First Aid, Chapter 3 Specific Immune Responses, Overview of hypersensitivity reactions

Question 1

What are the primary cells involved in immediate type 1 hypersensitivity? What are reactions amplified by? What is the primary immunoglobulin? What are examples?

Answer 1

Mast cells and basophils are the primary cells in immediate hypersensitivity or type I hypersensitivity reactions. The reaction is amplified or modified by platelets, neutrophils and eosinophils. IgE. Examples: allergic asthma, allergic conjunctivitis, allergic rhinitis (“hay fever”), anaphylaxis, drug allergy, and food allergy.

Question 2

Explain the process that occurs during initial exposure in immediate type 1 hypersensitivity. List the steps: ie - antigen presentation, antibody production, cytokines made, location that this all occurs, and cells involved.

Answer 2

Upon initial exposure, allergen/antigen is presented by antigenpresenting cells (APCs) to CD4+ Th2 cells specific to the antigen. These Th2 cells then drive B cells to produce IgE specific for the antigen (which is called sensitization) through cytokines such as interleukin 4 (IL-4) (which binds IL4Rα/γc and IL-4Rα/IL-13Rα1) and IL-13 (which binds IL-4Rα/IL-13Rα1). This process occurs primarily in the peripheral lymphoid organs.
The specific IgE (sIgE) binds high-affinity IgE receptors (FcεRI) on mast cells and basophils.

Question 3

What happens on reexposure to an antigen after initial sensitization in type 1 immediate hypersensitivity responses? Describe the steps that occur that lead to signalling and what types of reactions ensue.

Answer 3

Degranulation—Upon re-exposure, allergen binds the surface-bound sIgE on mast cells or basophils. When the receptors are cross-linked, intracellular signaling occurs and leads to cell degranulation (see Figure 2-6). This releases preformed mediators, enzymes, and cytokines (Table 2-8). These mediators act directly on tissues and recruit and activate additional inflammatory cells (eosinophils among others) which release more mediators and propagate the reaction.

• Immediate reaction—results from the release of preformed mediators
• Late reaction—results from the influx of inflammatory cells and generation of cysteinyl leukotrienes (lipid-derived mediators)

Question 4

What role does mas cell kininogenase and basophil kallikrein play in type 1 hypersensitivty?

Answer 4

Mast cell kininogenase and basophil kallikrein activate the contact system.

Question 5

What role does tryptase play in type 1 hypersensitivity?

Answer 5

tryptase has kallikrein activity [which can activate the contact system, complement cascade, and clotting cascade (via cleaving fibrinogen, which is a chemoattractant for neutrophils and eosinophils)].

Question 6

What role do platelet activating factor and tumor necrosis factor play in type 1 hypersensitivity?

Answer 6

Platelet-activating factor (PAF) from tumor necrosis factor (TNF) activation of nuclear factor kappa B (NFκB) induces clotting and disseminated intravascular coagulation; PAF also activates mast cells;

Question 7

What role does heparin and chymase play in type 1 hypersensitivity?

Answer 7

heparin inhibits clotting; and, chymase can convert angiotensin I to angiotensin II, which modulates hypotension.

Question 8

What are the steps that occur during primary exposure to antigen?

Answer 8

(1) Allergen/antigen is presented by APCs to CD4+ Th2 cells specific to the antigen; (2) these Th2 cells then drive B cells to produce IgE specific for the antigen (which is sensitization) through cytokines such as IL4 and IL-13; (3) the specific IgE (sIgE) binds high-affinity IgE receptors (FcεRI) on mast cells and basophils.

Question 9

What are the 2 types of anaphylaxis?

Answer 9

• Immunologic anaphylaxis—IgE-mediated reactions; non-IgE-mediated (i.e., not type I reactions), which include IgG-mediated reactions (which have not been identified in humans) and immune complex/complement-mediated reactions
• Nonimmunologic anaphylaxis—IgE-independent mast cell or basophil degranulation. This is also known as nonallergic anaphylaxis.

Question 10

What are the immunoglobulins involved in type 2 hypersensitivity? What other immune molecules and cells are involved?

Answer 10

IgG and IgM, complement, phagocytes.

Question 11

Name examples of type 2 hypersensitivity.

Answer 11

Hemolytic anemia, hemolytic disease of the newborn, Goodpasture’s syndrome, myasthenia gravis, and Graves’ disease.

Question 12

In summary, how does damage occur to cells in type 2 hypersensitivity reactions?

Answer 12

In summary, type II reactions occur when antibodies bind antigens on a target cell (e.g., for example, penicillin bound to red blood cells); target cell damage then occurs through:
o Cellular neutralization/blocking (i.e., myasthenia gravis),
o Cytotoxicity (i.e., hemolytic anemia), or
o Cellular stimulation (i.e., Graves’ disease)

Question 13

What are the steps of cytotoxicity via opsonization and phagocytosis in type 2 hypersensitivity reactions?

Answer 13

• IgG antibodies coat or opsonize microbes and promote phagocytosis (Figure 3-2).
• Mononuclear phagocytes and neutrophils have receptors for the Fc portions of the antibodies that specifically bind the opsonized microbes for intracellular killing.

-The phagocyte Fc receptors:
o Promote phagocytosis of opsonized particles.
o Deliver signals that promote killing of the microbes by the phagocyte.

-FcγRI (CD64) is a high-affinity phagocyte receptor that strongly binds IgG1 and IgG3 (two of the most efficient opsonins).

Question 14

Describe how cytotoxicity by complement fixation occurs.

Answer 14

• Out of the three major pathways of complement activation, the classical pathway is the only one activated by an antibody (IgG or IgM).
• The alternative pathway is activated by microbial cell surfaces and the lectin pathway is activated by plasma lectins, which bind to microbe mannose residues, both in the absence of antibody.
• All three pathways result in the generation of C3, the most abundant complement protein.
• With complement activation, C3 is proteolyzed to produce an active product C3b that attaches to microbes.
• As a result, microbes can be opsonized by complement particles, specifically C3b, and engulfed by phagocytes expressing receptors (CR1=CD35) specific for C3b.

Question 15

Which immunoglobulin(s) is/are involved in opsonization?

Answer 15

IgG

Question 16

What are the effector functions of IgG?

Answer 16

• Opsonization (namely, IgG1 and IgG3)
• Activation of classical pathway of complement (namely, IgG1 and IgG3)
• Antibody-dependent cell-mediated immunity (ADCC)
• Neonatal immunity as a result of placental transport

Question 17

What is the effector function of IgM?

Answer 17

Activation of classical pathway of complement.

Question 18

Describe the steps of cytotoxicity by antibody-dependent cell-mediated cytotoxicity (ADCC)

Answer 18

-A process whereby natural killer (NK) cells (and other leukocytes) bind to antibody-coated microbes to destroy them.
-NK cells express the FcγRIII receptor (a low-affinity Fc receptor; CD16) that binds to clustered IgG molecules (not to monomeric-circulating IgG) (Figure 3-3)
-An antibody-coated particle engages the FcγRIII receptor on the NK cell, which subsequently activates the NK cell to:
o Produce and secrete cytokines such as IFNγ.
o Discharge its granules.
o Kill the infected cell.

Question 19

What immunoglobulins does the poly Ig receptor transport?

Answer 19

IgG and IgM

Question 20

How is IgG transported across the placenta and infant gut lumen?

Answer 20

IgG is transported across the placenta and infant gut lumen by an IgG-specific Fc receptor called neonatal Fc receptor (FcRn), which resembles the major histocompatibility complex (MHC) class I molecule.

Question 21

How do antibodies block binding influenza?

Answer 21

Influenza virus uses its envelope hemagglutinin to infect respiratory epithelial cells. An antibody will bind the hemagglutinin and “neutralize” the microbe so it does not interact with cellular receptors. This is an example of steric hindrance.

Question 22

What are the major immune players in type 3 hypersensitivity?

Answer 22

Immune complexes, hence antigen, antibody, and complement, are the major players in immune complex-mediated or type III hypersensitivity reactions.

Question 23

What are examples of type 3 hypersensitivity reactions?

Answer 23

Examples include systemic lupus erythematosus (SLE), glomerulonephritis, serum sickness, and vasculitis.

Question 24

Generally describe the pathophysiology in type 3 hypersensitivity reactions.

Answer 24

Immune complexes are clusters of antigens and antibodies that are typically cleared by the spleen and liver. Under some circumstances, immune complexes are deposited in the blood vessels or tissues where they can cause disease. Damage is caused by formation or deposition of antigen-antibody complexes in vessels or tissue. The deposition of immune complexes causes complement activation and recruitment of neutrophils by interaction of immune complexes with Fc IgG receptors.

Question 25

In the precipitans curve, what is the most pathogenic point? Why?

Answer 25

Moderate antigen access. As antigen is added to serum with a fixed amount of antibody, small immune complexes are first formed in a state of antibody excess (left side of curve). As equivalence is reached, immune complexes begin to precipitate (middle of curve). With antigen excess, immune complexes again become smaller and do not precipitate (right side of curve). Immune complexes in this state are soluble (and hence difficult to phagocytose) and can easily fix complement and generate potent cleavage products (contributing to increased vascular permeability and extravascular movement of inflammatory cells).

Question 26

What factors determine whether immune complexes will be cleared or deposited in the tissue?

Answer 26

The relative concentration of antigen to antibody and their charge (amongst other factors).

Question 27

At what point do immune complexes form that are easily removed from circulation? How are they removed from circulation?

Answer 27

Immune complexes formed at equivalence (antibody number = antigen number) form a lattice and are rapidly removed from the circulation by mononuclear phagocytes, such as Kupffer cells in the liver.

Question 28

Describe specifically how charges play in a role in immune complex deposition.

Answer 28

The basement membrane is negatively charged. Positively charged immune complexes tend to deposit in the basement membrane of skin and kidneys (Figure 3-6), whereas neutral or negatively charged complexes do not. Hemodynamics also influence immune complex deposition.

Question 29

Describe what happens to immune complexes early in the immune response vs. later in the immune response.

Answer 29

―In general, early in an immune response, immune complexes that form with a low amount of antibody (antigen excess) tend to elicit further responses to antigen. Late in the immune response, complexes formed in antibody excess tend to suppress the response.

Question 30

What cytokines are associated with immune complex injury in tissues?

Answer 30

Immune complex injury in tissues is associated with the release of inflammatory cytokines, such as IL-1β, TNF, IL-2, and IFN-γ.

Question 31

Describe immunogencity in terms of duration of exposure to an antigen and amount of antigen and correlate it to vaccination.

Answer 31

• Exposure to a large amount of antigen tends to be more immunogenic.
• The longer the duration of exposure to an antigen, the more potent the immunologic stimulus.
• Example: SQ immunization offers better antibody production than a brief IV exposure to antigen.

Question 32

What occurs in arthrus reactions? What type of hypersensitivity response is this?

Answer 32

Arthus Reaction―When antigen is injected into the skin or tissue of an immunized individual, local edema, neutrophil migration, hemorrhage, and necrosis occur. This is called an Arthus reaction. This cutaneous inflammation is caused by local vasculitis due to immune complex deposition in vessel walls, with peak intensity occurring at 4–10 hours. It is a local type III hypersensitivity reaction as the target organs is the blood vessels of the dermis.

Question 33

Describe serum sickness in terms of timing, pathogenesis, symptoms, resolution, causes, and contrast it to an arthrus reaction.

Answer 33

Exposure to foreign proteins or haptens in unimmunized persons leads to antibody production and formation of soluble immune complexes in the circulation. This typically develops in 4–10 days (due to time needed to class switch). Pathogenesis is related to (1) immune complex deposition in blood vessels of the skin, joints, kidneys, and/or lungs and (2) immune complex fixing and activating of complement. Symptoms include: fever, rash, joint pain, and lymphadenopathy (all which are all self-limited once the foreign antigen is removed). Common causes of serum sickness are hypersensitivity reaction to medications (antibiotics) and foreign proteins. In contrast to the Arthus reaction, serum sickness is a systemic type III hypersensitivity reaction since the target organs are the blood vessels of the skin, joints, kidneys, lungs, etc.

Question 34

How quickly does serum sickness occur with reexposure to an antigen?

Answer 34

Upon re-exposure (i.e., previously immunized person), the amnestic IgG response is much more rapid. Thus, the symptoms of serum sickness may occur in 12–36 hours and be more severe.

Question 35

Describe the pathophysiology in vasculitis. What kind of inflammation occurs? What kind of antigens are found?

Answer 35

—Inflammation of small or large blood vessels can result in tissue damage. Immune complex deposition in endothelial basement membrane usually occurs in this disease. Inflammation can vary from necrosis and granulomatous change to fibrosis and scarring. In some individuals bacterial, viral and mycobacterial antigens have been detected in vessel walls.

Question 36

What correlates with disease activity in SLE patients?

Answer 36

High levels of circulating immune complexes.

Question 37

Where are immunoglobulins and complement deposits found in SLE?

Answer 37

Blood vessel walls and kidney glomeruli.

Question 38

What are the different mechanisms of pathophysiology in SLE?

Answer 38

SLE is a systemic autoimmune disease characterized by autoantibody production (against DNA), low levels of complement, hypergammaglobulinemia, and the presence of circulating immune complexes.

Question 39

Name the different glomerulonephritis diseases mediated by antigen-antibody complexes. Where are deposits seen in these diseases?

Answer 39

Glomerulonephritis—Immune-mediated glomerular disease with many subtypes mediated by antigen-antibody complexes, including post-streptococcal glomerulonephritis, lupus nephritis, and membranoproliferative glomerulonephritis. In these diseases, immunoglobulin and complement deposits are seen in the glomeruli.

Question 40

What is the major cell involved in Type IV hypersensitivity reactions? Name examples.

Answer 40

The major player of cell-mediated or delayed hypersensitivity (also called type IV hypersensitivity) reactions is the T-cell (CD4+ or CD8+); other cells involved depends on the subtype. Examples include: contact dermatitis, psoriasis, celiac disease, etc.

Question 41

Upon first exposure to a medication, when might a patient develop symptoms of serum sickness?

Answer 41

4–10 days

Question 42

Review the pathophysiology of type 4 hypersensitivity starting from T cells in the bone marrow, to circulation, to the roles of helper and cytotoxic cells, and finally lysis.

Answer 42

T Cells—T cells originate from hematopoietic stem cells in the bone marrow and mature in the thymus.  -Th0 (Naïve T cells)—Naïve T cells migrate from blood to peripheral lymphoid organs in search of antigen they recognize.  Naïve T cells express L-selectin (CD-62L). After seeing their antigen, they become activated, proliferate, and differentiate into effector T cells or memory T cells. 
-CD4+ T cells (Helper T Cells)—Subsets are listed in Chapter 2. CD4+ T cells respond to antigens that are internalized by APCs in association with MHC class II molecules. 
-CD8+ T Cells (Cytotoxic T Cells)—Naïve CD8+ T cells differentiate into effector T cells (CTLs) that recognize and kill cells expressing foreign peptides (specifically intracellular peptides, such as viruses) in association with class I MHC molecules. Refer to Chapter 1.  
o CD8+ T cells contain membrane-bound cytotoxic granules that contain perforin and granzymes. Like Th1 cells, CTLs are able to secrete cytokines: IFN-γ, TNF, and lymphotoxin. CTL killing is antigen-specific and contact-dependent. Lysis of target cells can occur via two mechanisms: perforin and granzyme released from the CTL that enters target cell and induces apoptosis; and, Fas ligand (FasL) expressed on CTL that binds target cell Fas, leading to apoptosis.

Question 43

What T cells are involved in type IVa hypersensitivity reactions? What other cells are involved? What are the target organs? What are examples?

Answer 43

T-cell involved: CD4+ Th1 cells (IFNy, TNFa, IL2)

Other cells: macrophases, NK cells

Target organs: skin, lung, GI

Ex: contact dermatitis, TB

Question 44

What T cells are involved in type IVb hypersensitivity reactions? What other cells are involved? What are the target organs? What are examples?

Answer 44

T-cell involved: CD4+ Th2 cells (IL4, IL5, IL13)

Other cells: Eosinophils, B cells

Target organs: skin, lung, GI

Ex: chronic allergic disease

Question 45

What T cells are involved in type IVc hypersensitivity reactions? What other cells are involved? What are the target organs? What are examples?

Answer 45

T-cell involved: CD4+ Th17 cells (IL17, IL21, IL22)

Other cells: neutrophils

Target organs: skin, lung, GI

Ex: psoriasis

Question 46

What T cells are involved in type IVd hypersensitivity reactions? What are the target organs? What are examples?

Answer 46

T-cell involved: CD8+ cells

Target organs: skin, systemic

Ex: contact dermatitis

Question 47

What is the mechanism of sensitization in delayed type hypersensitivity?

Answer 47

Contact sensitization to chemicals or subQ/ID injection of protein antigen (PPD).

Question 48

What kind of antigen modification occurs in delayed type hypersensitivity reactions?

Answer 48

Chemicals can bind and modify self-proteins, creating new antigens that are presented to CD4+ or CD8+ T cells. This is a type IV delayed hypersensitivity reaction involving an induction/sensitization phase (priming of the immune system) and elicitation phase (triggering of the reaction) and involves a cellmediated response.

Question 49

What are examples of delayed type hypersensitivity responses?

Answer 49

An example of DTH is allergic contact dermatitis. Agents implicated in allergic contact dermatitis include: nickel, Quaternium-15 in cosmetics, bacitracin, poison ivy (urushiol, which is a hapten) and resin. Evidenced by the name, these reactions are “delayed” (i.e., 48–72 hours).