Immunodeficiency Disease
• Def: Immunodeficiency- an abnormality of the immune
system that renders a person susceptible to diseases
normally prevented by a normal functioning immune
system
• Four Categories Immune Mechanisms
– Humoral (Antibody-mediated):
• Specific type of mechanism
– Cell-mediated (T-cell mediated)
• Specific type of mechanism
– Compliment system
• Non-specific type of mechanism
– Phagocytosis
• Non-specific type of mechanism
1
Immunoglobulins
• An antibody or immunoglobulin:
– Large Y-shaped protein
– Used by the immune system to identify and neutralize foreign
objects
• For example bacteria and viruses.
– Each antibody recognizes a specific antigen unique to its target.
– Two tips of the "Y" of the antibody contain a paratope (a
structure analogous to a lock) that is specific for one particular
epitope (analogous to a key) on an antigen, allowing these two
structures to precisely bind together.
– This precise binding mechanism allows an antibody to tag a
microbe or an infected cell for attack by other parts of the
immune system, or to directly neutralize its target (i.e. by
blocking a part of a microbe that is essential for its invasion
and survival).
– The production of antibodies is the main function of the
humoral immune system.
Antigen/Antibody Binding
• Immunodeficiency : Two types
– Primary immunodeficiency: congenital or
inherited
– Secondary immunodeficiency: acquired
• Regardless whether the cause is primary or
secondary the spectrum of the disease will be the
same
4
Humoral (B-cell) Immunodeficiencies
• Caused by the improper production of one or all of the
immunoglobins (antibodies)
– Results in an increased of infections from
Staphylococcus, Streptococcus, Haemophilus,and
Pseudomonas.
• Primary Humoral Immunodeficiencies include:
– X-Linked (Bruton’s) Agammaglobinulinemia
– Common Variable Immunodeficiency
– Selective Immunoglobin A Deficiency
• Secondary Humoral Immunodeficiencies:
– General comments
5
Primary Humoral Immunodeficiency
Disorders
• X-Linked (Bruton’s) Agammaglobinulinemia:
– Genetic disease that only affects males which results in
undetectable levels of all serum immunoglobins
– The genetic defect inhibits the differentiation of B-cells into
plasma cells which ultimately are responsible for producing
immunoglobins
– Because of abnormally low immunoglobin levels, the child is
susceptible to certain infections such as:
• Meningitis
• Recurrent ear infections
• Chronic sinus/upper respiratory infections
6
Primary Humoral Immunodeficiency
Disorders
•
Common Variable Immunodeficiency:
– Similar to X-linked agammaglobulinemia
– The terminal differentiation from mature B cells to plasma
cells is blocked resulting in reduced serum immunoglobin
levels
– Symptoms are similar to agammaglobulinemia, but the onset
occurs between 15 and 35 years.
– Patients have a tendency for chronic lung disease,
autoimmune disorders, hepatitis, gastric carcinoma, and
chronic diarrhea associated with malabsorption.
7
Primary Humoral Immunodeficiency
Disorders
• Selective Immunoglobin A Deficiency:
– Most common immunoglobin deficiency affecting 1 in 400
to 1 in 1000 persons
– Main physical characteristic is a severe reduction in the
levels of serum and secretory IgA that results from the
inability of mature B cells to transform into IgA secreting
plasma cells
– Usually there are no overt S/S because IgG and IgM can
compensate
– Persons with this disease tend to be affected with:
• Chronic upper respiratory infections
• Chronic GI infections
• Increased incidence of allergic diseases such as asthma
8
Secondary Humeral
Immunodeficiency Disorders
• Can occur as a consequence of selective loss of
immunoglobulin through the gastrointestinal or genitourinary tracts.
– Example would be a person with Nephrotic syndrome
who losses IgA and IgG in the urine because of
abnormal glomerular filtration.
9
Cellular (T-cell) Immunodeficiencies
• Caused by problem with T lymphocytes (both CD4+ helper cells
and CD8+ cytotoxic killer cells)
• Patient’s have more severe symptoms than with humeral
immunodeficiencies
• Children rarely survive beyond infancy or childhood
• Primary Cell Mediated Immunodeficiency disorders include:
– DiGeorge Syndrome
– X-Linked Immunodeficiency with Hyper-IgM
• Secondary Cell-Mediated immunodeficiency:
– General comments
10
Primary Cell-Mediated
Immunodeficiency Disorders
• DiGeorge Syndrome:
– Disease affecting both sexes
– Caused by embryonic developmental defect resulting in the
malformation of the:
• Thymus gland
• Parathyroid gland
• Head/neck area
• Heart
– Associated facial abnormalities include increased distance
between the eyes, upward bowing of upper lip (fish mouth),
low-set/posteriorly angulated ears, split uvula
– children are required to undergo blood transfusions/bone
marrow transplants in order to survive
11
Primary Cell-Mediated
Immunodeficiency Disorders
• X-Linked Immunodeficiency with Hyper-IgM
– Occurs only in males
– Characterized by low levels of IgA and IgG and high
levels of IgM
• Once thought of a B cell disorder, however, now
traced to T cells
• There is a failure of T cells to signal B cells to
produce IgA and IgG and instead only produce IgM
– Children become symptomatic the first 2 years of life
with recurrent pyogenic infections
12
Secondary Cell-Mediated
Immunodeficiency
• More common than primary cell-mediated
immunodeficiency
• Associated with acute viral infections (HIV, Herpesvirus)
and with certain malignancies (Lymphoma, Hodgkin's
disease).
13
Combined T-Cell and B-Cell
Immunodeficiencies
• Severe Combined Immunodeficiency (SCID)
– Caused by diverse genetic mutations resulting in the absence
of ALL immune function
– Infants with this disease lead a short life (avg 2 years) with
chronic opportunistic infections
– There is a milder form known as combined
immunodeficiency syndrome having a low, but not absent Tcell function. Antibody forming capacity is impaired, not
absent.
• Children are prone to recurrent pulmonary infections,
failure to thrive, oral and cutaneous candidiasis, chronic
diarrhea, recurrent skin infections, sepsis, and urinary tract
infections.
• Although they live longer than children with SCID they
often die early in life.
14
Combined T-Cell and B-Cell
Immunodeficiencies
• Ataxia – Telangiectasia:
– Results from a mutation on chromosome 11
– Condition consists of worsening ataxia (lack of coordination)
and telangiectasia (dilated capillaries and arterioles) on the
skin and conjunctiva.
• Also results in endocrine and hepatic abnormalities also
– Children have reduced levels of IgA, IgE, and IgG, and
decreased ratio of CD4+ helper T cells to CD8+ cells.
– Children are prone to recurrent upper and lower respiratory
infections and an increased risk of malignancy.
• Death from lymphoma is common
15
Combined T-Cell and B-Cell
Immunodeficiencies
• Wiskott-Aldrich Syndrome:
– Patient has decreased IgM and elevated levels of IgA and IgE.
• T-cell dysfunction is initially mild then progressively
worsens making child susceptible to Hodgkin’s disease and
lymphoma
– They are also susceptible to infections (including septicemia
and meningitis) caused by encapsulated microorganisms
– Signs and symptoms:
• eczema
• chronic infections
• low platelet counts
– Bone marrow transplants have been helpful in these children
16
Disorders of Complement System
• Complement system is an important part of the non-specific
immune response.
• Complement promotes chemotaxis, opsonization, and
phagocytosis of invasive pathogens, bacteriolysis, and
anaphylactic reactions.
• Primary complement disorders are caused by genetic problems
– Deficiency of C1 and C4 are not at increased risk for infection
because alternate pathways can be activated.
• These patients are more prone to autoimmune diseases
such as Lupus Erythematosus.
– Deficiency of C2: causes susceptibility to multiple life
threatening bacteria
17
Disorders of Complement System
• Secondary Disorders of Complement
– Occur in persons with normal complement systems who have
rapid activation or turnover of complement components
– Can also occur with conditions where there is a decreased
production complement components such as in liver cirrhosis
or malnutrition
18
Disorders of Phagocytosis
• Phagocytic system:
– Composed primarily of:
• Neutrophils
• Eosinophils
• Monocytes.
• Phagocytic cells function to migrate to site of infection,
adhere to the tissue, engulf invading material, and then
digest it.
• A defect in the phagocytic system results in a decreased
number of phagocytic cells.
• Persons are prone to bacterial infections, often by Candida
and filamentous fungi.
19
Hypersensitivity Disorders
• Hypersensitivity disorders are excessive or inappropriate
activation of the immune system caused by immune
responses to antigens that produce tissue-injury causing
inflammation
• hypersensitivity disorders are divided into 4 categories
– Type 1Hypersensitivity reaction
– Type 2 Hypersensitivity reaction
– Type 3 Hypersensitivity reaction
– Type 4 Hypersensitivity reaction
20
Type I Hypersensitivity (IgEMediated) Disorders
• Type I reactions are immediate-type (within 30 min)
hypersensitivity reactions that are triggered by the binding of
an antigen to IgE located on the surface of a mast cell
• Release of chemical mediators such as histamine produces an
allergic reaction that stimulates the inflammatory process
• Physiologic effects of histamine include:
– Promotes vasodilation of blood vessels
– Increases the permeability of blood vessels
– Causes smooth muscle contraction
– Causes bronchial constriction
21
• Examples of Type I hypersensitivity disorders include:
– Allergic Rhinitis:
• Typical S/S include:
– Sneezing
– Itching
– Watery discharge from eyes/nose
• Typical antigens include:
– Pollens from ragweeds, grass, weeds
– Fungal spores
– House dust mites
– Animal dander/feathers
– Food Allergies: the most common food allergies include:
milk, peanuts, shellfish, and eggs
• Food allergies may produce a severe allergic response
called anaphylaxis
22
• Type II-Antibody Mediated Disorders:
– AKA cytotoxic responses
– Result from the interaction between IgG and IgM
antibodies and antigens which results in the activation of
cytotoxic immune cells
– Examples include:
• Mismatched blood transfusions
• Hemolytic disease
23
• Type III- Immune Complex Disorders:
– Caused by the formation of insoluble antigen/antibody
complexes that adversely increases immune function
and result in the release of certain chemicals that cause
tissue damage
– Most common areas of the body affected by Type II
disorders include:
• Renal glomerulus
• Lung
• Synovial membrane of joints
– The two most common examples of Type II disorders
include:
• Rheumatoid arthritis (RA)
• Systemic Lupus Erythematosis (SLE)
24
• Type IV- Cell Mediated Disorders:
– Delayed type of reaction that is mediated by T-cells not
antibodies
– Usually occur 24 to 72 hours after antigen exposure
– Mediated by T lymphocytes
– Examples include:
• Allergic Contact Dermatitis- is an inflammatory
response confined to the skin that results when the skin
comes in contact with an irritating substance
» usually produces inflamed blisters on skin
» common causes include exposure to:
1. poison ivy
2. cosmetics
3. topical medications
4. latex
25
Autoimmune Disease
• Def: Self-tolerance: to function properly the immune
system must be able to distinguish foreign antigens and
self-antigens
• Autoimmune disease- occurs when the immune system
cannot differentiate antigens from self-antigens and begins
to attack host tissue of the body that results in localized or
systemic injury
– Examples of autoimmune diseases include:
• Myasthenia gravis (MG)
• Rheumatoid arthritis (RA)
• Systemic Lupus Erythematosis (SLE )
• Graves’ Disease
26
• Loss of B-Cell Tolerance: results in autoimmune diseases
that produce autoantibodies:
– Example is Graves disease: produces hyperthyroidism
due to autoantibodies that stimulate the TSH receptors
on the thyroid gland.
• Loss of T-Cell Tolerance: results from the release of selfreactive T cells from the thymus.
– Normally T-cells that have a high affinity for host cells
undergo apoptosis. If these cells do not die they leave
the thymus gland and cause tissue damage.
27
HIV AIDS
• The pathogen of AIDS is HIV (Human Immunodeficiency Virus)
• At the end of 2006:
– Nearly 40 million worldwide were living with HIV/AIDS
– 25 million people had died of the infection
– 4.3 million new infections (2006)
• 50% of these women and children
• Projected: over the 10 next years there will be 100 million people
infected with HIV.
– Most new infections: people under 25 in developing countries.
• Sub-Sarahan Africa will be most affected.
28
The AIDS Epidemic
• S/S associated with decreased immune function were first
recognized in homosexual men in 1981
• Although initially thought to affect the gay male population
specifically, AIDS cases began to be diagnosed in the following
high risk groups:
– IV drug users
– Hemophiliacs
– Blood transfusion recipients
– High risk heterosexuals
• As a result of HIV infection, the body’s immune system begins
to progressively fail making the infected person more susceptible
to infections that are normally harmless to the body
(Opportunistic infections)
29
Transmission of HIV
• Sexual contact:
– Most frequent mechanism
– 75-80% via unprotected sex
– The virus can pass from semen and vaginal secretions into the
bloodstream through mucous membranes and wounds in the
skin.
• Blood-to-blood contact:
– Needles, syringes, or Transfusions
• Perinatally:
– Transmission can occur in utero, during labor and delivery, or
by breast feeding
• Studies still show that HIV is not spread through casual contact
nor by vectors such as mosquitoes
30
• Def: Seroconversion: The point where an infected person
converts from being negative for HIV antibodies to having HIV
antibodies
– Occurs 1 to 3 months after exposure to HIV.
– But can take up to 6 months
• Def: Window period: The period of time after infection but
before seroconversion.
– During this time the patient does not have symptoms, nor
antibodies for HIV that can be picked up on a blood test.
– This patient can unknowingly transmit the disease
– As a result the FDA requires collection center to screen
potential donors through interviews designed to identify
behavior known to present risk for HIV infection.
31
Pathophysiology and Clinical Course
• 2 forms of HIV
– HIV 1
• Most associated with AIDS in the US, Europe, and Central
Africa
– HIV 2
• Prevalent in West Africa
• Spreads more slowly in comparison to HIV 1
• Causes disease more slowly in comparison to HIV 1
• Cells attacked by HIV
– CD4+ T lymphocytes
– Macrophages
– Dendritic cells: specialized protective cells found in tissues
where antigens enter the body
32
The HIV Virus
• HIV is a retrovirus: carries its genetic information on RNA
• The virus is spherical in shape with a core in the center
surrounded by a lipid envelope (membrane)
– Core: contains
• A protein (p24)
• Two copies of RNA
• 3 viral enzymes:
– Protease
– Reverse transcriptase
– Integrase
– Envelope: contains a protein matrix called p17 which lies
directly beneath the viral envelope. Viral envelope is
studded by 2 viral glycoproteins, gp120 and gp41 which are
important for the infection process
33
34
Life cycle of the HIV-1
Eight steps
1. Attachment of the HIV virus to CD4+ receptor:
a. Virus attaches to the surface of a CD4+ cell
b. The virus then binds its gp 120 and gp 41 glycoproteins
with chemokine receptors on the CD4+ cell
2. Internalization:
a. Once the virus has attached, viral peptides fuse
with the CD4+ cell membrane causing an uncoating
of the virus.
b. Viral contents (viral RNA, reverse transcriptase,
integrase, and protease) then enter the cell.
35
3. Reverse transcription:
a. Viral RNA must be converted to DNA (in order to
reproduce)
b. Done by the enzyme reverse transcriptase which produces
a mirror image of the viral RNA
c. The result is a double-stranded DNA molecule
4. Integration:
a. Newly created viral DNA enters nucleus of CD4+
b. Viral DNA becomes part of the cell DNA using integrase
enzyme
5. Transcription of inserted viral DNA:
a. Inserted viral DNA to produce viral mRNA
1. mRNA has the instructions for building new HIV
viruses
36
6.
7.
Translation of viral messenger:
a. rRNA uses the instructions of mRNA to create viral
proteins and enzymes known as polyprotein
1. Polyprotein enzymes are needed to construct viral
components into new viruses
Cleavage:
a. During this stage protease enzymes cut viral proteins into
single proteins
b. These proteins will make up the new viruses
37
8.
Assembly and release:
a. Proteins and viral RNA are assembled into new viruses
b. New viruses are built inside the cell resulting in the death of
the CD4+ cell
c. When the CD4+ cell dies, the viral particles (virions) are
released into the bloodstream to infect other CD4+ cells.
d. Every day millions of CD4+ cells are destroyed, releasing
billions of viral particles into the blood
e. The immune system is able to keep up with the infection by
producing new T-cells, however, over years, the T-cell count
decreases and the amount of virus in the blood increases.
f. Until a person’s T-cell count falls to a very low level, a
person can remain asymptomatic, even though viral
replication is taking place.
38
39
Infected helper T-cell; the small blue globules are HIV particles.
40
Classification of HIV
• 3 Categories relating to the amount of CD4+ cells per
microliter of blood (normal is 800 to 1000 cells/microliter)
– Category 1: >500 cells/microliter
– Category 2: 200 to 499 cells/mircroliter
– Category 3: <200 cells/microliter.
• 3 Clinical categories based on symptoms:
– Clinical Category A: persons who are asymptomatic or
have persistent generalized lymphadenopathy, or
symptoms of primary infection
– Clinical Category B: person has symptoms of immune
deficiency, however, not severe enough to be AIDS
– Clinical Category C: person has AIDS defining
illnesses such as pneumocystis carinii pneumonia.
41
Phases of HIV
• 3 phases which occur over 8 to 12 years
• Primary Infection phase:
– Signs and symptoms appear 2 to 4 weeks after exposure
lasting a few days to 2 weeks
– Patient has fever, fatigue, myalgia, sore throat, night seats,
GI problems, lymphadenopathy, maculopapular rash, and
headache.
– During this phase there is a high amount of viral replication
(up to 1 million/ml) and a decreasing amount of CD4+
– After a few weeks the immune system catches up controlling
viral replication where it remains for several years.
– If diagnosed in this stage and therapy is started treatment
may reduce the number of long-living CD4+ infected cells
42
• Chronic Asymptomatic (Latency Phase)
– Patient has no signs or symptoms of illness
– On average this phase lasts 10 years
– There is a decreasing amount of CD4+ cells down to
200 per microliter or lower.
• AIDS Phase
– Occurs when the CD4+ cell count falls less than
200/microliter
– Patient is susceptible to opportunistic infections
– Without antiretroviral therapy this phase can lead to
death within 2 to 3 years
43
Clinical Course of HIV
• Typical progressors: 60% to 70% acquire AIDS 10 to 11 years
after infection
• Rapid progressors: 10% to 20% progress rapidly and acquire
AIDS in less than 5 years
• Slow progressors: 5% to 15% are slow progressors, who do not
progress to AIDS for more than 15 years
– Long-term non-progressors: 1% have been infected for at least
8 years, are antiretroviral naive, have high CD4+ cell counts
and usually very low viral loads
44
Opportunistic Infections Affecting AIDS
• Bacterial opportunistic infections
– Bacterial pneumonia, TB , salmonella, mycobacterium aviumintracellulare complex (MAC)
• Fungal opportunistic infections
– Candidiasis, coccidiomycosis, cryptococcosis, and
histoplasmosis
• Protozoal opportunistic infections
– Cryptosporidiosis, isosporiasis, pneumocystiasis, and
toxoplasmosis
• Viral infections
– Cytomegalovirus (CMV), herpes, and progressive multifocal
leukoencephalopathy (PML)
45
Most Common Opportunistic Infections
Affecting AIDS in the U.S.
•
•
•
•
Pneumocystis carinii pneumonia (PCP)
CMV
Oropharyngeal or esophageal candidiasis (thrush)
Infections caused by MAC (mycobcacterium avium-intrcellulare
complex)
46
Clinical Manifestations
1. Respiratory Manifestations: the most common respiratory diseases
in person with AIDS include:
a) Pneumocystis carinii pneumonia (PCP)- is caused by
a protozoa that is common in soil, and houses
• patients tend to complain of:
– Cough, fever, shortness of breath, and weight loss
b) Mycobacterium tuberculosis: is the leading cause of death for
people with AIDS worldwide
• infections site is primarily in the lungs but may also be
found in the kidneys and bone marrow
• common S/S include: fever, night sweats, cough and
weight loss
47
2) Gastrointestinal Manifestations- diseases of the GI tract are
the most frequent complications of AIDS and usually
include:
a) Esophageal Candidiasis (Thrush)- presents as cheesy
matter along the entire GI tract including the mouth
b) Diarrhea (Gastroenteritis)- is the most common
complaint in persons with AIDS and is usually caused
by the protozoa Cryptosporidium parvum
48
49
3) Nervous System Manifestations: due to severe immune
compromise, both the CNS and PNS are susceptible to several
neurological disorders that can include:
a) AIDS Dementia Complex- is a syndrome involving both
cognitive and motor system dysfunction that is caused by the
pathological effects of HIV itself
• typical S/S include:
– loss of attention span/concentration
– decrease in mental speed and agility
– decrease in overall motor function
– apathetic behavior
b) Toxoplasmosis- is an opportunistic parasitic infection that
affects the CNS
• typical S/S include:
– fever
– headache
– confusion/lethargy
– visual disturbances
50
– seizure activity
4) Cancers and Malignancies- the increased incidence of
malignancies is directly related to the HIV-induced impaired
immune function and include:
a) Kaposi’s Sarcoma- is a malignancy of the endothelial cells
that line small blood vessels
• is the most frequent malignancy related to AIDS
• physical S/S include:
– dark plaque-like lesions located on the skin, oral cavity,
GI tract, lungs
– organ failure-related S/S occur due to tumor blocking
blood flow
b) Non-Hodgkin’s Lymphoma- is a malignancy of the lymph
nodes
• typical S/S include:
– fever
– night sweats
51
– weight loss
52
5) Wasting Syndrome- is characterized by involuntary weight
loss of at least 10% of baseline body weight in the
presence of no AIDS induced opportunistic infection
• typical S/S include:
– constant diarrhea
– chronic weakness
– fever
53
6) Metabolic Disorders- the two main AIDS induced metabolic
disorders include:
a) Lipodystrophy- alterations in body appearance due to
abnormal fat metabolism that present as:
• increase in abdominal girth
• abnormal fat deposition in the supraclavicular area
• wasting of fat from face/extremities
• breast enlargement in both sexes
• associated metabolic changes including elevated serum
cholesterol, elevated triglyceride levels, and insulin
resistance
» may be due to effects of protease inhibitor therapy
or nucleoside reverse transcriptase inhibitor
therapy
54
Diagnostic Methods
• Laboratory methods to determine infection
– HIV antibody test
• Most accurate and inexpensive
– Western blot test
• Used as a confirmatory test when the antibody test is
positive
• Test is more specific than the antibody test
– OraSure test
• Tests for antibodies from oral fluids
• Person collects their own sample and sends it to the lab
where the antibody and Western blot test are performed
55
– Polymerase chain reaction (PCR)
• Detects the presence of the virus rather than the
antibody
• Useful in infants who have maternal HIV antibodies,
yet they themselves may not be infected.
56
HIV Antiretroviral Medications
• Reverse transcriptase inhibitors
– Inhibit viral replication by acting on the enzyme reverse
transcriptase
• Protease inhibitors
– Inhibits the action of protease, thereby preventing the cleaving
of the polyprotein chain
• Fusion inhibitors
– Prevents HIV virus from fusing with the CD4+ cell, thereby
blocking the insertion of the viral genetic material.
57
HIV Infection in Pregnancy, Infants,
Children
• HIV can be passed from mother to infant
– During labor and delivery
– Through breast-feeding
• Diagnosis of HIV infection in children born to HIV infected
mothers is complicated by the presence of maternal HIV antibody
crossing the placenta to the fetus
• The course of HIV infection is different for children than adults
– Failure to thrive
– CNS abnormalities
– Developmental delays
58