PRIMARY IMMUNODEFICIENCIES

DISORDERS OF SPECIFIC IMMUNITY

Classification

A. Humoral immunodeficiencies (B cell defects)

1. X – linked agammaglobulinemia

2. Common variable immunodeficiency

3. Hyper IgM syndrome

B. Cellular immunodeficiency

1. Chronic mucocutaneous candidiasis

2. (DiGeorge’s syndrome) Thymic hypoplasia

C. Combined immunodeficiencies (B and T cell defects)--SWAIN

1. Severe combined immunodeficiency

2. Wiskott-Aldrich syndrome

3  Ataxia telangiectasia

4  Immunodeficiency with thymoma.

5. Nezelof syndrome

X-Linked Agammaglobulinemia (Bruton Disease)

1.     Cause: Mutation in tyrosine kinase.

2.     Inheritance: X-linked recessive.

3.     Clinical feature: Recurrent bacterial infection in childhood, chronic giardiasis.

4.     Diagnosis: Absent or decreased B cells, absent plasma cells, decreased Ig in serum.

5.     Treatment: IV gammaglobulin.

Common Variable Immunodeficiency

·        Defective humoral immunity due to lack of differentiation of B cells.

·        Clinical feature: Same as Bruton disease, onset is late, chronic giardiasis.

·        Diagnosis: Normal B cells but absent plasma cells.

·        Others: Increased chance of autoimmune diseases (hemolytic anemia, pernicious anemia) and lymphoid tumors.

Isolated IgA Deficiency

·        Most common of all the primary immunodeficiencies.

·        Clinical feature: Usually asymptomatic, chronic sinopulmonary infection and diarrhea.

Hyper-IgM Syndrome

·        Cause: Mutations in CD40L or CD40, resulting in defective isotype switching.

·        Inheritance: Usually X-linked.

·        Diagnosis: Normal or increased IgM but lack of IgG, IgA or IgE isotypes.

Severe Combined Immunodeficiency

·        Defects in both humoral and cell-mediated immunity.

·        Cause: X-linked – cytokine (IL-7) receptor mutation

·        Autosomal recessive – adenosine deaminase deficiency–the most common enzyme deficiency.

·        Clinical feature: Recurrent infection.

·        Treatment: Bone marrow transplantation.

Wiskott-Aldrich Syndrome

1.     There is loss of cellular as well as humoral immunity.

2.     Clinical feature: Characterized by thrombocytopenia, eczema and recurrent infection.

3.     Inheritance: X-linked.

4.     Diagnosis:

a.     Decreased T cell and defective cellular immunity,

b.     Defective antibody formation to polysaccharide (encapsulated organisms),

c.      Decreased IgM but IgG, IgA are normal or increased,

d.     IgE is also increased,

e.     Decreased ratio of CD4:CD8 cells,

f.       Small platelets in peripheral smear.

5.     Treatment: Bone marrow transplantation.

Thymic Hypoplasia (DiGeorge’s Syndrome)

1.     Cause: Deletion of chromosome 22q11.

2.     Clinical feature: Thymic hypoplasia leads to deficient T cell maturation → increased viral, fungal and protozoal infection.

3.     Parathyroid hypoplasia → hypocalcemic tetany.

4.     It is associated with Fallot’s tetralogy and other congenital anomalies and a characteristic facial appearance.

Nezelof Syndrome

1.     Depressed cell mediated immunity is associated with selectively elevated, decreased or normal levels of immunoglobulin.

Immunodeficiency with Thymoma Spindle cell thymoma

associated with hypogammaglobulinemia, impaired cell mediated immunity and aplastic anemia.

INHERITED DISORDERS OF PHAGOCYTIC FUNCTION

Classification

a. Defective adhesion – leukocyte adhesion deficiency

b. Defective chemotaxis –

1.     Shwachman’s disease,

2.     Lazy leukocyteyndrome,

3.     Job’s syndrome,   

c. Defective microbicidal activity –

1.     Chronic granulomatous disease,

2.     Myeloperoxidase deficiency,

3.     Chediac-Higashi syndrome.

Leukocyte Adhesion Deficiency

Defect:

• Type 1 – defective synthesis of CD18 β-subunit of

leukocyte integrins LFA-1 and Mac-1.

• Type 2 – absence of Sialyl-Lewis X (selectin receptor

on endothelium).

Clinical feature:

• Type 1 – delayed separation of umbilical cord, recurrent

infection.

• Type 2 – severe mental retardation, short stature, Bombay blood group, recurrent infection.

Hyper IgE-recurrent Infection (HIE) or Job’s Syndrome

·        Clinical feature: Eczema, cold abscess, recurrent staphylococcal pneumonia,

·        coarse facies,

·        bony abnormalities,

·        serum IgE > 2000 IU/ml.

Myeloperoxidase Deficiency

• Most common neutrophil defect.

• Usually asymptomatic.

Chediac-Higashi Syndrome

1.     Defect: Reduced chemotaxis and phagolysosome fusion.

2.     Clinical feature: Recurrent pyogenic infections specially with Staphylococcus aureus.

3.     Oculocutaneous albinism, nystagmus, peripheral neuropathy, mental retardation.

4.     Diagnosis: Giant primary granules in neutrophils.

Chronic Granulomatous Disease

1.     60 percent X-linked, 40 percent autosomal recessive.

2.     Defect: Lack of one of four NADPH oxidase subunit → absent respiratory burst → decreased production of H 2 O 2 .

3.     Clinical feature: Recurrent infection with catalase positive pyogenic organisms like Staphylococcus aureus.

4.     Lymph node suppuration, granuloma formation which may obstruct GI tract or genitourinary tract.

5.     Diagnosis:

a.     NBT test (screening test)

b.     Absent superoxide and H 2 O 2  production by neutrophils.

Shwachman’s Disease

1.     Decreased neutrophil mobility,

2.     pancreatic malfunction,

3.     bone abnormalities.