IMMUNODEFICIENCY

ASAD ALI
Lecturer (RMU)
MS (COMSATS University)
BS Hons (RMU)
 IMMUNODEFICIENCY

• Immunodeficiency is a state in which the ability of immune system is compromised

or entirely absent to fight against infectious diseases and cancer.
• It can be specific or non-specific
• Specific > Abnormalities of B & T cells
• Non-specific > Abnormalities of complement system and phagocytes
• Recurrent Infections with Pyogenic Bacteria indicate B-cell deficiency whereas
Infections with certain fungi, viruses or protozoa indicate T-cell deficiency
 TYPES OF IMMUNODEFICIENCY

IMMUNODEFICIENCY

Congenital/Primary/Hereditary Acquired/Secondary
 IMPORTANT CONGENITAL DEFICIENCIES

1.Wiskott-Aldrich Syndrome
1.Hereditary Angioedema
2.Ataxia-Telangiectasia
T-cell 2.Recurrent Infections
3.Thymic Aplasia
4.Cytokine Signaling Defects
Complement 3.Autoimmune Diseases
5.IL-12/γ-IFN or Their Receptor Deficiency 4.Paroxysmal Nocturnal Hemoglobinuria

1.Chronic Granulomatous Disease

Combined B 2.Chediak-Hegashi Syndrome
& T cell • Severe Combined Immunodeficiency 3.Job’s Syndrome
(SCID) Phagocytes 4.Leukocyte Adhesion Deficiency Syndrome
Deficiencies 5.MPO Deficiency
6.IFN-γ Receptor Deficiency

1.X-linked Hypogammaglobulinemia Pattern-Recognition 1.Surface Receptor Deficiency

2.Selective Immunoglobulin Deficiencies
B-cell 3.Hyper IgM Syndrome
Receptor
2.Cytoplasmic Receptors Deficiency
4.Common variable immunodeficiency
Deficiency
 T-CELL DEFICIENCIES

• Congenital T-cell deficiencies tend to be the most severe and easily recognized
immunodeficiency.
• Absence of T cells results in a broad range of unusual opportunistic infections (i.e., viruses,
bacteria, fungi, and protozoa that are rarely seen in healthy hosts)
• They are also usually associated with some degree of B-cell deficiency.
• Severe T-cell deficiency is not compatible with life; without a hematopoietic stem cell transplant
 T-CELL DEFICIENCIES

1. Wiskott-Aldrich Syndrome (WAS)

• Rare X-linked recessive disease characterized by eczema,

thrombocytopenia (low platelet count), immune deficiency, and
bloody diarrhea (secondary to the thrombocytopenia)
• Symptoms appear during the first year of life
• Mutation in WASp gene that results in the defect in actin
filament assembly that is important or the T cells to respond to
antigen presentation. Therefore, T cells are unable to get
activated
• WASp is also involved in Platelets activation
• Platelets are small and malformed. The spleen removes and
destroys them, causing the platelet count to be low
A) Multiple face petechiae B) Eczema of the foot.
• The first signs are usually petechiae and bruising; Recurrent and a hematoma under the
bacterial infections develop by three months right eye
• Bone marrow transplantation may be helpful
 T-CELL DEFICIENCIES

2. Ataxia–Telangiectasia (A-T)
• Rare, neurodegenerative, Autosomal recessive disease, causing severe
disability.
• Ataxia refers to poor coordination and telangiectasia to small dilated
blood vessels (conjunctivas & skin)
• Caused by mutations in the ATM gene that encode DNA repair enzymes
• A–T affects many parts of the body:
• Impairs cerebellum, causing difficulty with movement and coordination
• Lymphopenia with predisposition to infections as DSBs are not repaired after DNA
recombination; level of Ig is considerably reduced especially IgA
• Increased risk of cancer
• Blood tests to measure the levels of IgA and genetic tests can help confirm the
diagnosis
• Treatment designed to correct the immunodeficiency has not been successful
 T-CELL DEFICIENCIES

3. Thymic Aplasia (DiGeorge’s Syndrome)

• Both the thymus and the parathyroids fail to develop properly

• Caused by defect in the third and fourth pharyngeal pouches
due to deletion of a small segment of chromosome 22
• Severe viral, fungal, or protozoal infections occur in affected
infants early in life as a result of a profound deficit of T cells
• The most common presenting symptom is TETANY due to
hypocalcemia caused by hypoparathyroidism.
• Severe pyogenic infections can occur if accompanied by
decreased antibody production
• Transplant of fetal thymus may reconstitute T-cell immunity
Special Facial Features
 T-CELL DEFICIENCIES

4. Cytokine Signaling Defects

• Patients with defects in specific cytokines or their

receptors have increase susceptibility to specific
organisms. For example
• Patients with Chronic Mucocutaneous Candidiasis
have persistent or recurring infection with Candida
that are limited to mucosal surfaces, skin, and nails
• All other T-cell and B-cell functions are normal
except that there is deficiency specifically of IL-17
or IL-17R.
• Treatment consists primarily of antifungal drugs
 T-CELL DEFICIENCIES

5. IL-12/γ-IFN or Their Receptor Deficiency

• Patients with these deficiencies have disseminated

Mycobacterial infections
• The absence of the receptor prevents IL-12 from
initiating a Th-1 response, which is required to limit
Mycobacterial infections.
 COMBINED B & T-CELL DEFICIENCIES

Severe Combined Immunodeficiency Disease (SCID)/Bubble Boy Disease

David Vetter in Germ Free Bubble

• Group of rare disorders caused by mutations in different genes

involved in the development and function of infection-fighting
immune cells
• Also known as the Bubble boy disease because its victims are
extremely vulnerable to infectious diseases
• Recurrent infections caused by bacteria, viruses, fungi, and
protozoa occur in early infancy because both B cells and T cells
are defective
• Pneumocystis pneumonia and infections caused by C. albicans,
VZV, CMV, & RSC are common and fatal
 COMBINED B & T-CELL DEFICIENCIES

Severe Combined Immunodeficiency Disease (SCID)/Bubble Boy Disease

• Two Types
1. X-Linked (75%)
2. Autosomal (25%)

1. X-Linked
• Mutations in the gene encoding the common gamma
chain (γc), a protein that is shared by the Interleukin
receptors (IL-2 and IL-7)
• These interleukins and their receptors are involved in
the development and differentiation of T and B cells
• Mutation results in low or absent T cells and NK cells
and non-functional B cells
 COMBINED B & T-CELL DEFICIENCIES

Severe Combined Immunodeficiency Disease (SCID)/Bubble Boy Disease

2. Autosomal
• Mutation in number of genes can lead to SCID
1. Mutation in genes encoding ZAP70 (tyrosine kinase) and Janus Kinase 3 >> Signal Transduction
proteins
2. Mutation in the RAG-1 or RAG-2 genes >>
• Involved in DNA Recombination necessary to generate TCR & IgM on B-cells
3. Hereditary absence of Adenosine Deaminase (ADA) & Purine Nucleoside Phosphorylase (PNP)
• Enzymes that recycle nucleotides for DNA synthesis >> decrease dNTPs >> Consequent decrease of B &
T-cells
• Bone marrow transplantation can be helpful; Injection of ADA reduce severity;
 COMBINED B & T-CELL DEFICIENCIES

1. Severe Combined Immunodeficiency Disease (SCID)/Bubble Boy Disease

2. Autosomal
4. Bare Lymphocyte Syndrome (BLS)
• Caused by mutations in certain genes of the major T-cell
histocompatibility complex or genes involved with the
processing and presentation of MHC molecules
• Patients have defective class I or class II MHC proteins or
both, unable to present antigens to T-cells
• Sign & Symptoms similar to SCID
• Blood tests are done to measure the number and
functioning of B and T cells
• Genetic tests to identify the specific mutation
• Patients kept in a Sterile environment to prevent exposure
to possible infections APC
• Only effective treatment is transplantation of stem cells
 B-CELL DEFICIENCIES

• Congenital deficiencies in the number or function of B cells cause low or absent

antibody levels
• Patients with these deficiencies are protected from infections by maternal antibody
until the age of 6 to 12 months, at which point they begin to have recurrent Bacterial
infections
• These infections are often in the oropharynx and respiratory tract, including sinusitis,
otitis, and pneumonia, as these are the sites protected by antibody
 B-CELL DEFICIENCIES

1. X-Linked Hypogammaglobulinemia (Bruton’s Agammaglobulinemia)

• Very low levels of all immunoglobulins (IgG, IgA,

IgM, IgD, and IgE) and a virtual absence of B cells
• Pre-B cells are present, but they fail to differentiate
into B cells
• Mutation in the gene encoding Tyrosine kinase
(important signal transduction protein)
• Cell-mediated immunity is relatively normal
• Recurrent pyogenic bacterial infections occur in
infants at about 6 months of age
• Treatment with pooled gamma globulin reduces the
number of infections
 B-CELL DEFICIENCIES

2. Selective Immunoglobulin Deficiencies

• It results in a low level of one class of antibody, but levels of other immunoglobulins are
normal.
• IgA deficiency is the most common caused by failure of heavy chain gene switching
• Patients with a deficiency of IgA typically have recurrent sinus and lung infections
• IgA deficient patients should not be treated with gamma globulin preparations??
• IgM/IgG deficiencies are rarer but can lead to recurrent Sinopulmonary infections caused
by pyogenic bacteria such as S. pneumoniae, H. influenzae, or Staphylococcus aureus.
 B-CELL DEFICIENCIES

3. Hyper-IgM Syndrome
• Hyper-IgM syndrome is an immunoglobulin (Ig) deficiency
characterized by elevated serum IgM levels and decreased
levels or absence of other serum immunoglobulins (IgG, IgE,
IgA), resulting in susceptibility to bacterial infections
• Caused by Mutation is in the gene encoding the CD40 ligand
(CD40L) in the CD4-positive helper T cells.
• The failure to properly interact with CD40 results in an
inability of the B cell to switch from the production of IgM to
the other classes of antibodies
• Severe, recurrent pyogenic bacterial infections resembling
those seen in X-linked hypogammaglobulinemia begin early in
life
• Treatment with pooled gamma globulin results in fewer
infections
 B-CELL DEFICIENCIES

4. COMMON VARIABLE IMMUNODEFICIENCY

• Characterized by recurrent infections, caused by pyogenic bacteria and low antibody levels,
specifically of IgG type
• "Variable" refers to the heterogeneous clinical manifestations of this disorder, which include
recurrent bacterial infections, increased risk for autoimmune disease and lymphoma, as well as
gastrointestinal disease
• The cause of CVID is poorly understood But it may results from functional defects in helper T
cells rather than in B cells
• Intravenous gamma globulin given monthly reduces the number of infections.
 COMPLEMENT DEFICIENCIES

1. HEREDITARY ANGIOEDEMA

• This is an uncommon autosomal dominant disease caused by a

deficiency of C1 inhibitor
• In the absence of inhibitor, C1 continues to act on C2 & C4 to
generate C2a/C4a and subsequently additional vasoactive
components such as C3a and C5a
• This leads to capillary permeability and edema in several organs
• The skin of the face, normally around the mouth, and the mucosa
of the mouth and/or throat, as well as the tongue, swell over the
period of minutes to hours
• The diagnosis is made on the clinical picture
 COMPLEMENT DEFICIENCIES

2. RECURRENT INFECTIONS

• Patients with deficiencies in C1, C3, or C5 or the later

components C6, C7, or C8 have an increased susceptibility to
bacterial infections.
• Patients with C3 deficiency are particularly susceptible to sepsis
with pyogenic bacteria such as S. aureus.
• Those with reduced levels of C6, C7, or C8 are especially prone
to bacteremia with Neisseria meningitidis or Neisseria
gonorrhoeae
 COMPLEMENT DEFICIENCIES

3. AUTOIMMUNE DISEASES

• Primary deficiency of C1, C2 or C4 is closely linked to development of

systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA)
• Deficiency of C2 is most common
• Underlying mechanism is thought to be due in part to the inability of
complement to clear immune complexes
 COMPLEMENT DEFICIENCIES

4. PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

(PNH)

• Rare disease is characterized by episodes of brownish urine

(hemoglobinuria), particularly upon arising
• Hemoglobinuria is due to complement-mediated hemolysis
• Caused by deficiency of GPI anchor for CD59 protein in
the cell membrane of RBCs, leading to an increased
activation of complement
• Hemolysis occur especially at night because the lower
oxygen concentration in the blood during sleep
• There is no specific treatment; Iron can be given for the
anemia
 PHAGOCYTE DEFICIENCIES

CHRONIC GRANULOMATOUS DISEASE (CGD)

• Hereditary diseases in which certain cells of the immune system have

difficulty forming the reactive oxygen compounds (most importantly
the superoxide & H2O2 radical) used to kill certain ingested pathogens.
This leads to the formation of granulomas in many organs
• Defect in the intracellular microbicidal activity of neutrophils as a
result of a lack of NADPH oxidase
• Patients with this disease are very susceptible to opportunistic
infections with certain bacteria (esp. Catalase positive) and fungi
(e.g,S. aureus); enteric gram-negative rods, especially Serratia and
Burkholderia; and Aspergillus fumigatus
• Diagnosis can be confirmed by Nitroblue tetrazolium (NBT) dye
reduction test or DCF test
• Prompt, aggressive treatment of infection with the appropriate
antibiotics is important
 PHAGOCYTE DEFICIENCIES

2. CHÉDIAK-HIGASHI SYNDROME

• Rare autosomal recessive disorder

• Caused by mutation in a gene that results in failure of the lysosomes of neutrophils to fuse with
phagosomes
• Degradative enzymes are not available to kill the ingested organisms.
• Patients suffers from recurrent pyogenic infections, caused primarily by Staphylococci & Streptococci
• Genetic testing is done to diagnose the disease
• Treatment involves Antimicrobial drugs
 PHAGOCYTE DEFICIENCIES
3. LEUKOCYTE ADHESION
DEFICIENCY SYNDROME
(LAD)
• Rare Autosomal Recessive disorder
characterized by pyogenic infections
• Caused by defective adhesion proteins
LFA-1 present on the surface of
phagocytes
• Defective adhesion results in inadequate
phagocytosis of Bacteria
4. CYCLIC NEUTROPENIA
(CYN)
• Rare Autosomal Dominant disorder
characterized by recurrent episodes of
abnormally low levels of neutrophils,
<200/µl (3 to 6 days of a 21-day cycle)
• During the neutropenic stage, patients are
susceptible to life-threatening bacterial
infections
• Caused by Mutation in the gene encoding
neutrophil elastase with Increased apoptosis
of neutrophils
• Still unclear how it contributes to cyclic
nature
 PATTERN-RECOGNITION RECEPTOR (PRR) DEFICIENCY
1. RECEPTORS ON THE
SURFACE OF INNATE IMMUNE
CELLS
• Deficiency of Toll-like receptor-5 (TLR-5)
results in a failure to recognize flagellin on
bacteria and a marked susceptibility to
Legionella infections. This deficiency is
quite common.
• Deficiency of MBL results in a failure to
activate complement, leading to severe
infections by gram-negative bacteria such as
Neisseria
2. RECEPTORS WITHIN INNATE
IMMUNE CELLS
• NOD receptors in the cytoplasm recognize the
peptidoglycan of gram-positive and gram-
negative bacteria.
• Deficiency of NOD-2 results in a defect in gut
immunity that is involved in the pathogenesis of
Crohn’s disease.
• RIG helicase receptors recognize viral double-
stranded RNAs.
• Deficiency of these receptors results in a reduced
interferon response to various viruses (i.e.,
influenza virus)
 ACQUIRED IMMUNODEFICIENCIES

1. Common Variable
1.Liver Failure
B-cell Hypogammaglobulinemia
2. Malnutrition
Complement
2.Malnutrition

1. Acquired Immunodeficiency
1. Neutropenia
T-cell Syndrome (AIDS)
2. Measles
Phagocytes 2. Chronic Fatigue Syndrome
 B-CELL DEFICIENCIES

1. Asplenia 2. Malnutrition

• Severe malnutrition can reduce the

• Patients with Splenectomy (Malignancy, supply of amino acids and thereby
Splenic Puncture) and functional Asplenia
(Sickle Cell Disease) have poor antibody
reduce the synthesis of IgG.
response to new antigens. • This predisposes to infection by
• Patients are predisposed to pneumococcal pyogenic bacteria
sepsis & babesiosis caused by B.microti
 T-CELL DEFICIENCIES

ACQUIRED IMMUNODEFICIENCY SYNDROME

(AIDS)

• Chronic, potentially life-threatening condition caused by the human immunodeficiency virus

(HIV)
• Patients with AIDS present with opportunistic infections caused by certain bacteria, viruses,
fungi, and protozoa
• This is due to greatly reduced helper T-cell numbers caused by infection with HIV
• HIV specifically infects and kills cells bearing the CD4 protein as a surface receptor
• HAART is given to increase life span of patients
 T-CELL DEFICIENCIES

MEASLES

• Patients with this disease have transient suppression of CMI, manifested by loss of PPD
reactivity
• TB can reactivate in these patients
 COMPLEMENT DEFICIENCIES

1. LIVER FAILURE 2. MALNUTRITION

• Severe malnutrition can reduce the supply of

• Liver failure caused by alcoholic cirrhosis or by amino acids and thereby reduce the synthesis of
chronic hepatitis B or hepatitis C can reduce complement proteins by the liver.
the synthesis of complement proteins by the
liver to a level that can result in severe • This predisposes to infection by pyogenic
pyogenic infections bacteria.
 PHAGOCYTE DEFICIENCIES

1. NEUTROPENIA

• Patients with neutropenia present with severe infections caused by pyogenic bacteria
• Neutrophil counts below 500/μL predispose to these infections
• Common causes of neutropenia include
• Cytotoxic drugs, such as those used in cancer chemotherapy;
• Leukemia, in which the bone marrow is “crowded out” by leukemic cells
• Autoimmune destruction of the neutrophils