Congenital and Acquired

Immunodeficiencies

Assoc. Prof. Emrah Şefik

Abamor
 Immunodeficiency Diseases

vThe normal function of the immune system is to

defend individuals against infections and certain
cancers.
vDiseases caused by impaired immunity are called
immune deficiency diseases.
 Immunodeficiency Diseases
1. Congenital (Primary) Immunodeficiencies

2. Acquired (Secondary) Immunodeficiencies

Congenital (Primary) Immunodeficiencies

• Some of these diseases are caused by genetic

anomalies in one or more components of the
immune system, which are called innate
(primary) immune deficiencies.
 Acquired (Secondary) Immunodeficiencies

• Other disorders in the immune system occur as a

result of treatments that cause no or insufficient
function in various components of the immune
system, nutritional disorders and infections, which
are called acquired (secondary) immune deficiencies.
 Congenital (Primary)
Immunodeficiencies
• Common to all congenital immune deficiencies
characteristic is the development of complications related
to infection.
• Different congenital immunodeficiency diseases have
different clinical and pathological features.
• Some of these diseases appear immediately after birth
and are fatal if the immunological deficiency is not
corrected.
Deficiencies in Maturation of Lymphocytes
• Most congenital immune deficiencies are the result
of genetic abnormalities that interrupt the
maturation of B lymphocytes, T lymphocytes, or
both.
• Diseases that are deficient in both the B and T cell
arms of the adaptive immune system are classified
as severe combined immune deficiency (SCID).
 Severe Combined Immune Deficiencies

• Severe Combined Immunodeficiency Syndrome; It

represents a group of diseases characterized by
disorders in the development and functions of T
and B lymphocytes and natural killer cells.
• It constitutes the most severe form of primary
immunodeficiency syndromes.
 Severe Combined Immune
Deficiencies
• Severe combined immunodeficiency is characterized
by life-threatening opportunistic bacterial, viral
(especially cytomegalovirus, parainfluenza and
rotavirus) and fungal (Pneumocystis pneumoniae,
Candida, Aspergillus) infections which usually occur
in the first year of life.
 Severe Combined Immune
Deficiencies

• Early diagnosis is vital for these patients.

• While these infections usually involve the
respiratory tract and gastrointestinal tract,
meningitis, arthritis, and urinary tract infections
can also be seen.
Severe Combined Immunodeficiencies

About 50% of severe X-linked combined

immunodeficiency cases are caused by mutations in a
signaling subunit of the cytokine receptor and affect only
boys.
– This subunit is called the common γ chain (γc), because
it is the common chain that enters the structure of many
cytokine receptors such as IL-2, IL-4, IL-7, IL-9 and IL-15.
• When the γc chain fails to function, immature
lymphocytes at the pro-T cell and pro-B cell stage
cannot proliferate even in the presence of a major
growth factor for these cells, such as IL-7.
– As a result of this deficiency, a significant decrease
in the number of mature T cells, deficiency in cell-
mediated immunity and incomplete humoral
immunity occur.
 ADA (Adenosine deaminase)
Deficiency
• ADA is an enzyme involved in purine
metabolism in cells.
• It catalyzes the breakdown of adenosine to
inosine.
• Although it is found in all mammalian cells, it
is known that it primarily functions in
immune system cells.
 ADA (Adenosine deaminase)
Deficiency
• ADA deficiency leads to accumulation of
toxin purine metabolites in actively
proliferating cells and stops T cell
maturation.
• Patients do not have NK cells in addition
to T and B lymphocytes in the
circulation.
 B Cell Immunodeficiencies
• The most common clinical syndrome that occurs with
interruption in B cell maturation is
agammaglobulinemia inherited by the X chromosome.
• The disease is due to a mutation in the gene encoding
B cell tyrosine kinase (Btk). The enzyme gene is on the
X chromosomes.
• Women who carry the Btk mutant allele on one of
their X chromosomes are carriers of the disease, and
their sons with abnormal X chromosomes will get the
disease.
 Defects in Activation and Functions
of Lymphocytes
q X-linked hyper-IgM syndrome is characterized by
a defect in B cell heavy chain isotype conversion
resulting in severe deficiency in cellular mediated
immunity against intracellular microorganisms.
q The disease is caused by mutations in the CD40
ligand. CD40 ligand is a protein found in T helper
cells that binds CD40 in B cell and macrophages
q It provides T-cell dependent activation of B cells
and macrophages.
qCommon variable immune deficiency (CVID) is a
heterogeneous group of diseases.
qThese diseases are characterized by a weak
antibody response to infections and a decrease in
serum levels of IgA and IgE, often IgG.
qWhile the IgM level may remain low, it remains high
in most cases.
 T Cell Immunodeficiencies

• DiGeorge syndrome, on the other hand, is caused

by the developmental deficiency of the thymus
and creates a deficiency in T cell maturation. Bone
marrow transplantation is the most common
treatment.
 Deficiencies in Innate Immunity

In the two components of The phagocyte oxidase

innate immunity; enzyme mutation, which
phagocytosis and catalyzes microbicidal
complement system reactive oxygen
abnormalities are intermediates in lysosomes,
important causes of causes chronic
immune deficiency. granulomatous disease.
• The phagocyte oxidase enzyme mutation, which
catalyzes microbicidal reactive oxygen
intermediates in lysosomes, causes chronic
granulomatous disease.
• As a result, neutrophils and macrophages cannot
kill the phagocytosed microorganisms.
Ø The immune system tries to compensate for this
deficiency by calling more macrophages to the
environment and activating T cells, which
stimulates the activation of more phagocytes, as it
fails to kill the microorganisms.
Ø Therefore, phagocyte accumulation occurs, but
microorganisms cannot be effectively eliminated.
Ø This accumulation causes the granuloma-like
formation that gives the disease its name.
 Deficiencies in Innate
Immunity
• Mutation of genes encoding enzymes or integrins
required for ligand expression for selectin causes
leukocyte adhesion deficiency. Integrin and selectin
are involved in the adhesion of leukocytes to other
cells.
• As a result of these mutations, leukocytes cannot
bind strongly to the vascular endothelium and
cannot accumulate at the infection site.
Acquired (Secondary) Immunodeficiencies
• Immune system deficiencies can often develop
due to non-genetic but acquired abnormalities
during life.
• The most important of these abnormalities is HIV
infection.
• Protein-calorie malnutrition actually results in
deficiencies in all elements of the immune system
and is the most common cause of immune
deficiency in underdeveloped countries.
• Cancer treatment with chemotherapeutic agents
and radiotherapy damages proliferating cells,
including bone marrow progenitor cells and mature
lymphocytes, and causes immune deficiency.
• Other treatments (for example, to prevent graft
rejection) are arranged to suppress the immune
response.
• Therefore, immunodeficiency is a common
complication of such treatments.
 Acquired Immunodeficiency
Syndrome (AIDS)

• AIDS is an infection caused by the human

immunodeficiency virus (HIV).
• It is estimated that more than 35 million people in
the world are infected with the HIV virus and more
than 3 million deaths occur each year due to this
disease.
 Human Immunodeficiency Virus
(HIV)
• HIV is a retrovirus that infects immune system cells,
usually CD4+ T lymphocytes, and causes severe
damage to these cells.
• The infectious HIV particle contains single-stranded
RNA within the protein capsid. The viral capsid is
surrounded by a lipid cover derived from host cells.
• Viral RNA encodes structural proteins, various
enzymes, and proteins that regulate the
transcription of viral genes and the life cycle of the
virus.
The life cycle of HIV consists of
the following steps:

INFECTION PRODUCTION OF VIRAL EXPRESSION OF VIRAL

OF CELLS DNA AND INTERACTION GENES AND
WITH THE HOST PRODUCTION OF VIRAL
GENOME PARTICLES
• HIV infects immune system cells through a major
envelope glycoprotein called gp120, which it does so
by binding specifically to chemokine receptors
(CXCR4 and CCR5) and CD4 in human cells.
• Thus, the virus infects only cells expressing CD4 and
these chemokine receptors.
• The major cell type that can be infected with HIV is
CD4 T lymphocytes, but macrophages and dendritic
cells are also infected with the virus. Different cell
populations may use different chemokine receptors
to bind to different strains of the virus.
• After binding to the cell receptor, the viral membrane
fuses with the host cell membrane and the virus
enters the cell cytoplasm.
• Here, the virus disrupts its own structure with the
viral protease it contains and viral RNA is released
into the cell.
• A DNA copy of the viral RNA is made by the viral
reverse transcriptase enzyme, and the DNA
integrates into the host cell's DNA through the
activity of the integrase enzyme.
• This integrated viral DNA is called provirus.
• If an infected T cell, macrophage, or dendritic cell is
activated by external stimuli, such as another
infectious microorganism, the cell produces intense
cytokines and responds to stimuli by initiating
transcription of its own gene.
• The unfortunate consequence of this normal
response is that activation of cells also activates the
provirus, leading to the production of viral RNAs
and later proteins.
 Human Immunodeficiency virus (HIV)

Thus, the virus forms its nucleus, migrates to the cell membrane,
acquires a lipid envelope from the host and is ready to spread as
an infectious viral particle ready to infect another cell.

t is possible for the integrated HIV provirus to remain latent in

infected cells for months or years, hiding from the patient's
immune system.

HIV-1 is the cause of the majority of AIDS cases. HIV-2, a virus

associated with it, appears to be the cause of the disease in
some cases.
 AIDS PATHOGENESIS
• HIV creates a latent infection of immune system cells
and can be reactivated to produce infectious virus.
• This viral production not only causes death of
infected cells but also kills non-infected
lymphocytes with the activity of cytotoxic T cells,
and then immunodeficiency and AIDS clinic develops.
• HIV infection is transmitted through sexual
intercourse, the use of contaminated needles in
intravenous drug users, transplacental transmission,
or transfusion of infected blood and blood products.
 AIDS PATHOGENESIS

1. After infection, when the virus is detected in the blood,

there may be a short-lived acute viremia and the host
responds as with any mild viral infection.
2. The virus infects blood CD4 T cells, dendritic cells and
macrophages, epithelial entry sites, and most lymphoid
organs such as lymph nodes.
3. Dendritic cells capture the virus when it enters the
epithelium and transport the virus to the peripheral
lymphoid organs, where it infects T cells.
4. The integrated provirus can be activated by another
infection, causing the production of viral particles and the
spread of the infection.
ü Activated CD4 T cells are the main source of
infectious viral particles during the course of HIV
infection; Dendritic cells and macrophages are the
reservoir of infection.
ü Depletion of CD4 T cells after HIV infection is
associated with the cytopathic effect of the virus.
After the production of viral particles, the death of
non-infected cells with the cytopathic effect causes a
decrease in the number of T cells.
 Clinical Symptoms of AIDS

• The clinical course of HIV infection is characterized

by immunodeficiency.
• Associated with the early onset of viremia after
HIV infection, patients may experience a mild
acute illness accompanied by fever and malaise.
• This disease state regresses in a few days and the
latent period of the disease begins.
 Clinical Symptoms of AIDS

• During the latent period, there is usually a

continuous loss of CD4 T cells in lymphoid tissues
and the structure of the lymphoid tissue is
disrupted.
• As AIDS becomes chronic, the body becomes
predisposed to infections and certain cancers as
a primary consequence of immune deficiency.
HIV

• Infections with viruses normally fought by T-cell-

mediated immunity, fungi such as Pneumocystis carinii,
and intracellular microorganisms such as atypical
mycobacteria are common in patients.
• Some microorganisms are present in the body, but they
do not infect healthy individuals with a healthy immune
system.
• These microorganisms seize the opportunity to cause
infection in individuals with immune deficiency, which
are called opportunistic infections.
Human Immunodeficinecy Virus
(HIV)

• AIDS patients are at risk for extracellular bacterial

infections because the helper T cell-dependent

antibody response to bacterial antigens is

impaired.
• Patients may also be predisposed to cancers caused
by oncogenic viruses.
• The two most common types of cancer are B-cell
lymphoma, caused by the Epstein Barr virus, and
Kaposi's sarcoma, caused by the herpes virus.
• AIDS patients in the advanced period experience
serious weight loss due to the change in metabolism
and decreased calorie intake, that is, they are caught
in Wasting syndrome.
• Some AIDS patients develop a dementia due to an
infection of the macrophages (microglia) in the brain.
 Human Immunodeficinecy Virus
(HIV)

• The immune response against HIV is

insufficient to control the spread and
pathological effect of the virus. Infected
individuals produce antibodies and CTLs
against viral antigens, and this response is
sufficient to limit early acute HIV syndrome.
• However, these immune responses often
cannot prevent the chronic progression of
the disease.
• Antibodies against envelope glycoproteins such as
GP120 are ineffective because the virus rapidly
mutates the gp120 region, which is the target of
many antibodies.
• CTLs are ineffective in killing infected cells in chronic
AIDS because the virus inhibits the expression of
MHC class I molecules by infected cells.
• The immune response to HIV reverses the spread of
the infection.
 Treatment and Vaccination Strategies

• The current treatment goal of AIDS is to control the

proliferation of HIV and the infectious complications
of the disease.
• Drug mixtures that inhibit the activity of viral
reverse transcriptase, protease and integrase
enzymes are currently applied in the early stages of
infection and provide considerable benefit. This
treatment is called highly active antiretroviral
therapy.
 Treatment and Vaccination Strategies

• Effective vaccine development is needed to control

HIV worldwide.
• A successful vaccine should be able to induce an
innate immune response, a high titer of
neutralizing antibodies, a strong T-cell response,
and a strong mucosal immunity. Another aspect is to
provide protection against all subgroups of HIV.