IMMUNODEFICIENCY DISEASES

presented by
 Immunodeficiency

primary Secondary
 What is Immunodeficiency?
 A failing of one or more of the body’s defensive
mechanisms resulting in morbidity or mortality.
 Any part of the immune system can be deficient
cells, proteins, signalling mechanisms…….
 The body is susceptible to infection by organisms
that meet with little or no resistance.
 Or, in certain cases, other homeostatic systems in
the body will be disrupted by the defect.
 Severity is variable.
 Immunodeficiency may be Primary or Secondary.
 Primary or
Congenital
Immunodeficiency
 Secondary Immunodeficiency:

 Infection
 Renal failure, or protein losing enteropathy
 Leukaemia or Lymphoma
 Myeloma
 Extremes of age
 Certain Drug Therapies
 Clinical features associated with
immunodeficiency
Feature frequency present and highly
suspicious:
 Chronic infection
 Recurrent infection (more than expected)
 Unusual microbial agents
 Incomplete clearing of infection
 Incomplete response to treatment
Clinical features associated with
immunodeficiency
 Feature moderately suspicious
Diarrhea (chronic)
Growth failure
Recurrent abscesses
Recurrent osteomyelitis
 Feature associated with specific
immunodeficiency disorder
Telangiectasia
Partial albinism
IMMUNODEFICIENCIES
 SPECTRUM OF IMMUNE
RESPONSIVENESS
Protectiv Self-
e Toleranc
Immunity e
HEALTH
Immune
Positive Negativ
Respons e
e
DISEASE
AutoImmunity Immunodeficien
Hypersensitivity cy
Basten. In: The Autoimmune Diseases, Acad. Press, 1998
 Immunodeficiencies

Primary = hereditary Secondary = acquired

Due to genetic defects in the
production, maturation, or To infections (e.g. AIDS),
function of malnutrition, burns, ionizing
1. B cells radiation, immunosuppres-
2. T cells sive drugs (e.g. cortico-
3. Severe Combined Immune steroids, cytostatics), stress,
Deficiencies (SCID) – T + B alcohol, various other
defects illnesses in a previously
4. Phagocytes normal person
5. Complement
 Clinical Manifestations of
Immunodeficiency
1.Increased susceptibility
to infection:
> Humoral defects -
bacterial, viral, parasitic
> Cell mediated immunity
- viral, parasitic, fungal,
intracellular microbes
2.Increased incidence of Treatment: antibiotics, IgG
autoimmunity and injections, bone marrow or
malignancy fetal thymus transplantation,
gene therapy
,000
 When to suspect immunodeficiency
• >10 episodes of otitis • recurrent abscesses
media per year • autoimmunity in
• >2 episodes of children
consolidated pneumonia • dysmorphic features
per year with recurrent infections
• >2 life-threatening • Infections with unusual
infections such as organism (fungi
meningitis, sepsis [Aspergillus, Candida],
• >2 serious sinus Pneumocystis carinii),
infections in one year e.g. oral thrush
oral thrush = oral candidiasis
 Primary B-cell and
antibody deficiencies
Transient Hypoglobulinemia of Infancy
• As maternal IgG levels in the infant decline (age
3 – 6 mo), some infants fail to produce
adequate amounts of IgG.
• Infections may not be severe
• IV immunoglobulin is unnecessary
• Deficiency spontaneously resolves in 1st to 2nd
year of life. If does not resolve – consider
possible Bruton’s agammaglobulinemia or
class/sublass deficiency.
 Common Variable Immunodeficiency (CVID)
• The most prevalent primary immunodeficiency
• Heterogeneous, sporadic or familial syndrome
• Manifests at any time from infancy to after 40 y.o. (peaks of
onset in children aged 1-5 years and in persons aged 16-20
years).
• Normal to low peripheral B cells, but absence of plasma cells.
Variable low IgG, IgM, IgA
• Recurrent bacterial, viral, parasitic infections infections;
increased incidence of autoimmune disease and malignancy
• Various etiology - B cell defects, deficient T cell help, or
excessive suppressor T cell activity; often unknown
• Treatment - Ig replacement therapy or bone marrow transplant
 Bruton's agammaglobulinemia, or
X-linked agammaglobulinemia (XLA)
• Among the most common primary immunodeficiencies. Only boys (X-linked gene)
• Bruton's tyrosine kinase (BTK) gene defect
• In the absence of BTK, B lymphocytes do not differentiate or mature. Without mature
B lymphocytes, antibody-producing plasma cells are also absent. T cells normal.
• Recurrent pneumonias and other bacterial sinopulmonary infections, sepsis,
meningitis, and diarrhea
• Autoimmunity is common (RA-like illness).
 IgA Deficiency
• A very common congenital immunodeficiency (1 in
600-700); many patients unaware that they have
this disease.
• Autosomal inheritance
• Serum IgA is low.
• Clinically may be normal or may have pulmonary
and gastrointestinal infections
• Autoimmune diseases
• May react to IgA in transfusions (it is a non-self
protein to these patients), so need to avoid the
infusion of serum

Deficiencies of other classes (e.g. IgM) and

subclasses (e.g. IgG2 or IgG3) also occur, alone or in
combination
 X-linked Lymphoproliferative
Syndrome
• Rare defect in the immune response to
Epstein-Barr Virus (EBV)
• Leads to severe, often deadly,
mononucleosis, malignant lymphoma,
hypogammaglobulinemia
• Fail to make anti-EBV Ab, defective
cytokine production, low CD4/CD8 ratio
Primary T cell-mediated
deficiencies
• Defects in T cell maturation and
activation
• Mutations - absence of T cell receptor
chains (CD3 epsilon or gamma
chains), ZAP-70, reduced gamma-
interferon and IL-2 production or lack
of cytokine receptors.
DiGeorge’s Syndrome (Thymic Hypoplasia)
Sporadic disturbed
development of the 3rd
and 4th pharyngeal
pouches before the 8th
week of gestation –
deletion in 22
chromosome or non-
4 weeks gestation genetic (teratogens)
http://www.med.unc.edu/

6 weeks gestation
DiGeorge’s Syndrome (Thymic Hypoplasia)
Partial or complete loss of:
• the thymus - absent or
reduced T cells;
mycobacterial, viral, fungal
infections (severity depends
http://www.osel.cz/

on the degree of defect).

• parathyroids - tetany due to
hypocalciemia
• thyroid - hypothyroidism
Also craniofacial defects:
micrognathia (abnormally
small jaws, esp. the mandible),
hypertelorism (abnormal distance between two paired
organs), abnormal external ears; cardiovascular defects
(heart and great vessels); esophageal atresia: cognitive,
behavioral, and psychiatric problems. Treat with fetal thymic
transplant.
 Chronic Mucocutaneous
Candidiasis (CMC)
• T cell dysfunction specifically
against a yeast-like fungus
Candida albicans due to various
molecular defects
• Usually presents in infancy or
early childhood, with a mean
onset at 3 years, but adult onset
also reported
• Candidal infection of skin, nails,
and/or mucous membranes.
http://www.emedicine.com/DER
M/
 X-linked Immunodeficiency
with Hyper IgM
• Failure of
immunoglobulin
isotype switching
due to mutation of
CD40L gene on X
chromosome –
boys only
• Deficiency of all Ig
classes while
excess IgM due to
failure to switch
• Primary T cell
defect manifesting antibody deficiency
 Combined
Immunodeficiencies
often due to primary T helper defects
 Severe combined
immunodeficiency(SCID)
• Defective B and T cell maturation or
activation.
• Recurrent bacterial, fungal, protozoal
infections.
• All have abnormal T cell function, B cell
abnormalities are more variable.
 SCID - ”Bubble Boy Disease”
• X-linked
• Lack the common gamma chain (γc) which
is shared by the IL-2, IL-4, IL-7, IL-9, IL-
15, IL-21 receptors
• Reduced T cell numbers
• B cell numbers are not reduced
• Serum IgG is reduced
 SCID - ADA deficiency
• Adenosine deaminase deficiency
• Autosomal recessive
• Affects the purine salvage pathway resulting in
accumulation of deoxyadenosine and S-
adenohomocysteine. Toxic to lymphocytes.
• Reduced T and B cell numbers.
• Pseudochondrodysplasia-defect in cartilage
formation.
 SCID - Purine nucleoside
phosphorylase deficiency
• PNP is an enzyme involved in purine
metabolism, deficiency leads to accumulation of
deoxyguanosine and dGTP, both toxic to
immature T cells cells and to lesser extent to B
cells.
• Reduced T cell numbers.
• Reduced T cell mediated responses and Ab
production to T dependent antigens.
SCID - Reticular dysgenesis

• Defect at level of the stem cell, though

specific defect is unknown.
• T, B cells, granulocytes virtually absent.
• Patients rarely survive more then a few
days, and are commonly still-born.
• Has been successfully treated with bone
marrow transplantation.
SCID - Other Causes

• Bare Lymphocyte Syndrome-Deficient in either

MHC Class I or II expression
• JAK-3 mutations- few T cells, normal B cells
• Mutation in Rag-1 or Rag-2, resulting in failure of
Ig and TCR gene rearrangement
• Profound deficits in T and B cell numbers
secondary to the resulting developmental arrest
 Wiskott-Aldrich syndrome
(immunodeficiency, thrombocytopenia,
eczema)

• X-linked recessive (affects only boys) genetic

defect in a protein called Wiskott-Aldrich syndrome
protein (WASp)
• The gene is on the X chromosome; expression
limited to cells of hematopoetic origin. The protein
normally regulates actin cytoskeleton of
lymphocytes and platelets; participates in cell
growth, endocytosis, exocytosis, and cytokinesis.
Wiskott-Aldrich syndrome http://www.emedicine.com/ped

• Always a T-cell deficit, often also a B-cell

deficit; poor response to polysaccharide
antigens – susceptible to polysaccharide-
coated bacteria, e.g. Streptococcus
pneumoniae,

Haemophilus influenzae, Staphylococcus aureus.

• Often present with petechiae and ecchymoses of
the skin and oral mucosa, and bloody diarrhea;
recurrent infections (e.g. otitis media);
autoimmune disorders (autoimmune hemolytic
anemia, arthritis, nephritis)
Causes of death include recurrent infections
(immunodeficiency), bleeding (thrombocytopenia),
or malignancy (immunodeficiency). Rarely survive
 J Neurol Sci 2006, 241:1-6
Ataxia-Telangiectasia (A-T)
• Mutations in a gene encoding a protein kinase that
plays a key role in signaling and repair of DNA
damage (ATM - ataxia telangiectasia, mutated)
• Autosomal recessive
• Cerebellar atrophy and loss of function leading to
uncoordinated (ataxic) movements, choreoathetosis
(abnormal body movements), progressive dysarthria

Am J Ophthalmol 2002,
(speech defects), characteristic eye movement
abnormalities – become wheelchair-bound early in
life
• ocular telangiectasia (dilated blood vessels of the

134:891
eye), spider angiomas
Conjunctival
vascular
telangiectasia in
patients with A-T
(nasal and temporal
interpalpebral
conjunctiva).
 Ataxia-Telangiectasia (A-T)
• In addition to ataxia and
telangiectasias, the genomic
instability in the A-T patients
leads to extreme
EMBO Rep 2004, 2:772

radiosensitivity, sterility,
tumors, and
immunodeficiency
• Effects both T and B cells.
Decreased or absent IgA
leading to recurrent
respiratory infections,
although severe
infections are rare. Gamma-globulin bacterial
injections mayorbe
given to help supplementviral opportunistic
the weakened immune
system.
 Phagocytic Defects
phagocytes = neutrophils and
macrophages
 Characteristics
• Bacterial, fungal, viral and protozoal
infections
• Skin infections, chronic osteomyelitis
(Klebsiella/Serratia)
• Defective killing mechanisms, inability to
phagocytose, or reduced numbers of
phagocytes.
 Chronic Granulomatous Disease
• X-linked defect in phagocytic cells
• Mutations in phagocyte NADPH oxidase system
resulting in defective production of superoxide (O2-)
and peroxide (H2O2) that are normally involved in killing
bacteria (oxidative burst).
• Leukocytes fail to kill bacteria in vitro.
• Early onset - by 2 to 5 years of age.
• Severe recurrent fungal and bacterial infections,
frequently fatal.
• granulomas in the skin, GI tract, and genitourinary tract
 Chediak-Higashi Syndrome
• Microtubular and lysosomal defect of
phagocytes, resulting in defective
phagocytosis and lysosomal dysfunction
in lymphocytes, neutrophils, macrophages
• Recurrent pyogenic infections
(strep and staph)
• Platelet function is abnormal – prolonged
bleeding time, easy bruisability

• Hypopigmentation of the skin, eyes, and hair –

light blue eyes and very light blond hair
Leukocyte Adhesion Deficiency (LAD)
• Type I: defect in CD18 (beta 2 integrin) – loss of
expression on lymphocytes, macrophages, and
neutrophils
• Type II: defect in fucosyltransferase resulting in
the loss of the carbohydrate ligand for P-selectin
and E-selectin on leukocytes
• Leukocytes fail to traffic to sites of infection,
leading to infections, poor wound healing.
• Both are rare. Type I: patients succumb to
infections commonly before 2 years of age. Type
II: better survival, but have severe growth and
mental retardation, and neurological problems
 Job Syndrome
•Rare. Autosomal
dominant. Etiology
uncertain.
•Recurrent sinopulmonary
infections, skin infections,
deep sub-cutaneous
abscesses (reference to
biblical Job). Most
infections due to S. aureus.
•Very high levels of IgE – also called
“hyperimmunoglobulinemia E syndrome”
•Retained primary teeth, noneruption of
permanent teeth, double rows of teeth
with both primary and permanent
intermixed teeth