Transcript Chapter 19

Chapter 19
Disorders Associated
with the Immune System
Introduction
• Hay fever/allergies, autoimmune disease,
and transplant rejection are examples of
harmful immune reactions
• Infection and immunosuppression are
failures of the immune system to function
properly.
• Superantigens cause indiscriminate
activation of many T cell receptors at once
to release excessive quantity of cytokines
that cause adverse host responses
Hypersensitivity
• An antigenic response leading to damage
instead of protection (immunity)
– Allergy = hypersensitivity
• Occurs in a person who has been sensitized
by previous exposure to an Ag (allergen)
• Re-exposure with the same allergen cause
the immune system to react in a damaging
manner
Type I (Anaphylactic) Reactions
• Reactions occur within 2 to 30 minutes after reexposure in a sensitized person Ag + IgE Ab
+ mast cells or basophils
• Localized: hay
fever, hives or
asthma from
contact, inhaled or
ingested antigens
• Systemic: shock and breathing difficulties from
injected Ag (sometimes ingested Ag for food);
can be fatal
Figure 19.1a
Type I (Anaphylactic) Reactions
• Skin testing may be helpful in diagnosing
allergens
inflammation = allergen
– Not reliable for food-related allergies
• Avoid contact
• Desensitization
– inject a series of
dosages of the Ag
beneath the skin to
cause the production
of IgG instead of
IgE Abs
Figure 19.3
Type II (Cytotoxic) Reactions
• Involve Ags located on cell or tissue surfaces,
IgG or IgM antibodies, and complement
• Complement activation causes cell lysis or
damage by macrophages & other cells that
attack Ab-coated cells (delayed for 5 - 8 hr)
• E.g. Transfusion reactions (ABO/Rh Ags on
the red blood cells, RBCs)
– Incompatible ABO blood type
formation of
Ag-Ab complex (in vitro = agglutination; in vivo =
complement-mediated lysis of the donor RBCs)
Type II (Cytotoxic) Reactions
– Rh incompatibility induce Abs production against
donor’s Rh+ Ag in Rh- recipient (sensitization)
when Rh+ blood is transfused into the same
Rh- recipient again
agglutination (in vitro) or
complement-mediated hemolysis (in vivo)
• E.g. Hemolytic Disease of the Newborn
(HDNB) = Rh incompatibility during
pregnancy (if mother is Rh- & father is Rh+)
– Passive immunization of mother with anti-Rh Abs
after the birth of first Rh+ baby to prevent HDNB
ABO blood group system
Table 19.2
Hemolytic disease of the newborn
Figure 19.4
Drug-induced thrombocytopenic purpura
• Destruction of platelet
by drug-induced
cytotoxic reactions
– Results in hemorrhages
& purple spots (purpura)
on the skin
– Similar phenomena
exist for drug-induced
cytotoxic reactions of
white blood cells or
RBCs (hemolytic
anemia)
Figure 19.5
Type III (Immune Complex Reactions)
• Involves Abs (usually IgG) against soluble
Ags circulating in the serum
• Small Ag-Ab complexes formed (escape
phagocytosis) are deposited in the basement
membrane beneath the cells or organs to cause
inflammatory damage (mediated by
complement)
• E.g. glumerulonephritis
cause
inflammatory damage to the kidney glomeruli
(sites of blood filtration)
Type III (Immune Complex) Reactions
• IgG antibodies and antigens form complexes that
lodge in basement membranes.
Figure 19.6
Type IV (Cell-Mediated) Reactions
• Delayed-type
hypersensitivities due
to TD cells (TB skin
test)
• Upon re-exposure to
the same foreign Ags,
memory T cells
secrete cytokines to
attract macrophages
and initiate tissue
damage (by TC cells)
Figure 19.8
Type IV (Cell-Mediated) Reactions
• E.g. Allergic contact dermatitis (poison ivy,
cosmetics, and the metals in jewelry)
– Caused by haptens that combine with proteins
in the skin of some people
– Hypersensitivity to latex (reaction against
chemicals used in manufacturing of latex) may
cause anaphylactic shock (leading to death)
– Patch test used to determine environmental
factor inducing dermatitis
look for
inflammation in 48 hr
Autoimmune Diseases
• Clonal deletion during fetal development
ensures self-tolerance
• Autoimmunity is loss of self-tolerance
• Autoimmune disease: damage to one’s own
organs due to action of the immune system
(production of Abs or by sensitized T cells
against one’s own tissue Ags)
– Relatively rare; affect about 5% of population in
the developed world; about 75% of the cases
selectively affect women
Autoimmune Diseases
• Autoimmune reaction can be cytotoxic,
immune complex, or cell-mediated in nature
• Type I
Due to antibodies against
pathogens which end up attacking self cells
(due to similarity between Ags)
• Type II Antibodies react with cell-surface
antigens, but no cytotoxic destruction of the
cells; e.g. Graves’ disease & myasthenia
gravis
Autoimmune Diseases
• Type III (Immune Complex)
immune
complexes (formed by Ag + IgM, IgG +
complement) deposited in tissues; e.g. Systemic
lupus erythematosus (mainly in women; deposit in
the kidney glomeruli), & rheumatoid arthritis
(deposit in the joints)
• Type IV
mediated by T cells to attack or destroy
self components; e.g. Multiple sclerosis (myelin
sheath of nerves), & insulin-dependent diabetes
mellitus (insulin-secreting cells of the pancreas)
Reactions Related to the Human
Leukocyte Antigen (HLA) Complex
• Histocompatibility antigens: self antigens on
cell surfaces (inherited genetic differences
among individuals)
• Major histocompatibility complex (MHC):
genes encoding histocompatibility antigens
• Human leukocyte antigen (HLA) complex:
MHC genes in humans
• Most Ags stimulate immune response only if
they are associated with an MHC molecule
HLA Typing
• Used to identify and compare HLAs
– Can identify susceptibility to diseases
HLA Typing
– Used to match donor
& recipient of
transplantation
(tissue typing) to
avoid rejection
• Also need to match
ABO blood type
– PCR can be used in
HLA typing
Figure 19.9
Reactions to Transplantation
• Transplants may be attacked by T cells (direct
lysis of grafted cells/tissues), macrophages, and
complement-fixing antibodies if recognized as
nonself.
• Transplants to privileged sites (cornea & brain)
do not cause an immune response.
• Stem cells may allow therapeutic cloning to
avoid rejection.
– Stem cells can give rise to more stem cells &
generate different cell types (nerves, blood, or liver
cells)
Grafts
•
•
•
•
Autograft: use of one's own tissue
Isograft: use of identical twin's tissue
Allograft: use of tissue from another person
Xenotransplantation product: use of non-human
tissue (need to overcome hyperacute rejection)
• Graft-versus-host disease can result from
transplanted bone marrow that contains
immunocompetent cells
– Cell-mediated immune response by transplanted bone
marrow against host’s tissue
Immunosuppression
• Immunosuppression prevents an immune
response to transplanted tissues
– Generally suppress cell-mediated immunity using
immunosuppressant drugs
• Cyclosporine suppresses IL-2
• Mycophenolate mofetil inhibits T cell and B cell
proliferation
• Sirolimus blocks IL-2 & inhibit both cell-mediated &
humoral immunity
– Ideal solution = induce tolerance (see transplants
as self)
Immune Deficiencies
• Absence of a sufficient immune response
• Congenital: due to defective or missing genes
– Selective IgA immunodeficiency
– Severe combined immunodeficiency
– Nude mouse (lack thymus = no T cells); DiGeorge
syndrome in human (lack a thymus gland)
• Acquired: develop during an individual's life,
due to drugs, cancers, or infections
– Artificial: Immunosuppression drugs
– Natural: HIV infections
The Immune System and Cancer
• Immunological surveillance: body’s
immune response to cancer
– Cancer cells arise by mutation or virus-induced
changes by escaping the immunological
surveillance and becomes resistant to immune
rejection
– Immune system (esp. cell-mediated immunity)
constantly patrols and eliminates mutated cells
before they become established tumors
• Cancer cells possess tumor-specific Ags
The Immune System and Cancer
• TC cells recognize and lyse cancer cells
• Cancer cells may lack tumor antigens; kill TC
cells; grow faster to outpace the immune
response
Figure 19.11
Immunotherapy
• Treatment of cancer using immunologic methods
• Tumor necrosis factor, IL-2, and interferons may
kill cancer cells
• Immunotoxins link poisons with an monoclonal
antibody (Mab) directed at a tumor antigen
Mab selectively locates the cancer cell and
destroy only the cancer cell
• Vaccines containing tumor-specific antigens has
been effective for a type of cancer in poultry
Acquired Immunodeficiency
Syndrome (AIDS)
• 1981
• 1983
In U.S., cluster of Pneumocystis
and Kaposi's sarcoma in young
homosexual men discovered.
The men showed loss of immune
function.
Discovery of virus (HIV) causing
loss of immune function that
selectively infects T helper cells
The Origin of AIDS
• AIDS is the final stage of HIV infection
• Crossed the species barrier into humans in Africa
in the 1930s
• Patient who died in 1959 in Congo is the oldest
known case
• Spread in Africa as a result of urbanization
• Spread in world through modern transportation
and unsafe sexual practices
• Norwegian sailor who died in 1976 is the first
known case in Western world
Structure of HIV (human
immunodeficiency virus)
• Retrovirus
(genus Lentivirus)
with 2 identical
strands of RNA
Figure 19.12a
Multiplication of Retroviridae
Capsid
Reverse
transcriptase
DNA
Virus
Two identical + stands of RNA
1 Retrovirus penetrates
host cell.
Host
cell
DNA of one of the host
cell’s chromosomes
5 Mature
retrovirus
leaves host
cell, acquiring
an envelope as
it buds out.
Viral RNA
Identical
strands of
RNA
4 Transcription of the
Viral proteins
RNA
Reverse
transcriptase
provirus may also occur,
producing RNA for new
retrovirus genomes and
RNA that codes for the
retrovirus capsid and
envelope proteins.
Provirus
Viral DNA
2 Virion penetrates
cell and its DNA is
uncoated; reverse
transcriptase
produce doublestranded DNA
from viral RNA
3 The new viral DNA is
transported into the host cell’s
nucleus and integrated as a
provirus. The provirus may
divide indefinitely with the
host cell DNA.
Figure 13.19
HIV Infection
• Spikes (gp120)
enable the virus to
attach to the CD4
receptor in
association with
coreceptor (CXCR4)
on the T helper cells,
macrophages, and
dendritic cells
Figure 19.12b
HIV Infection
• Following attachment, HIV penetrate the
host cell (uncoating of virion) & viral RNA
is transcribed into double-stranded DNA by
viral reverse transcriptase
• Viral DNA gets incorporated into the host
chromosomal DNA (provirus)
– Provirus evades host immune system
– Proviral DNA can cause active HIV infection or
latent infection
HIV Infection (T cells)
• Active infection: proviral DNA directs synthesis of
new viruses; new virus bud from the host cell
• Latent infection: proviral DNA stays dormant; no viral
genes nor new viruses are made
Figure 19.13
HIV Infection (macrophages)
Figure 19.14
HIV Infection
• HIV evades the immune system by staying as
provirus (latency), latent virions in vacuoles,
cell-cell fusion (to move to adjacent uninfected
cell), and rapid antigenic changes (no
proofreading mechanism for reverse
transcriptase)
• Clades: subtypes (of HIV)
– HIV-1 is the most common. It has 11 clades:
• 90% of U.S. infections caused by clade B
• Clade C predominates in sub-Saharan African
• Clades B, C, & E are in south and southeast Asia
– HIV-2 is seen in western Africa
The Stages of HIV Infection
(Persistent infection by
Candida albicans)
(Clinical AIDS;
CMV, TB,
Pneumocystis,
toxoplasmosis, &
kaposi’s sarcoma)
Figure 19.15
Some Common Diseases Associated with
AIDS
Table 19.5
Diagnostic Methods
• Seroconversion (Ab testing) takes up to 3
months
• HIV antibodies detected by ELISA
• HIV antigens detected by Western blotting
• Plasma viral load tests (detect and quantify
HIV circulating in the blood) is determined
by PCR or nucleic acid hybridization
– PCR testing narrow the window of
nondetection to about 12 days
HIV Transmission
• HIV survives 6 hours outside a cell
• HIV survives >1.5 days inside a cell
• Infected body fluids transmit HIV via:
–
–
–
–
–
–
–
Sexual contact
Breast milk
Transplacental infection of fetus
Blood-contaminated needles
Organ transplants
Artificial insemination
Blood transfusion
Modes of HIV Transmission
Figure 19.17
AIDS Worldwide
• Global pandemic – rapid & continuing spread of
new infections
• Three basic epidemiological patterns
• U.S., Canada, western Europe, Australia,
northern Africa, South America
– Injecting drug use, male-to-male sexual contact
• Sub-Saharan Africa
– Heterosexual contact
• Eastern Europe, Middles East, Asia
– Injecting drug use, heterosexual contact
AIDS Worldwide
Figure 19.16
Prevention of AIDS
• Use of condoms and sterile needles
• Health-case workers use universal precautions
– Wear gloves, gowns, masks, goggles
– Do not recap needles
– Risk of infection from infected needlestick injury is
0.3%
• HIV vaccines
– Rapid mutation rate of HIV  difficult to develop a
vaccine effective for all forms of HIV
Prevention and Treatment of AIDS
• Current vaccine development
– Whole-cell Salmonella with gp120 gene
– Subunit vaccine using gp120 expressed in
Saccharomyces
– Canarypox virus with HIV capsid protein genes
– Naked DNA consisting of tat (transcription factor) or
gag (capsid protein) genes
• Available drugs only delay the progress of the
infection; do not cure HIV infection
– Treat opportunistic infections & to inhibit HIV
multiplication
Treatment of AIDS (Chemotherapy)
• Nucleotide Reverse Transcriptase Inhibitors
• Non- Nucleoside Reverse Transcriptase
Inhibitors
• Protease Inhibitors
• Virus decoys
• Highly Active Antiretroviral Therapy
(HAART): combinations of nucleoside
reverse transcriptase inhibitors + Nonnucleoside reverse transcriptase inhibitor or
protease inhibitor
Chapter Review
1. Know how hypersensitivity occurs and the
four classes of hypersensitivity.
• An antigenic response leading to damage
instead of protection (immunity)
–
•
•
Allergy = hypersensitivity
Occurs in a person who has been
sensitized by previous exposure to an Ag
(allergen)
Re-exposure with the same allergen cause
the immune system to react in a damaging
manner (IgE + mast cells or basophils)
Chapter Review
2. Know how autoimmune diseases occur and
four types of autoimmune diseases.
• Autoimmunity is loss of self-tolerance;
reaction can be cytotoxic, immune complex,
or cell-mediated in nature
• Autoimmune disease: damage to one’s own
organs due to action of the immune system
(production of Abs or by sensitized T cells
against one’s own tissue Ags)
Chapter Review
– Type I: due to antibodies against pathogens which
end up attacking self cells (due to similarity
between Ags)
– Type II: antibodies react with cell-surface antigens,
but no cytotoxic destruction of the cells; e.g.
Graves’ disease & myasthenia gravis
– Type III (Immune Complex): immune complexes
(formed by Ag + IgM, IgG + complement)
deposited in tissues; e.g. Systemic lupus
erythematosus (mainly in women; deposit in the
kidney glomeruli), & rheumatoid arthritis (deposit
in the joints)
Chapter Review
– Type IV: mediated by T cells to attack or destroy
self components; e.g. Multiple sclerosis (myelin
sheath of nerves), & insulin-dependent diabetes
mellitus (insulin-secreting cells of the pancreas)
3. Know what HLA typing is used for, different
types of grafts & how transplantation is
rejected.
• Used to identify and compare HLAs (self
MHC)
– Can identify susceptibility to diseases
– Used to match donor & recipient of
transplantation (tissue typing) to avoid rejection
Chapter Review
• Transplants may be attacked by T cells
(direct lysis of grafted cells/tissues),
macrophages, and complement-fixing
antibodies if recognized as nonself.
• Autograft: use of one's own tissue
• Isograft: use of identical twin's tissue
• Allograft: use of tissue from another person
• Xenotransplantation product: use of nonhuman tissue (need to overcome hyperacute
rejection)
Chapter Review
4. Know what immunosuppression is and what
immune deficiency is.
• Immunosuppression prevents an immune
response to transplanted tissues
– Generally suppress cell-mediated immunity using
immunosuppressant drugs
• Immune deficiency: absence of a sufficient
immune response
• Congenital: due to defective or missing genes
• Acquired: develop during an individual's life, due to
drugs, cancers, or infections
Chapter Review
– Artificial: Immunosuppression drugs
– Natural: HIV infections
5. Know how cancer develops
• Immunological surveillance: body’s immune
response to cancer
– Cancer cells arise by mutation or virus-induced
changes by escaping the immunological
surveillance and becomes resistant to immune
rejection
Chapter Review
– Immune system (esp. cell-mediated immunity)
constantly patrols and eliminates mutated cells
before they become established tumors
• Cancer cells possess tumor-specific Ags
• TC cells recognize and lyse cancer cells
• Cancer cells evade immune surveillance by:
may lack tumor antigens; kill TC cells; grow
faster to outpace the immune response
Chapter Review
6. Know why HIV infection is classified as
acquired immunodeficiency; how HIV
infection occurs and how it evades the host
immune system
• HIV infection results in absence of a
sufficient immune response because it
destroys certain component of the immune
system (by infecting T helper cells, and
APCs such as macrophages and dendritic
cells)
Chapter Review
• Spikes (gp 120) allows HIV to attach to a
host CD4 receptor and coreceptor. Virus
enters the host cell (uncoating of viral
RNA). Viral RNA transcribed into doublestranded DNA by viral reverse transcriptase.
Viral DNA gets incorporated into the host
chromosomal DNA and can cause an active
infection (host may or may not die) or
become a latent infection.
Chapter Review
• HIV evades the immune system by staying
as provirus (latency), latent virions in
vacuoles, cell-cell fusion (to move to
adjacent uninfected cell), and rapid
antigenic changes (no proofreading
mechanism for reverse transcriptase).