Chapter 5: Hypersensitivity: Immunologically Mediated Tissue Injury

Question 1

Just read

Answer 1

Immune responses that normally are protective also are
capable of causing tissue injury. Injurious immune reactions are grouped under hypersensitivity, and the resulting
diseases are called hypersensitivity diseases. This term originated from the idea that persons who mount immune
responses against an antigen are sensitized to that antigen,
so pathologic or excessive reactions represent manifestations of a hypersensitive state. Normally, an exquisite
system of checks and balances optimizes the eradication of
infecting organisms without serious injury to host tissues.
However, immune responses may be inadequately controlled or directed against normally harmless antigens or
inappropriately targeted to host tissues, and in such situations, the normally beneficial response is the cause of
disease.

Question 2

What is meant by autoimmunity?

Answer 2

Reactions against self antigens.

Question 3

What phenomenon normally controls how our body reacts to our own antigens?

Answer 3

Self tolerance, the body is able to tolerate its own antigens.

Question 4

What term is used for when the system of self-tolerance fails?

Answer 4

Autoimmunity and autoimmune diseases

Question 5

What happens when hypersensitivy occurs due to a reaction against a microbe?

Answer 5

In some cases the reaction to a microbe seems to be excessive or the microbe itself is persistent. The antibodies that are then produced bind to the microbial antigens to form complexes that are deposited in tissue where they can trigger (severe) inflammation.

Question 6

Name three factors that result in hypersensitivy.

Answer 6

• autoimmunity
• (excessive) reaction against microbes
• reaction against environmental antigens.

Question 7

Name a fundamental reason why once a hypersensitivity reaction starts it is difficult to control or terminate.

Answer 7

In diseases where hypersensitivity occurs the immune response is triggered and inappropiately maintained. The stimuli that trigger the abnormal immune respons are difficult/impossible to eliminate (self antigens, persistent microbes or environmental antigens). Besides this, the immune system has many intrinsic positive feedback loops. So once a hypersensitivity reaction starts, it is very difficult to terminate it.

Question 8

Name the four types of hypersensitivity reactions.

Answer 8

Type I: immediate hypersensitivity
Type II: antibody-mediated hypersensitivity
Type III: immune complex-mediated hypersensitivity
Type IV: cell-mediated hypersensitivity

Question 9

What is another name for type I immediate hypersensitivity?

Answer 9

Allergy

Question 10

What happens during type I immediate hypersensitivity? (by what molecules is the injury caused)?

Answer 10

The injury is caused when tissue is exposed to an allergen. The allergen is taken up by dendritic cells, which activate naïve T cells and B cells. The naïve T cel develops into a Th2 cell, which helps the B cell to produce IgE-secreting plasma cells (by secreting cytokine IL-4 that stimulates isotype switching) IgE bindt via its receptor (FcεRI) to mast cells. Mast cells are activated and release their mediators (vasoactive amines, lipid mediators and cytokines).

Question 11

When the mast cells are activated during a type I hypersensitivity reaction, they release their content. Some mediators will result in immediate hypersensitivity and other mediators will be released in a later phase of the reaction. Which two groups of mediators are released by mast cells during the acute phase and which group of mediators is released by mast cells during the late phase?

Answer 11

Vasoactive amines and lipid mediators are part of the immediate hypersensitivity reaction. Cytokines are part of the late phase reaction.

Question 12

Th2 cells often are recruited to the site of allergic reaction in response to chemokines that are produced locally. What chemokine is locally produced and what else is its function?

Answer 12

The chemokine eotaxin is produced, which also recruits eosinophils to the same site.

Question 13

How are FcεRI-receptors always occupied by IgE, even though the serum concentration of IgE is so low?

Answer 13

Because of the fact that the FcεRI-receptors have a very high affinity towards IgE.

Question 14

What is meant by the fact that antibody-bearing mast cells are sensitized?

Answer 14

So that if the person is reexposed to the allergen, the allergen can bind to the antigen-specific IgE molecules on mast cells and can immediately trigger a reaction.

Question 15

Which three cells express FcεRI?

Answer 15

Mast cells, basophils and eosinophils.

Question 16

What is an example of a vasoactive amine and what will it cause when released during type I hypersensitivity?

Answer 16

Histamine is an example. It causes vasodilation, increased vascular permeability (which results in vascular leakage and edema), smooth muscle contraction and increased secretion of mucus.

Question 17

Just read and know that there are other mediators that are rapidly released during type I hypersensitivity and mostly result in tissue damage.

Answer 17

. Other rapidly released
mediators include chemotactic factors for neutrophils and eosinophils as well as neutral proteases
(e.g., tryptase), which may damage tissues and also
generate kinins and cleave complement components
to produce additional chemotactic and inflammatory
factors (e.g., C5a) (Chapter 3). The granules also
contain acidic proteoglycans (heparin, chondroitin
sulfate), the main function of which seems to be as a
storage matrix for the amines.

Question 18

What are examples of lipid mediators and what will it cause when released during type I hypersensitivity?

Answer 18

Prostaglandins and leukotrienes. Prostaglandin (D2) causes bronchospasm and increased mucus secretion. Leukotrienes (LTC4 and LTD4) are potent vasoactive and spasmogenic agents (much more potent than histamine) and play a crucial role in chemotaxis of neutrophils.

Question 19

What cytokines are produced during the late phase reaction of type I hypersensitivity?

Answer 19

TNF, chemokines and IL-4 and IL-5.

Question 20

Wat is atopy?

Answer 20

An increased tendency to develop immediate hypersensitivity (or allergies).

Question 21

Fill in the gap:

Atopic individuals tend to have higher serum levels of…(1) and more … (2) cells that produce … (3).

Answer 21

1. IgE
2. Th2
3. IL-4

Question 22

What genes are implicated in susceptibility to asthma and other atopic disorders?

Answer 22

Genes that encode HLA molecules, cytokines, a component of the FcεRI and ADAM33 (metalloproteinase that may be involved in tissue remodeling in the airways).

Question 23

Just read

Answer 23

It is estimated that 20% to 30% of immediate hypersensitivity reactions are triggered by nonantigenic stimuli
such as temperature extremes and exercise, and do not
involve TH2 cells or IgE. It is believed that in these cases
mast cells are abnormally sensitive to activation by various
nonimmune stimuli.

Question 24

What observation can be made in developed countries regarding allergies and how do we define this observation?

Answer 24

That the incedence of many allergic diseases is increasing in developed countries and seems to be related to a decrease in infections during early life. This is called the hygiene hypothesis.

Question 25

What does the hygiene hypothesis hypothese?

Answer 25

That early childhood and even prenatal exposure to microbial
antigens educates the immune system in such a way that
subsequent pathologic responses against common environmental allergens are prevented. Thus, too much hygiene
in childhood may increase allergies later in life.

Question 26

Systemic exposure to protein antigens (e.g., in

bee venom) or drugs (e.g., penicillin) may result in systemic ….

Answer 26

anaphylaxis

Systemic exposure means that the whole body gets exposed to the antigen/drug.

Question 27

What is anaphylaxis?

Answer 27

This is a very strong allergic reaction to being systemically exposed to protein antigens or drugs. Symptoms are: itching, urticaria (hives), skin erythema, pulmonary bronchoconstriction, hypersecretion mucus, upper airway obstruction, musculature gastrointestinal tract is affected (vomiting, abdominal cramps, diarrhea), vasodilation and decrease in bloodpressure (anaphylactic shock). Eventually (without intervention) death within minutes.

Question 28

What are examples of localized allergic reactions?

Answer 28

Atopic dermatitis, food allergies, hay fever and certain forms of asthma.

Question 29

How does type II antibody-mediated hypersensitivity occur?

Answer 29

Type II occurs when antibodies are directed against target antigens on the surface of cells or other tissue components. It is mostly seen as auto-immunity.

Question 30

In what clinical situations does antibody-mediated cell destruction and phagocytosis occur?

Answer 30

Transfusion reactions, in which cells from an incompatible donor react with preformed antibody in the host.
Another example is hemolytic disease of the newborn (antibodies from the mother attack fetal red blood cells). Autoimmune hemolytic anemia, agranulocytosis and thrombocytopenia.

Question 31

How can a red blood cell become a target for phagocytosis by neutrophils and macrophages and what type of hypersensitivity is this?

Answer 31

The red blood cell gets coated/opsonized with autoantibodies (with or without complement proteins). This is type II hypersensitivity (antibody-mediated).

Question 32

Through what molecule are phagocytes able to bind to an opsonized red blood cell?

Answer 32

These phagocytes express a receptor for the Fc tails of IgG antibodies and a receptor for breakdown products of the C3 complement protein.

Question 33

Why can it be a clinical benefit to remove the spleen from a individual with an antibody-mediated disease?

Answer 33

Because opsonized cells are usually eliminated in the spleen.

Question 34

How is inflammation of tissue induced during antibody-mediated hypersensitivity?

Answer 34

Antibodies bind to cellular or tissue antigens and activate the classical pathway of the complement system. One of its functions is to recruit neutrophils and monocytes, triggering inflammation in tissues.

Question 35

Just read

Answer 35

Antibody-mediated
inflammation is responsible for tissue injury in some
forms of glomerulonephritis, vascular rejection in organ grafts, and other disorders.

Question 36

How can antibody-mediated cellular dysfunction occur?

Answer 36

Graves disease (for example): antibodies stimulate the thyroid-stimulating hormone receptor by binding to the receptor. The epithelial cell is then stimulated to secrete thyroid hormones (resulting in hyperthyroidism). Antibodies can also block a receptor, or bind to hormones and neutralize them.

Question 37

What is typical about type II hypersensitivity (immune complex-mediated)?

Answer 37

Antigen-antibody (immune) complexes are formed in the circulation and deposit in blood vessels.

Question 38

What disease has been studied and helped in understanding the pathogenesis of systemic immune complex diseases?

Answer 38

Acute serum sickness, this disease is usually seen in individuals who receive antibodies from other individuals or species.

Question 39

Describe in short the three steps of the pathogenesis of systemic immune complex disease.

Answer 39

1. the protein antigen is introduced in the blood circulation which triggers an immune response that results in the formation of antibodies. They react with the antigen and form an antigen-antibody complex.
2. The circulating antigen-antibody complex is deposited in tissue (through local vascular alterations and characteristics of the complex)
3. Once deposited, immune complex initiate acute inflammation via complement activation and engagement of leukocyte Fc receptors.

Question 40

Why do immune complex diseases often affect glomeruli and joints?

Answer 40

Organs where blood is filtered at high pressure to form other fluids, like urine and synovial fluid, are sites where immune complexes become concentrated and deposited.

Question 41

What can be used as a marker for disease activity of antigen-antibody complex-mediated disease?

Answer 41

A decrease in serum levels of complement proteins can be found during the acute fase (complement proteins are used and therefore decrease).

Question 42

How is the inflammatory lesion termed if it occurs in blood vessels, renal glomeruli or joints?

Answer 42

Blood vessels -> vasculitis.
Renal glomeruli -> glomerulonephritis
Joints -> arthritis

Question 43

When does acute serum sickness occcur and when does chronic serum sickness occur?

Answer 43

Acute serum sickness is induced by adminsistration of a single large dose of antigen, the lesions resolve as a result of phagocytosis and degradation of the immune complexes.
Chronic serum sickness results from repeated or prolonged exposure to an antigen.

Question 44

What is meant by the Arthus reaction?

Answer 44

A model of local immune complex diseases in which an area of tissue necrosis appears as a result of acute immune complex vasculitis.

Question 45

The arthus reaction is experimentally produced. How?

Answer 45

By injecting an antigen into the skin of a previously immunized animal with preformed antibody. An immune complex is formed and the complex is deposited into the vascular wall where it triggers a inflammatory reaction resembling systemic immune complex disease.

Question 46

There are two ways T cells can induce T cell-mediated disease (type IV hypersensitivity). What two ways are there?

Answer 46

Inflammation induced by cytokines that are produced by CD4+ T cells.
Direct cell cytotoxicity mediated by CD8+ T cells.

Question 47

What is an example of CD4+ T cell-mediated inflammation?

Answer 47

Delayed-type hypersensitivity (DTH). Here, an antigen is administered into the skin of a previously immunized individual which results in a cutaneous reaction within 24-48 hours.

Question 48

What cells are typical for a classical delayed T cell-mediated hypersensitivity?

Answer 48

Mainly Th1 effector cells, beside this also Th17 cells. Th1 cells secrete IFN-γ, which are responsible for many of the manifestations of delayed-type hypersensitivity. Th17 cells secrete cytokines that rectuit neutrophils and monocytes.

Question 49

What is the morphologic characterisation of delayed-type hypersensitivity?

Answer 49

Accumulation of mononuclear cells, mainly CD4+ T cells and macrophages around venules. (perivascular cuffing).

Question 50

How does granulomatous inflammation occur during prolonged delayed-type hypersensitivity?

Answer 50

The initial perivascular infiltrate of CD4+ T cells is slowly replaced by macrophages. They are activated and become large, flat and eosinophilic (epithelioid cells). These cells can also fuse under the influence of cytokines and form multinucleate giant cells. An aggregate of epithelioid cells, typically surrounded by a collar of lymphocytes is called a granuloma.

Question 51

What is the difference between an old and young granuloma?

Answer 51

An older granuloma develops an enclosing rim of fibroblasts and connective tissue.

Question 52

In what type of infections regarding delayed-type hypersensitivity are Th2 cells involved? And what cells are then prominent in the lesion?

Answer 52

Infections by helminths (parasitic), eosinophils are prominent in the lesion.

Question 53

What is contact dermatitis?

Answer 53

This is a type of tissue injury resulting from a delayed-type of hypersensitivity. It occurs when coming into contact with urushiol (antigenic component of poison ivy). The antigenic component binds to and structurally modifies self proteins. Peptides dervied from these modified proteins are recognized by T cells and elicit a reaction.

Question 54

Rheumatoid arthritis, multiples sclerosis and inflammatory bowel disease are a result of what kind of inflammation?

Answer 54

CD4+ T cell-mediated inflammation.

Question 55

Diabetes 1 is a result of what kind of inflammation?

Answer 55

CD8+ T cell-mediated cytotoxicity

Question 56

What happens in CD8+ T cell-mediated cytotoxicity?

Answer 56

Here CD8+ CTLs kill antigen-expressing target cells, for example virus infected cells. But in the act of killing these cells, the cytotoxic CD8+ cells also produce cytokines (IFN-γ) that result in inflammatory reactions of tissue.