Congenital Immunodeficiency disorders

Dr. Ashok Kumar

 Immunodeficiency disorders

➨ Immunodeficiency:
➱ Quantitative or qualitative defects of the immune system

➱ May involve defects in


B cells

T cells

Complement

Phagocytic cells
➨ Associated with an increased susceptibility to infections,
and cancer development.
 Immunodeficiency disorders

➨ Two types:
1. Congenital Immunodeficiency disorders
2. Acquired immunodeficiency disorders (most
common):
1. AIDS**
2. Due to chemotherapy, radiation, etc
3. Diabetes
CONGENITAL Immunodeficiency Disorders
 Congenital Immunodeficiency disorders

A. B cell disorders:
1. X linked Bruton’s agammaglobulinemia*
2. IgA deficiency*
3. Common variable immunodeficiency
B. T cell disorders:
1. DiGeorge syndrome**
C. Combined B and T cell disorders
1. Severe combined immunodeficieny (SCID)**
2. Wiskott-Aldrich syndrome**
D. Defects in complement
E. Defects in phagocytic cells (neutrophils)
 B cell disorders

Result in recurrent bacterial infections

(esp. encapsulated bacteria)
 X linked Brutons agammaglobulinemia:
➱ Affects boys (X-linked disease)
➱ Due to mutation of B cell Btk (Bruton tyrosine kinase)
Failure to assemble complete immunoglobulin molecules
➱ Agammaglobulinemia: Absent or markedly decreased all
classes of immunoglobulins (Igs).
➱ Clinical findings: after 6 months age (maternal IgG ab
protective up to 6 months after birth)
➱ Recurrent encapsulated bacterial infections
(S.pneumoniae) of upper and lower respiratory tract
infections: Otits media, pharyngitis, pneumonia, bronchitis
 IgA deficiency
➨ MC congenital immunodeficiency (1 in 850 people)
➨ Failure of IgA B cells to mature into plasma cells
➨ Clinical findings: Mucosal secretions passages infections
➨ Respiratory, gastrointestinal, and urogenital tract
➱ recurrent Sinusitis, and pulmonary infections

➱ recurrent Urinary infections, and Diarrhea

➱ Giardiasis

➱ ↓ IgA and secretory IgA

➱ Rarely, Anaphylaxis if exposed to blood products

that contain IgA (patient’s IgG against donor’s IgA)

 Common variable immunodeficiency
➨ Is characterized by defect in B cell maturation to plasma cell resulting
in hypogammaglobulinemia.
➨ Mutations in signal transduction for B cell activation (CD19, CD20,
CD21, CD80 ) is the cause.
➨ Clinical findings: Boys and girls affected equally
➱ Onset is in late childhood

➱ Recurrent bacterial (pyogenic) Sino-Pulmonary, and GIT infections

➱ ↓ Immunoglobulins

➨ Complications:
➱ Increased susceptibility to develop autoimmune diseases


(ITP and AIHA)
➱ Increased risk of lymphoma and gastric cancer.
 T cell disorders

Recurrent infections caused by

intracellular pathogens (Fungi, viruses
and protozoa)
 DiGeorge syndrome
➨ Embryologic Failure of third and fourth pharyngeal
pouches to develop resulting in
➱ Absence of thymus and parathyroid glands, plus

➱ Abnormalities of mandible, ear and aortic arch

➨ Clinical findings:
➨ T cell deficiency
➱ Recurrent infections with viral and fungal

organisms (Pneumocystis jirovecii)

➱ Absent thymic shadow on radiograph

➨ Tetany: Hypoparathyroidism with hypoclacemia

 DiGeorge syndrome
➨ Can be summed up by the acronym:

➱ CATCH 22

Cardiac defects

Abnormal facies

Thymic hypoplasia

Cleft palate

Hypocalcemia

Microdeletion of chromosome 22
Combined B and T cell disorders

Recurrent infections caused by

bacterial, viral and fungal pathogens.
 Combined B and T cell disorders

➨ Includes:
➱ Severe combined immunodeficiency (SCID)

➱ Wiskott-Aldrich syndrome
 Severe combined immunodeficiency (SCID)
➨ Characterized by marked deficiency of both B and T
lymphocytes
➨ Manifests as profound lymphopenia and severe defect in both
humoral and cell mediated immunity.
Types:
1. X-linked: mutation in the common γ-chain (γc) subunit of
cytokine receptor. mostly Boys affected.
2. ADA deficient: Adenosine deaminase (ADA) deficiency Results
in accumulation of deoxyadenosine and deoxy ATP  toxic to
lymphocytes
3. RAG-deficient: Recombinase-activating genes
 Severe combined immunodeficiency (SCID)
➨ Clinical features:
➱ Defective cell mediated immunity and decreased

immunoglobulins results in

Severe infections (bacterial, viral and fungal)
➱ Failure to thrive, usually with fatal outcome in infancy

➨ Treatment:
➱ Gene therapy

➱ Bone marrow

transplant

Bubble-boy disease
 Wiskott –Aldrich syndrome
➨ X-linked recessive disorder, mutations in WAS gene.
➨ Characterized by triad of:
➱ Eczema, thrombocytopenia (bleedings) and

recurrent infections
➱ predilection to develop lymphoma

➱ Progressive deletion of B and T cells results in

➱ Defective cellular and humoral immunity

➱ Decreased Serum IgM, but increased IgE and IgA

Complement System Disorders
 Complement System Disorders

1. Hereditary angioedema
2. C2 deficiency
3. C6-C9 deficiency
4. Paroxysmal nocturnal hemoglobinuria
 Hereditary Angioedema

➨ Deficiency of C1 esterase inhibitor

➨ Continued C1 activation  increases cleavage
of C2 and C4 products (mainly C2a and C2b) 
have anaphylotoxic activity (increased vascular
permeability and vasodilation)
➨ Swelling of face and oropharynx
➨ Decreased C2 and C4 (as these are cleaved)
➨ Normal C3
NORMAL EXPERIENCING AN EPISODE

Hereditary angioneurotic edema

EDEMA IS DUE TO EXCESSIVE C2-KININ (from C2b)
(Not due to excessive activity of C3 & C5 convertases)
 C2 Deficiency

➨ Most common complement deficiency

➨ Associated with:
➨ Serious infections with encapsulated
organisms and Septicemia
➨ Autoimmune condition: Lupus-like syndrome in
children
 C6-C9 deficiency

➨ Increased susceptibility to disseminated

Neisseria gonorrhoeae and N. meningitidis
infections.
 Paroxysmal nocturnal hemoglobinuria (PNH)
➨ Acquired somatic mutation PIG-A in a multipotent hematopoietic stem
cell (HSC) = Deficient protein GPI (glycosylphosphatidylinositol).
➨ Absence of GPI results in absence of DAF (CD55, CD59).
➨ DAF normally degrades C3 and C5 convertase on hematopoietic cell
membranes.
➨ Due to DAF absence, C3 & C5 convertase produces complement
products, which cause intravascular lysis of RBCs (hemoglobinuria),
platelets and neutrophils.
➨ Blood cells lack CD55 and CD59 (due to lack of anchor GPI).
➨ Age of onset of the clinical disease is the early 30s, although it can
present at all ages. 
Paroxysmal Nocturnal Hemoglobinuria due to:
absent GPI, which results in absence of DAC (CD55, CD59).
Normally, DAF inhibits C3 convertase.
 Hereditary Defects in NEUTROPHILS
➨ Result in impaired acute inflammatory response.
1. CGD (Chronic granulomatous disease of childhood) =
X-linked; absent NADPH oxidase; Catalase+ infections;
NBT dye test negative
2. MPO (Myeloperoxidase) deficiency Absent HOCL;
Mild effect; Candida infection
3.Chediak-Higashi syndrome LYST protein
deficiency; Albinism, bleeding, infection
4. Leukocyte adhesion deficiency Delayed
umbilical cord separation, severe gingivitis, poor
wound healing. Types: LAD1 (beta 2 integrins), LAD2
(sialyl Lewis X), LAD3 (Kindlin)
Chronic granulomatous disease of childhood
(CGD)

➨ X linked, recessive dis. chr. by absence of

NADPH oxidase activity.
➨ Marked by phagocytic cells that ingest but do
not kill certain microorganisms.
Chronic Granulomatous Disease.
Skin suppurative infection, and
A suppurative granuloma in the lung from a child with recurrent bacterial
infections.
 Chronic granulomatous disease…
➨ Catalase positive (S.aureus) organisms infection: ingested but not killed.
➱ Enzyme deficient Neutrophils can not produce H2O2.
➱ Bacterial H2O2 destroyed by bacterial catalase.
➱ H2O2 not available as a substrate for MPO
➱ MPO-halide system of bacterial killing fails.
➱ Respiratory burst : Nitroblue tetrazoliun (NBT) dye test
negative
➨ Catalase negative (Streptococci) organisms: ingested and killed, as
Streptococci produce sufficient H2O2 to permit MPO-halide system to
proceed.
 Chronic granulomatous disease…

➨ Clinically characterized by severe infections

involving:
➱ Lungs, skin, visceral organs and bones

➨ Histologically characterized by:

➱ Granulomatous inflammation

➱ Nitroblue tetrazolium dye screening test (NBT

Test) is negative.
 Myeloperoxidase (MPO) deficiency

➨ Autosomal recessive disorder

➨ Differs from CGD in that both
➱ Superoxide and H2O2 are produced (normal

respiratory burst)
➨ However absence of MPO
➱ prevents synthesis of HOCl

➨ Infections with candida

➨ Usually little clinical consequence.
 Chediak-Higashi syndrome
➨ AR disease affecting multiple systems in the body.
➨ It is caused due to defects in the lysosomal transport protein
LYST, encoded by the gene CHS1 at 1q42.
➨ It is characterized by:
➱ Defective fusion of phagosome and lysosome in phagocytes 

repeated infections
➱ Abnormalities in


Melanocytes  albinism

Cells of nervous system  nerve defects

Platelets  bleeding disorder
➨ Neutrophils contain giant granules (abnormal phagolysosome
fusion)
 Chediak-Higashi syndrome
Patients present with:
Albinism, prolonged bleeding time, peripheral
neuropathy & a tendency to develop repeated infections.

Giant lysosomes
 Leukocyte adhesion deficiency
LAD type 1: defective synthesis of integrins LFA-1 and Mac-1 (beta
2 integrins).
LAD type 2: Absence of sialyl Lewis X on neutrophils.
LAD type 3: defect in Kindlin, involved in activating the ligand
affinity of β2 integrins.

➨Clinicalfindings
➱ Delayed separation of the umbilical cord (>1 month) as
Neutrophil enzymes are important in cord separation.
➱ Severe gingivitis, poor wound healing, peripheral blood
neutrophilic leukocytosis
Leukocyte adhesion deficiency

Neutrophil count in blood  high

Margination pool is low
 Defects in leukocyte function
Disease Defect
Genetic
1. LAD-1 Beta 2 integrin
2. LAD-2 Sialyl Lewis X
3. LAD-3 Kindlin
4. CGD NADPH oxidase
5. MPO deficiency Absent MPO
6. Chediak-Higashi Chemotaxis &
syn degranulation

Acquired
1. DM, sepsis Chemotaxis
2. DM, alcoholism Adhesion
SELF STUDY:
Free Radicals

Glucose-6-phosphate dehydrogenase is required for the production of NADPH, an essential component of

the NADPH oxidase system (1). The phagocyte NADPH oxidase system generates O - 2 by transferring e- from
NADPH to O2 (2). Superoxide is metabolized to H2O2 by superoxide dismutase (3). H2O2 can follow different
metabolic pathways inside the cell. Myeloperoxidase can convert it into HOCl (4), which is involved in the
oxygen-dependent killing of microorganisms in combination with other reactive oxygen species (5).
Alternatively, hydrogen peroxide can be degraded to H 2O and O2, thereby avoiding deleterious effect on the