  • Iodine contrast
  • Chlorhexidine
  • Latex
• Clinical effects
  • Circulatory collapse: profound vasoplegia  distributive shock
  • Airway obstruction: angioedema, bronchospasm,

Pathophysiology

• Multiple exposures to target allergen
• 1st exposure: allergen presented by T helper cells to B cells → B cells produce specific IgE to target allergen
• Circulating IgE attach to mast cells → sensitization
• Subsequent exposure to allergen → allergen binds specific IgE on mast cells → mast cell degranulation → release of allergenic mediators
• Mediators trigger disseminated vasodilation + ↑ vascular permeability +/- bronchospasm → anaphylaxis
  • Histamine: Localised release → urticaria; Systemic release → H1 + H2 → vasodilation, ↑vascular permeability → ↓MAP
  • Bradykinin: ↑production PGI2, NO → vasodilation, ↑ vascular permeability → ↓MAP
  • Prostaglandins: PGID2 → vasodilation, ↑ vascular permeability, bronchoconstriction, chemotactic for neutrophils + activates eosinophils
  • Leukotrienes: LTE B4: chemotactic agent; LTE D4 + E4: angioedema, clotting/ thrombolysis/ DIC
  • Tryptase: activates complement, coagulation, kallikrein-kinin pathways → ↓ BP, angioedema, clotting/ thrombolysis/ DIC
  • TNF-a: cytokine → propagates anaphylactic reaction
  • NO: vasodilates
  • Serotonin: vasodilation, bronchoconstriction, aplatelet activation
  • Platelet activating factor: acts at PAF Rs

Management of Anaphylaxis

• Oxygen
• IV Fluids
• Adrenaline is the drug of choice, as it treats cardiovascular collapse, bronchospasm, and decreases oedema formation.
  • Stabilises mast cells to prevent degranulation
  • Low doses: Beta agonism at (inotropy and chronotropy) and causing smooth muscle relaxation (including bronchorelaxation).
  • Higher doses: alpha effects and causes vasoconstriction.
  • In adults, 0.3-0.5mg IM Q5-15min
  • In children, 0.01mg/kg IM Q5-15min
• Glucagon may be used in β-blocked patients resistant to adrenaline.
  • In adults, 1-5mg IV over 5 minutes, followed by infusion at 5-15microg/min
  • In children, 20-30mcg/kg up to 1mg over 5 minutes

Adjunctive agents include antihistamines and steroids. They are second line as they do not attenuate cardiovascular collapse, resolve airway obstruction, or have strong evidence behind their use. They include:

• Steroids:
  • Work by binding to the cell nucleus and switching off the transcription of various genes which encode for inflammatory mediators such as cytokines, chemokines, adhesion molecules and arachidonic acid.
  • They also activate anti-inflammatory genes such as MAP (mitogen activated protein) and increase the expression of beta2 receptors.
  • Methylprednisolone, Hydrocortisone or Prednisolone
• Antihistamines:
  • Binds to H1 receptors to block the effects of the histamine released from mast cells-
    • inhibition of vasodilatation
    • increased vascular permeability
    • contraction of non-vascular smooth muscle
  • Diphenhydramine 25-50mg IV (Children: 1mg/kg up to 40mg) up to 200mg in 24/24
• Salbutamol, for bronchodilation
• Other Non-pharmacological management includes early intubation to protect against airway obstruction due to angioedema

Kerr / JC 2019

2016B 09: 32% of candidates passed this question.
It was expected candidates would detail the process of IgE mediated type I hypersensitivity reaction with some discussion of the mediators (Histamine / tryptase and others) and their consequences. Some detail describing time frame of response and the pre-exposure to Antigen (or a similar Antigen) was expected. Drug treatments would include oxygen and fluids as well as more specific agents such as adrenaline and steroids. Adrenaline is the mainstay of therapy and some comment on its haemodynamic role and prevention of ongoing mast cell degranulation was required. Better answers noted steroids take time to work and some also discussed the role of histamine blocking agents.

JC 2019

2013A 17:
This question asked candidates to compare and contrast the mechanism of action, pharmacokinetics, and side effects of these drugs in the context of the treatment of anaphylaxis. Information beyond that did not score marks. A structured approach (e.g. a table) assisted in presenting the information.

Immune System: complex network of cells and proteins that defends the body against infection.

Physical barriers

• Skin
• Cilia
  • Respiratory tract
• Acidic environment
  • Stomach

Innate immunity

Recognize generic pathogenic motifs and directly attack or opsonize and phagocytose

• Defensins – perforate pathogenic membranes
• Compliment cascade – opsonize and signal for phagocytosis and directly lyse via membrane attack complex
• Innate immune cells
  • Neutrophils
    • Degranulate cytotoxic contents and cause oxidative damage to pathogens
  • Macrophages
    • Phagocytose and kill opsonized pathogens
  • Dendritic cells
    • Phagocytose and present antigen to cells of acquired immune system
  • Natural Killer cells
    • Recognize abnormal cell surface expression (e.g. lack of MHC, abnormal MHC proteins) due to intracellular pathogens (e.g. virus) and directly kill infected cells

Acquired immunity

• Pathogenic antigens presented to B cells and T cells via APCs such as dendritic cells
• Show: Specificity, Memory, Diversity, Immunological tolerance
• B cells (20%, Humoral Immune reponse)
  • Produce antibody against antigen
  • Antibodies opsonize and target for T cell killing, phagocytosis and compliment cascade
  • B cells become memory B cells and plasma cells, primed for explosive antibody production on subsequent exposure to the same antigen
• T cells (80%, Cell-mediated immune reponse)
  • Major subtypes into CD8 (Killer) T cells and CD4 (Helper) T cells
  • CD8 (Cytotoxic/Killer) T cells recognize specific antigen presented to them via TCR and lyse pathogens and infected cells
  • CD4 T (Helper) cells produce cytokines for adjacent B cells that recognize the same antigen, allowing B cell differenciation and antibody production
  • CD28 (Regulatory) T cells dampen the immune reaction, preventing or limiting autoimmune damage.
  • Memory T Cell: Reside in lymphoid tissue and induces more rapid and powerful immune response with 2nd exposure to Ag

Sakurai 2016

2010B 09: 8 (53%) of candidates passed this question.
For a good answer candidates were expected to describe physical barriers, innate and acquired immunity. Physical barriers such as skin, mucous membranes, normal flora, secretions, etc were poorly covered. Aspects of immunity such as cellular and humoral were better covered but often lacked a sufficient depth of knowledge.
Syllabus: M2a References: Guyton and Hall Textbook of Medical Physiology, Chp 33 and 34

Lymphocytes are responsible for acquired immunity

Antigens on foreign material stimulate proliferation and immune response

• In T and B cells, there a millions of different clones  which express different antigen binding site
• Each lymphocyte clone is highly specific for a particular antigen, and can only be activated by it 

Mooney 2016

2012A 07: 4 (40%) of candidates passed.
A structured response was required for this question. Candidates were expected to mention the origin of the cells, sites of differentiation (foetal liver, lymph nodes, bone marrow in early childhood for T lymphocytes and thymus for B lymphocytes), antigen receptors and what they bind with (highly specific IgM surface antibodies that bind with extracellualr antigens for T lymphocytes and surface receptors that bind to antigen presenting cells for B lymphocytes), type of activation cell, type of immunity (humoral for T lymphocytes, cell mediated for B lymphocytes), their functions and life span (T lymphocytes much shorter than B lymphocytes. Although some candidates found this question challenging, of those who passed it, most achieved a high score.

Definition

• Proteolytic enzyme amplification cascade system; forms part of innate + acquired immune response
• Components circulate as inactive precursors
• Activation amplifies as a cascade; regulated by regulator proteins e.g. C1 esterase inhibitor
• Proteins produced by liver
• 9 complements: C1(q, r, s), C2, C3, C4, C5, C6, C7, C8, and C9
  • Also B, D, H, I and properdin

Main functions

• cell lysis of bacteria (MAC)
• opsonisation → ↑phagocytosis
• release of mediators via mast cell degranulation
• local vasodilation
• neutrophil aggregation
• chemotaxis

Components (7 functional)

Pathways

1. Classical – activation by Ag-Ab complex
   • system of 11 enzymes
   • pathway activated by formation of Ag-ab complexes, CRP, aggregated Ig (IgM or certain IgG)
   • activates C1 → reactions involving C4+C2 → formation of enzymatic complex C4b-C2a → cleaves C3a and C3b → common pathway
2. Alternate – activation by lipopolysaccharides
   • C3 undergoes slow, spontaneous conversion to hydrolysed C3
   • Multiple steps leading to complex ith C5 convertase → activation of common pathway
   • Nil ab required
3. Lectin – activation by mannose on surface of parasites, candida, viruses etc

Mechanism

following activation → triggers final common pathway → C3 activation → C3b acts as C5 convertase → C5b binds C6-C9 → forms membrane attack complex → inserted into target cell membrane → leakage of cellular material → cell lysis + destruction

Regulation

• Half of all complement proteins serve regulatory function
• goal
  • to prevent complement damage to normal host tissue (inappropriate / wrong target)
  • fluid-phase activation (no target)
• deficiencies lead to excessive complement activation
• Regulatory proteins inhibit system by destabilizing activation complexes and mediating specific proteolysis of actication-derived fragments
• Complement pathways are regulated at the following critical steps
  • Activation (initiation) – C1 inhibitor (C1inh) in classic and lectin pathways
  • Amplification (convertase formation) – e.g. binding proteins to C3 convertases
  • Membrane attack (lysis) – S-protein prevents insertion of Membrane attack complex (MAC) into membrane, CD 59 (protectin) bind C8 and C9 inhibiting final steps of Membrane attack complex
  • Anaphylactoids – carboxypeptidases inactivate C3a,C4a,C5a

Sources: Kerr’s notes, biosciencenotes.com

2023B 15: 8% of candidates passed this question.

Based on the question stem answers should have been structured to address the components of the complement system as well as the role, activation and regulatory mechanisms. A description of the components should include the number and type of molecule highlighting the important combinations of complement to produce the membrane attack complex. A description regarding the role in the innate immune response against bacterial infections was then required with a detailed description regarding the many ways this is achieved including opsonisation, phagocytosis, chemotaxis, mast cell/basophil activiation, lysis of cells and clearance of immune complexes. Information about the 3 pathways of activation where expected; classic, alternate and lectin pathyway, with some detail regarding the downstream effect of each that would take into account for the amplication of the response. The cessation of complement response is largely due to the limitatations of the half lives of the particular complement glycol-proteins or presence of specific inactivators.

Definitions

Immune System: complex network of cells and proteins that defends the body against infection. They can be classified as:

• Physical barries
• Innate Immunity: Recognize generic pathogenic motifs and directly attack or opsonize and phagocytose
• Acquired immunity: Pathogenic antigens presented to B cells and T cells via APCs such as dendritic cells

Immunization: A process by which a person becomes protected against a disease through vaccination. This term is often used interchangeably with vaccination or inoculation.

Vaccine: A product that stimulates a person’s immune system to produce immunity to a specific disease, protecting the person from that disease.

Immunization:

• Passive
• Active

• Passive Immunization:
  • transfer of preformed antibodies to an unimmunized individual.
  • develop temporary immunity to the particular organism or toxin
  • Once these preformed antibodies have been destroyed, the individual would no longer have immunity to this microorganism or toxin.
  • e.g: Natural: passage of maternal antibodies through the placenta to the fetus
  • e.g: Artificial: administration of pooled human immune gamma globulin and antivenin
• Active immunization:
  • occurs with the exposure of an unimmunized individual to a pathogenic agent
  • Immune system begins the process of developing immunity to this agent
  • produces long-term immunity due to the stimulation of the individual’s immune system.

Stimulation of Immunity by vaccines:

Detection:

• by innate immune system, and/or B-cells
• recognize epitopes on antigens

Primary Response to vaccine administration:

• Innate Immune System activation:
  • Opsonize or bind to agent → aid in engulfment by Antigen-presenting cells (macrophages or monocytes) → insert processed antigen + MHC protein onto its surface
• Complex presented to Adaptive Immune System:
  • Viral: Antigen + MHC I complex → presented to CD8 cell → trigger cell mediated immunity
  • Bacterial or parasitic: Antigen + MHC II protein → presented to CD4 cell → trigger antibody- mediated immunity
• Memory T-cells and B-cells formed → undergo clonal selection following infection, which increases antigen-binding affinity

Subsequent Infection: 2° immune response

• Subsequent exposure to Ag
• memory T cells rapidly proliferate into active helper and cytotoxic T cells specific to that antigen
• memory B cells rapidly produce antibodies to neutralize the pathogen.
• more rapid, prolonged and powerful immune response

Types of vaccines:

• Live attenuated vaccines: produce a strong cellular and antibody responses and typically produce long-term immunity with only one to two doses: MMR, Typhoid
• Inactivated vaccines: Influenza
• Toxoid: Tetanus, diphteria
• Subunit vaccines: Hepatitis B
• Conjugate vaccine: Haemophilus Influenza B vaccine
• Outer membrane vesicle vaccine: B-Meningococcal
• Heterotypic/Heterologous: BCG
• Viral vector: Ebola
• RNA: Pfizer–BioNTech COVID-19 vaccine

JC 2020

2011A 20: 1 (8%) of candidates passed this question.
Providing a statement about what vaccines do followed by some detail about the processes involved in triggering a response and the nature of that response in both Innate immunity and acquired immunity would have achieved a good pass. Many candidates failed to adequately describe the nature of the primary and the secondary response to antigen exposure. The fact that previous immunisation enabled a brisk secondary response was recognised by most candidates but that this was largely due to the proliferation of IgG antibody producing B lymphocytes and effector T cells was not appreciated. Many answers simply did not include sufficient information to achieve a pass mark.
Syllabus: M2i
Recommended sources: Review of Medical Physiology, Ganong, Chp 3