Kwame Nkrumah University of

Science & Technology, Kumasi, Ghana

Pharm 266. Applied Immunology

- Immunodeficiency

Stephen Yao GBEDEMA (PhD)

Department of Pharmaceutics
FPPS, College of Health Sciences

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• Introduction:
The immune system is a complex network of
cells and molecules responsible for providing
defense against pathogens, performing tumour
immuno-surveillance and maintaining
immunological tolerance.
Immunodeficiency (ID) is the absence or
failure of normal function of one or more
elements of the immune system.

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General diagnosis of immunodeficiency disorders
Diagnosis of ID diseases (primary/inherited or secondary/acquired) involves a
comprehensive evaluation to identify the defects in the immune system:
Clinical Evaluation
• Medical History: such as recurrent, severe or unusual infections; Poor
response to standard treatments.
• Physical Examination: such as assessment for signs of infection (e.g, swollen
lymph nodes); Growth parameters in children (weight, height).
Laboratory Evaluation
• Basic Blood Tests: Complete Blood Count (Evaluate WBCs, RBCs and
platelets) and Differential blood count (Assess the proportion of
different types of white blood cells).
• Quantitative Immunoglobulins: Measurement of serum levels of
IgG, IgA, IgM, and sometimes IgE. Comparison to age-appropriate
reference ranges. Specific antibody responses to vaccines, etc.
Imaging Studies
• Chest X-ray or CT Scan: Evaluation of the thymus (particularly in young
children);
Assessment for lung abnormalities, etc.
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General management of Primary ID disorders
Management of ID disorders involves a combination of strategies aimed at
preventing infections, treating any underlying or associated conditions, and
improving the patient’s quality of life.
• Preventive Measures
 Ig replacement therapy
 Vaccinations (non live vaccines recommended)
 Antibiotic Prophylaxis
• Treatment of Infections
• Management of Associated Conditions such as autoimmune dss, chronic
lung dss and gastrointestinal issues.
• Advanced Therapies such as Hematopoietic Stem Cell Transplantation
(HSCT) for Severe Combined Immunodeficiency (SCID), Wiskott-Aldrich
Syndrome, and other severe primary immunodeficiencies.
• Regular Monitoring and Follow-Up
• Patient Education and Support
• Lifestyle and Nutritional Modifications

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HUMORAL IMMUNODEFICIENCIES
1. Common Variable Immunodeficiency: CVID usually occur
sporadically but can occur in a familial setting.
• Characterized by low levels of serum antibodies (usually IgG, IgA and
sometimes IgM), resulting in increased susceptibility to infection
(bacterial, viral, or fungal).
• The degree and type of deficiency of serum antibodies, and the clinical
course, varies from person to person, hence, the word “Variable ID".
• It is typically diagnosed in adulthood, although it can occur at any age.
• Symptoms: Recurrent respiratory (sinusitis, bronchitis, pneumonia) and
GIT infections, increased risk of malignancies and autoimmune diseases.
• Diagnosis:
• Measurement of Ig levels,
• poor vaccine response, and
• exclusion of other causes of hypogammaglobulinemia.
• Treatment: Ig replacement therapy,
• antibiotics for infections, and
• management of autoimmune complications.
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2. Selective IgA Deficiency (SIgAD): is characterized
by an undetectable level of IgA in the blood and
secretions but normal IgG and IgM in an individual
age 4 and older.
• Clinical presentation vary widely and may
include recurrent infections of the respiratory
and GIT tracts, autoimmune and allergic
disorders.
• Diagnosis: Lab measurement of serum IgA
levels (<7 mg/dL). Clinical evaluations.
• Management: prophylaxis and treatment of
infections, nutritional support, education.

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Differences between CVID and Selective IgA Deficiency
1.Immunoglobulin Levels: CVID involves low levels of multiple
Igs (IgG, IgA, and sometimes IgM), while SIgAD specifically
affects only IgA levels.
2.Clinical Presentation: CVID typically presents with more
severe and frequent infections, autoimmune diseases, and an
increased risk of malignancies, whereas SIgAD may be
asymptomatic or cause milder infections and is associated more
with allergic and autoimmune conditions.
3.Diagnosis and Age of Onset: CVID is often diagnosed later in
life with more pronounced symptoms, while SIgAD can be
diagnosed at any age and is frequently found incidentally.
4.Treatment: CVID requires Ig replacement therapy and more
intensive management of complications, while SIgAD focuses on
treating symptoms and infections as they arise.
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3. X-linked Agammaglobulinemia (XLA): (Bruton
agammaglobulinemia) is genetic disorder characterized by a
deficiency of mature B cells and antibodies.
• It is caused by mutations in the gene encoding Bruton's
tyrosine kinase (BTK), an enzyme essential for B cell
development and function,
• The patients lack mature B cells and have extremely low levels
of all types of Ig.
• Symptoms: Recurrent bacterial infections, especially in the
respiratory tract and GIT system, in early childhood (around 6
months of age) as the maternal antibodies acquired begin to
wane out.
• Diagnosis: Absence of B cells in peripheral blood, low levels of
Igs, and genetic testing for BTK mutations confirmation.
• Treatment: Lifelong replacement therapy with IV or
subcutaneous Ig and prompt treatment of infections.
Prophylactic antibiotics and supportive care are also hlpful

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4. Transient Hypogammaglobulinemia of Infancy (THI):
is a primary ID caused by a transitory drop in the levels
of IgG in an infant btn 5 and 24 months of age.
• Symptoms include recurrent upper respiratory tract
infections, ear infections.
• Lower respiratory tract infections, such as bronchitis
and pneumonia, can also occur.
• Levels typically return to reference range at ages 2 to 6
years.
• Antibiotic prophylaxis may be given to children with
frequent/severe infections.
• Majority of children with THI do not require Ig
replacement therapy.

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5. Hyper-IgM Syndrome: an ID disorder, characterized by elevated
blood levels of IgM and decreased levels or absence of other Igs (IgG,
IgA and IgE).
• It results from defects in the processes that allow B cells to switch
from producing IgM to other types of Igs (class-switch
recombination).
• B Cell Function: Due to the impaired class switch recombination,
B cells cannot produce a diverse range of Igs, leading to an
increased susceptibility to infections, particularly encapsulated
bacteria infection.
• can be inherited as autosomal recessive traits
• The most common form of Hyper IgM Syndrome is X-linked,
caused by mutations in the CD40 ligand (CD40L) gene on T cells.
• CD40L is essential for the interaction between TH cells and B
cells, which is necessary for class switch recombination in B cells.

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• This defective interaction impairs the ability of T cells to
help B cells to effectively switch from IgM to other Igs.
• Defective T cell function can lead to increased
susceptibility to opportunistic infections such as
Pneumocystis jirovecii and Cryptosporidium.
• General Clinical Manifestations of Hyper-IgM
Syndrome: Symptoms usually show at 1-2 years of age,
and include
 recurrent upper and lower respiratory tract and GI
infections,
 neutropenia with oral ulcers and skin infections,
 autoimmune disorders,
 lymphoid hyperplasia.

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CELLULAR IMMUNODEFICIENCY DISEASES

• T cells are crucial for the adaptive immune response, including

the activation of other immune cells, direct killing of infected
host cells, and regulation of the immune response.
• T cell defects therefore lead to a variety of immunodeficiency
disorders.
• T cell defect disorders can have significant clinical implications,
including recurrent infections, autoimmune diseases, and an
increased risk of malignancies.
• Diagnosis and management often involve
• genetic testing,
• immunological assessments, and
• tailored therapies to address the specific immune
deficiencies and associated complications.

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1. Congenital Thymic aplasia (DiGeorge Syndrome or 22q11.2
Deletion Syndrome): is caused by a defective development of the
thymus (and other organs) and creates a deficiency in T cell
maturation.
• DGS is a genetic disorder caused by eletion of a small piece of
chromosome 22 at the q11.2 region.
• DGS affects multiple body systems and results in a wide range of
clinical features including Immunodeficiency (ID), congenital
heart defects, and developmental delays.
• In DGS of Thymic aplasia: the thymus is either absent or
underdeveloped, leading to a significant reduction in T cell
production (T-cell lymphopenia), which can range from mild to
severe, resulting in increased susceptibility to infections.
• Clinical Manifestations: Recurrent infections, particularly with
viral, fungal, and opportunistic pathogens.
• Live vaccines can pose a risk to these patients.
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2. Wiskott-Aldrich Syndrome (WAS) is an X-linked recessive ID disorder
characterized by thrombocytopenia, eczema, and increased susceptibility to
infections.
• It is caused by mutations in the WAS gene, which encodes the Wiskott-
Aldrich syndrome protein.
• The WAS protein plays a crucial role in the regulation of actin cytoskeleton,
which is important for various cellular processes including cell signaling,
movement, and immune synapse formation.
• Mutations in the WAS gene lead to dysfunctional WAS protein, resulting in
impaired T-cell and B-cell function, abnormal platelet development, and
defective cellular signaling.
• Clinical manifestations:
• Increased susceptibility to infections (bacterial, viral, fungal).
• Recurrent otitis media, pneumonia, skin infections, and sepsis.
• Poor response to polysaccharide vaccines due to B-cell dysfunction.
• Thrombocytopenia, severe and refractory eczema,
• Higher risk of developing Epstein-Barr virus (EBV)-associated
lymphomas and leukemias.

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3. Chronic mucocutaneous candidiasis (CMC): can result from
immunodeficiency;
• It is characterized by persistent and recurrent Candida albicans
infections of the skin, nails, and mucous membranes.
• Results from T-Cell dysfunction: some specific subsets of T-
cells, are crucial for coordinating the immune response against
fungal infections. Eg TH17 cells, are particularly important in
mucosal immunity against Candida.
• TH17 cells secrete certain cytokines, particularly IL-17 and IL-
22, which play significant roles in the immune response to
fungal infections by recruiting neutrophils and enhancing
epithelial barrier function.
• Defective TH 17 cell leads to lack of these ILs on mucosal
surfaces and hence the recurrent and persistent fungal
infections.

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• Clinical Features of CMC are
 Oral Candidiasis (Thrush),
 Cutaneous Candidiasis (Red, itchy, and painful skin
lesions in areas such as the groin, armpits, and under
the breasts).
 Nail Infections.
• Other Features include
 Endocrinopathies (hypoparathyroidism and adrenal
insufficiency),
 Ectodermal Dysplasia (abnormalities in the skin, hair,
teeth, and nails)
 Autoimmune conditions (thyroid disease, type 1
diabetes).

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4. Severe Combined Immunodeficiency (SCID) is a group of
rare disorders caused by mutations in some genes involved in
the development and function of lymphocytic cells.
• SCID people have low numbers of T cells and natural killer
cells, and their B cells do not function.
• This results in lack of immune protection from bacteria,
viruses, and fungi.
• SCID can be inherited in an autosomal recessive pattern, e.g
Adenosine Deaminase (ADA) deficiency – infants (boys &
girls) lack the ADA enzyme necessary for T-cell survival.
• ADA-deficient SCID is characterized by severe
lymphocytopaenia affecting T- and B-cells and NK cells
• SCID can also be X-linked; occurs exclusively in males.

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• Symptoms of SCID occur in infancy. They are prone to
repeated/recurrent and persistent infections, often caused
by opportunistic organisms, such as
• pneumonia caused by Pneumocystis jirovecii
• meningitis
• Chronic diarrhea.
• Candida infections of the mouth and diaper area

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5. Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare
genetic disorder that results from mutations in the FAS gene (aka
Tumor Necrosis Factor Receptor Superfamily Member 6
(TNFRSF6)).
• ALPS inheritance can be by autosomal dominant/recessive or sporadic.
• The FAS gene plays a crucial role in apoptosis (programmed cell
death); which maintains immune system balance by eliminating excess
or harmful cells.
• The mutations cause the immune system to remain active even when no
infection is present, leading to excessive number of lymphocytes.
• These cells accumulate in various tissues and organs
• Clinical manifestations, include
• lymphadenopathy
• splenomegaly and
• autoimmune cytopenias, (such as autoimmune hemolytic anemia,
thrombocytopenia and neutropenia).
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6. Bare Lymphocyte Syndrome (BLS) is a rare, inherited ID
disorder characterized by the absence or severe reduction in
the level of MHC molecules (class I or II) on the surface of
cells.
• It is an autosomal recessive inheritance, caused by mutations
in genes involved in MHC molecules expression and
regulation.
• Two Types:
 Type I: Deficiency in MHC class I expression
 Type II: Deficiency in MHC class II expression
• Immunological effects include
 Impaired antigen presentation
 Defective T cell development and function
 Reduced CD4+ T cell counts (in Type II)
 Normal or elevated immunoglobulin levels
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• Clinical features of BLS:
 Recurrent bacterial, viral, and fungal infections
 Chronic diarrhea
 Failure to thrive
 Respiratory tract infections
 Skin lesions

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Phagocyte Immunodeficiencies
 Chronic Granulomatous Disease
 Leukocyte Adhesion Deficiency
 Chediak-Higashi Syndrome
 Severe Congenital Neutropenia

!!!!!Students to read and make notes

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 Kwame Nkrumah University of
Science & Technology, Kumasi, Ghana

Cytokines and Immunotherapy

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What are cytokines?
• Soluble proteins
• Low molecular mass (about 8 – 25 kDa)
• Secreted by a large number of different cell
types.
• They regulate many important biological
processes
• They are mediators of cell – cell communication
in the immune response system
• They regulate the intensity and duration of the
immune response
• They are NOT hormones!
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• Cytokines are low molecular weight (8 –
25kDa), soluble proteins that are produced in
response to an antigen and function as chemical
messengers for regulating the innate and
adaptive arms of the immune systems.
• Cytokines are
Pleiotropic – (act on different types of cell) a single
cytokine can have multiple effects on different cell
types. This allows cytokines to participate in a wide
range of biological processes, including cell growth,
differentiation, and immune responses.

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 Redundant – different cytokines can perform similar
functions. This ensures that if one cytokine is absent or
dysfunctional, others can compensate, ensuring the
robustness of the immune response.
 Multifunctional –. They can have different effects
depending on the context (ie same cytokine is able to
regulate a number of different functions), such as the type of
cell they interact with, the presence of other cytokines, and
the state of the cell (e.g., resting vs. activated). This allows
cytokines to finely tune immune responses and other
physiological processes.

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Cytokines with chemotactic activity are called
Chemokines
Cytokines released by
• Lymphocytes are also called Lymphokines
• Monocytes and macrophages are called Monokines
• Leukocytes that act on other leukocytes are referred
to as Interleukins (IL)
Three functional categories of cytokines:
• Cytokines that regulate innate immune responses
• Cytokines that regulate adaptive immune responses,
• Cytokines that stimulate hematopoiesis.

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Functional Cytokine Categories
1. Cytokines act as mediators and regulators of innate
immunity:
• Initiation and Regulation of Inflammatory Responses:
 Cytokines such as IL-1, TNF, and IL-6 are essential for
initiating and regulating inflammation.
 They help recruit immune cells to the site of infection or
injury and activate these cells to fight off pathogens.
• Activation of Innate Immune Cells:
 Cytokines activate various innate immune cells, such as NK
cells, macrophages and neutrophils.
 E.g. interferon-gamma (IFN-γ) enhances the microbicidal
activity of macrophages, helping them to destroy ingested
pathogens.
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 Promotion of Antimicrobial Responses:
 Some types of cytokines promote the production of
antimicrobial peptides and proteins.
 E.g., IL-22 and IL-17 stimulate epithelial cells to
produce defensins, which are antimicrobial peptides
that help to protect against infections.
 Coordination of Immune Responses:
 Cytokines coordinate the interactions between different
cell types in the immune system.
 They ensure that the immune response is efficient and
targeted. Eg, IL-12 produced by macrophages and dendritic
cells can stimulate NK cells to produce IFN-γ, which
enhances immune response against intracellular pathogens.

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 Regulation of Immune Homeostasis:
 Cytokines play a role in maintaining immune
homeostasis and preventing excessive inflammation.
 Regulatory cytokines like IL-10 and TGF-β help to
limit and resolve inflammatory responses, preventing
tissue damage and maintaining immune balance.
 Enhancing Barrier Functions:
 Cytokines such as IL-22 contribute to the
maintenance and repair of epithelial barriers in the
gut, skin, and other tissues.
 This helps to prevent pathogen entry and promote
healing of damaged tissues.

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2. Cytokines act as mediators and
regulators of adaptive immunity
T Cell Differentiation and Activation:
 Interleukin-2 (IL-2): Critical for the growth,
proliferation, and differentiation of T cells after their
initial activation.
 IL-12: Promotes the differentiation of naive T cells into
Th1 cells, which are essential for cell-mediated
immunity against intracellular pathogens.
 IL-4: Drives the differentiation of naive T cells into
Th2 cells, which are important for humoral immunity
and the defense against extracellular pathogens.

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B Cell Activation and Antibody Production:
 IL-4 and IL-5: Stimulate B cell proliferation and
differentiation into plasma cells that produce antibodies.
 IL-21: Enhances the production of high-affinity antibodies
and the formation of memory B cells.
Regulation of Immune Responses:
• IL-10: An anti-inflammatory cytokine that limits immune
responses to prevent tissue damage and maintain immune
homeostasis. It inhibits the function of antigen-presenting
cells and reduces the production of pro-inflammatory
cytokines.
• Transforming Growth Factor-beta (TGF-β): Promotes
the differentiation of regulatory T cells (Tregs) that
suppress immune responses and maintain tolerance to self-
antigens, preventing autoimmunity.

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Enhancement of Cytotoxic Responses:
 IL-2 and IL-12: Enhance the cytotoxic activity of
CD8+ T cells and NK cells, which are crucial for killing
virus-infected cells and tumor cells.
 Interferon-gamma (IFN-γ): Produced by Th1 cells,
enhances the killing ability of macrophages and boosts
antigen presentation, enhancing the overall adaptive
immune response.
Development of Memory Cells:
 IL-7: Important for the survival and homeostasis of
memory T cells, ensuring long-term immunity and
quicker responses upon re-exposure to the same
antigen.

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Modulation of Immune Responses:
 IL-17: Produced by Th17 cells, it recruits neutrophils and
enhances the immune response against fungal and bacterial
infections.
 IL-23: Supports the maintenance and expansion of TH17 cells,
playing a role in chronic inflammation and autoimmunity.

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3. Cytokines act as stimulators of haematopoiesis:
Some cytokines regulate proliferation, differentiation,
and survival of hematopoietic stem and progenitor cells.
 Erythropoietin:
• Function: stimulates the production of red blood
cells (erythrocytes) from erythroid progenitor
cells.
• Source: this cytokine is mainly produced by the
kidneys in response to low oxygen levels in the
blood.

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 Granulocyte Colony-Stimulating Factor (G-CSF):
• Function: Promotes the production and maturation of
neutrophils from progenitor cells.
• Source: Produced by various cells, including
macrophages, fibroblasts, and endothelial cells.
 Granulocyte-Macrophage Colony-Stimulating Factor
(GM-CSF):
• Function: Stimulates the production of granulocytes
(neutrophils, eosinophils, and basophils) and
monocytes/macrophages.
• Source: Produced by T cells, macrophages, endothelial
cells, and fibroblasts.
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 Macrophage Colony-Stimulating Factor (M-CSF):
• Function: Encourages the production and
differentiation of monocytes and macrophages.
• Source: Secreted by various cells, including
macrophages, endothelial cells, and fibroblasts.
 Interleukin-3 (IL-3):
• Function: Supports the proliferation and
differentiation of multipotent hematopoietic stem
cells into various blood cell lineages, including
myeloid and lymphoid progenitors.
• Source: Produced by activated T cells and mast cells.

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 Interleukin-6 (IL-6):
• Function: Has a broad role in stimulating
hematopoiesis, especially in promoting the production
of platelets by megakaryocytes.
• Source: Produced by T cells, macrophages, and
endothelial cells.
 Thrombopoietin (TPO):
• Function: Stimulates the production and maturation of
platelets from megakaryocytes.
• Source: Primarily produced by the liver and kidney.
 Stem Cell Factor (SCF):
• Function: Essential for the survival, proliferation, and
differentiation of hematopoietic stem cells.
• Source: Produced by stromal cells in the bone marrow.
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 Cytokines in Immunotherapy
Cytokines play a significant role in immunotherapy by leveraging the
immune system to treat diseases, particularly cancer.
Types of Cytokines in Immunotherapy include
• Interleukins
1. IL-2: it promotes the proliferation and activation of T cells and
NK cells. High-dose IL-2 therapy has been used to treat
metastatic renal cell carcinoma and melanoma.
2. IL-7: Supports the survival and expansion of T cells, making it
useful in restoring immune function in immunodeficient
patients.
3. IL-12: Enhances the cytotoxic functions of T cells and NK cells
and promotes Th1 responses. It is being investigated for its
potential to boost anti-tumor immunity.

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Interferons
1.IFN-α: Used to treat certain cancers (e.g. melanoma,
renal cell carcinoma) and viral infections (e.g.
hepatitis B and C). It boosts the immune response and
has direct anti-proliferative effects on tumor cells.
2.IFN-γ: Enhances the killing activity of macrophages
and promotes antigen presentation, making it useful in
certain cancer therapies and chronic infections.
Tumor Necrosis Factor (TNF)
TNF-α: Has potent anti-tumor effects (but its systemic
toxicity limits its use). It has been used for treating limb
sarcomas and melanomas.

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Colony-Stimulating Factors (CSFs)
1.Granulocyte-Macrophage CSF (GM-CSF): main
function is to stimulates the production and
activation of granulocytes and macrophages. Used to
enhance the immune response in cancer vaccines
and to recover bone marrow function after
chemotherapy.
2.Granulocyte CSF (G-CSF): Used to stimulate the
production of neutrophils, helping to prevent
infections in patients undergoing chemotherapy.

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• Aldesleukin
• Anakinra
• Oprelvekin
• Efineptakin alfa
• Palifermin
• Epoetins

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