immunology

CHAPTER 15
ALLERGY AND HYPERSENSITIVITIES
2020-2021

Dr. Refif S. Al-Shawk

Lec 2/ semester 2/immune
2020-2021
Type II Hypersensitivity

► Examples
► Blood transfusions
► Hemolytic disease of the newborn
 Type II Hypersensitivity
Type II hypersensitivity reactions involve antibody-mediated
destruction of cells by IgG and IgM immunoglobulins.
Antibody bound to a cell-surface antigen can induce death of the
antibody-bound cell by three distinct mechanisms:
► First, certain immunoglobulin subclasses can activate the
complement system, creating pores in the membrane of a foreign
cell.
► Secondly, antibodies can mediate cell destruction by antibody
dependent cell-mediated cytotoxicity (ADCC), in which cytotoxic
cells bearing Fc receptors bind to the Fc region of antibodies on
target cells and promote killing of the cells.
► Finally, antibody bound to a foreign cell also can serve as an opsonin,
enabling phagocytic cells with Fc or C3b receptors to bind and
phagocytose the antibody-coated cell
Type II – Antibody-Mediated Cytotoxic Hypersensitivity
⦿ Transfusion Reactions
⚫ Due to exposure to microorganisms in gut, individuals have antibodies
to blood types not their own
⚫ Antibody attaches to RBC and initiates complement system to lyse
RBC(Within hours)
⚫ complement mediated lysis triggered by the IgM isohemagglutinins.
⚫ After lysis:
○ Hemoglobin detected in plasma, starts to filter through kidneys and found in
urine (hemoglobinuria)
○ Hemoglobin converted to bilirubin – toxic at high levels
○ Fever, chills, blood clotting

► Antibodies Rh factor may result from repeated blood transfusions.

delayed hemolytic transfusion reactions
► These antibodies are IgG class.
► Hemolysis develop between 2 and 6 days after transfusion WHY ??.
Because IgG is less effective than IgM in activating complement,
Type II – Antibody-Mediated Cytotoxic Hypersensitivity

⦿ Hemolytic disease of newborn

⚫ Rh+ fetus, Rh- mother
⚫ IgG antibodies cross placenta
⚫ Some of these antibodies may be anti-Rh antibodies
- Can have severe consequences
⚫ Antibodies against ABO blood groups produce less consequences, can be easily
treated

⚫ Rhogam shot
○ Given to mother
○ Anti-Rh antibodies bind to fetal cells that might have entered mother’s
system during birthing process, facilitates clearing before there is a B cell
response
Type II – Antibody-Mediated Cytotoxic
Hypersensitivity

► Hemolytic Anemia Can Be Drug Induced

► Certain antibiotics (e.g., penicillin, cephalosporins, and
streptomycin), as well as other well-known drugs can adsorb
nonspecifically to proteins on red blood cell membranes
forming a drug protein complex.
► In some patients, such drug-protein complexes induce
formation of antibodies. These antibodies then bind to the
adsorbed drug on red blood cells, inducing
complement-mediated lysis and thus progressive anemia.
► Watch this video on Type II:
► https://www.youtube.com/watch?v=kLaUz58CBMc
 Type III Hypersensitivity
► Antigen-antibody complexes facilitate the clearance of antigen by
phagocytic cells and red blood cells. In some cases:
• The presence of large numbers and networks of immune complexes
can lead to tissue-damaging type III hypersensitivity reactions.
► The magnitude of the reaction depends on:
• The levels and size of immune complexes
• Their distribution within the body
• The ability of the phagocyte system to clear the complexes and thus
minimize the tissue damage.
► Or from:
• The antigen itself, or disorders in phagocytic machinery.
► The deposition of immune complexes in the blood vessels or tissues
initiates reactions that result in the recruitment of complement
components and neutrophils to the site, with resultant tissue injury.
Type III Hypersensitivity
► Examples:
► Arthus reactions (more severe reaction to antigen injected into skin)
► Serum sickness
► Pathogens
► Meningitis
► Hepatitis
► malaria

► Drugs
► Sulfonamides, penicillin

► Autoimmune:
► Rheumatoid arthritis
► Lupus

► Complexing of antigen plus antibody facilitates phagocytosis and

clearing of antigen
► Large amounts of these complexes can lead to tissue damage
 Examples of conditions involving type III
hypersensitivity reactions
► Spontaneous recovery is seen.
► when glomerulonephritis is initiated following a streptococcal infection.
Streptococcal antigen–antibody complexes bind to the basement membrane of the
kidney and set up a type III response, which resolves as the bacterial load is
eliminated.
► If the antigen in the immune complex is an auto-antigen (self antigen), it cannot be
permanently eliminated; hence type III hypersensitivity reactions cannot be easily
resolved. In such situations, chronic type III responses develop.
► in systemic lupus erythematosus, persistent antibody responses to auto-antigens
such as DNA and various nuclear proteins are an identifying feature of the disease,
and complexes are deposited in the joints, kidneys, and skin of patients.
► Localized type III hypersensitivity reaction
► If an animal or human subject is injected intradermally with an antigen to which large amounts
of circulating antibodies exist (or have been recently introduced by intravenous injections),
antigen will diffuse into the walls of local blood vessels and large immune complexes will
precipitate close to the injection site. This initiates an inflammatory reaction that peaks
approximately 4 to 10 hours post-injection and is known as an Arthus reaction.

► Arthus reactions are examples of immune complex (type III) hypersensitivity

reactions and can be induced by insect bites, as well as by inhalation of fungal or
animal protein in individuals with antibodies to those antigens.
 Type III – Immune complex-mediated hypersensitivity
► Immune Complexes Can Damage Various
Tissues:
► Immune complexes bind to mast cells,
neutrophils, and macrophages via Fc
receptors, triggering the release of
vasoactive mediators and inflammatory
cytokines,which interact with the capillary
epithelium and increase the permeability
of the blood vessel walls.
► Immune complexes then move through
the capillary walls and into the tissues
where they are deposited and set up a
localized inflammatory response.
► Complement fixation results in the
production of the anaphylatoxin
chemokines C3a and C5a, which attract
more neutrophils and macrophages.
► These in turn are further activated by immune complexes
binding to their Fc receptors to secrete proinflammatory
chemokines and cytokines, prostaglandins, and proteases.
► Proteases digest the basement membrane proteins collagen,
elastin, and cartilage.
► Tissue damage is further mediated by oxygen free radicals
released by the activated neutrophils.
► In addition, immune complexes interact with platelets and
induce the formation of tiny clots.
► Complex deposition in the tissues can give rise to symptoms
such as fever, urticaria (rashes), joint pain, lymph node
enlargement, and protein in the urine.
► The resulting inflammatory lesion is referred to as
vasculitis if it occurs in a blood vessel, glomerulonephritis if
it occurs in the kidney, or arthritis if it occurs in the joints.
► Watch this video on Type III:
► https://www.youtube.com/watch?v=SyxzU2Sl_Yw
Type IV Hypersensitivity

► Examples:
► Contact dermitis
► Tubercular lesions
► Graft rejection
 Type IV Hypersensitivity

► Some subpopulations of T cells

encounter antigen, secrete
cytokines and induce localized
inflammatory response

► CD4+ T cells (TH1 and TH17

cells) and CD8+ CTLs

► Causing: Cytokine-mediated
inflammation and Direct target
cell killing, cytokine-mediated
inflammation respectively
Type IV: Sensitization phase and
Effector phase of DTH

🡪 In the sensitization phase after initial

contact with antigen (e.g., peptides derived
from intracellular bacteria), TH cells
proliferate and differentiate into TH1 cells.
Cytokines secreted by these T cells.

🡪In the effector phase after subsequent

exposure of sensitized TH cells to antigen,
TH1 cells secrete a variety of cytokines and
chemokines. These factors attract and
activate macrophages and other nonspecific
inflammatory cells. Activated macrophages
are more effective in presenting antigen,
thus perpetuating the DTH response, and
function as the primary effector cells in this
reaction.
🡪 Other helper T-cell subsets are now
thought to participate in DTH (TH2 and
TH17) and CD8 T cells also contribute.
Cytokine mediated inflammation
► In immune-mediated inflammation, TH1 and TH17 cells
secrete cytokines that recruit and activate leukocytes.
► IL-17, produced by TH17 cells, promotes neutrophil
recruitment; (IFN-γ), produced by TH1 cells, activates
macrophages; and (TNF) and chemokines, produced by T
lymphocytes and other cells, are involved in the
recruitment and activation of many types of leukocytes.
► Tissue injury results from the products of the recruited
and activated neutrophils and macrophages, such as
lysosomal enzymes, reactive oxygen species, nitric oxide,
and proinflammatory cytokines.
► The inflammation associated with T cell–mediated
diseases is typically chronic, but bouts of acute
inflammation may be superimposed on a background of
chronic inflammation.
► Delayed-type hypersensitivity (DTH) is an example of
such inflammatory reactions.
Type IV – contact dermatitis
Diseases Caused by Cytotoxic T Lymphocytes
CTL
► responses to viral infection can lead to tissue injury by killing
infected cells, even if the virus itself has no cytopathic
effects. Example of viral infections in which the lesions are due
to the host CTL response and not the virus itself include
certain forms of viral hepatitis in humans .
► CTLs may contribute to tissue injury in autoimmune disorders
in which destruction of particular host cells is a prominent
component, such as type 1 diabetes, in which insulin-producing β
cells in pancreatic islets are destroyed.
► Many organ-specific autoimmune diseases are caused by interaction of
autoreactive T cells with self antigens, leading to cytokine release and
inflammation. rheumatoid arthritis (RA), multiple sclerosis, type 1 diabetes,
psoriasis, and other autoimmune diseases
► T cell reactions specific for microbes and other foreign antigens may also
lead to inflammation and tissue injury. Intracellular bacteria such as
Mycobacterium tuberculosis induce strong T cell and macrophage responses
that result in granulomatous inflammation and fibrosis the inflammation and
fibrosis may cause extensive tissue destruction and functional impairment,
typically in the lungs.
► A variety of skin diseases that result from topical exposure to chemicals and
environmental antigens, called contact sensitivity, are due to inflammatory
reactions, presumably triggered by neoantigens formed by the binding of the
chemicals to self proteins. Both CD4+ and CD8+ T cells may be the source of
cytokines in contact sensitivity reactions. Examples of contact sensitivity
include rashes induced by poison ivy and poison oak (in which T cells react
against self proteins that are modified by chemicals made by the plants
called urushiols), and rashes induced by contact with metals (nickel and
beryllium) and a variety of chemicals, such as thiuram, which is used in the
manufacture of latex gloves. Some of these reactions become chronic and
clinically are called eczema.
► T cell responses against intestinal bacteria are believed to underlie some
forms of inflammatory bowel disease.
Prolonged DTH can lead to formation of granuloma

Tuberculosis test is done this way

► Watch this video on Type IV:
► https://www.youtube.com/watch?v=C3E5COZ1XC8
► Refferences :
❖ Immunology , Kuby, seventh edition 2013
❖ Immunology , Kuby, eighth edition 2019
❖ Medical microbiology, Jawetz, 26th edition
❖ Cellular and Molecular Immunology, Abul K. Abbas, 8th edition.