L23 - Immunodeficiency 2

• Congenital or Primary Immunodeficiencies

  Many congenital immunodeficiencies are the result of genetic abnormalities that cause blocks in maturation and activation of B-cells, T-cells or both
• Humoral Immunodeficiencies (B-cell defects)


  • X- Linked agammaglobulinema
  • Transient hypogammaglobulinemia of infancy
  • Late onset hypogammaglobulinema (Common variable immunodeficiency)
  • Selective immunoglobulin deficiencies (IgA, IgM or IgG subclasses)
  • Immunodeficiencies with hyper IgM
  • Transcobalamin II deficiency
• Cellular Immunodeficiencies (T cell defects)

  • Thymic hypoplasia (DiGeorge syndrome)
  • Purine nucleoside phosphorylase deficiency
  • Defective class II MHC expression (Bare lymphocyte syndrome)
• Combined Immunodeficiencies (Both B & T cell defects)

  • Cellular immunodeficiency with abnormal immunoglobulin synthesis
  • Ataxia – telangiectasia
  • Wiskott – Aldrich syndrome
  • Immunodeficiency with short limbed dwarfism
• Severe combined immunodeficiency diseases (SCID)

  • X- Linked SCID
  • Autosomal SCID
• Complement deficiency


  • Complement component deficiencies
• Thymic hypoplasia (DiGeorge syndrome)

  • A disorder caused by a defect in chromosome 22-q11
  • The immunodeficiency primarily involves cell mediated immunity
  • This is a developmental defect leads to aplasia or hypoplasia of the thymus & parathyroid glands
  • Thymus dependent areas of the lymph nodes & spleen are depleted of T cell & failure of T cell maturation
  • Antibody response to primary antigenic stimuli is normal but secondary response to many antigens is impaired
• DiGeorge syndrome


  • More frequent cleft lip/ palate
  • Small jaw
  • Small upper lip/mouth
  • Eyes slanted upward or downward
  • Abnormal folding of ears
  • Short stature, Undeveloped parathyroid & thymus
  • Cardiac malformations
• Infants with DiGeorge syndrome are extremely vulnerable to viral, fungal, intracellular bacterial and protozoan infections
• Deletion occurs in chromosome 22q11 – leads to developmental malformation affecting 3rd & 4th pharyngeal pouches in embryonic life
• Purine nucleoside phosphorylase (PNP) deficiency

  • PNP is known as a housekeeping enzyme
  • It clears away waste molecules that are generated when DNA is broken down
  • Mutations in the PNP gene – no activity of purine nucleoside phosphorylase
  • The resulting excess of waste molecules - deoxyguanosine triphosphate (dGTP)
  • The dGTP are toxic to lymphocytes
  • Immature lymphocytes in the thymus are particularly vulnerable to dGTP, which damages them and triggers their self-destruction (apoptosis)
• The enzyme PNP is involved in the sequential degradation of purines to hypoxanthine and finally to uric acid formation
• PNP deficiency


  an autosomal recessive inherited trait show decreased CMI
• PNP deficiency


  • Hypoplastic anaemia, Recurrent pneumonia, Diarrhea & candidiasis & widespread skin rashes
• Defective class II MHC expression (Bare lymphocyte syndrome)


  • It is a combined immunodeficiency resulting from the lack of expression of either class I or class II MHC molecules at the cell surface
  • The main clinical manifestations are infections of the respiratory or the digestive tract
  • The immunodeficiency involves the absence of antibody formation and the absence of cell-mediated response to specific antigen
• The mutation occurring in the gene(s) of chromosome 6
• The bare lymphocyte syndrome, type II (BLS II) & type I is a rare recessive genetic condition
• Cellular immunodeficiency with abnormal immunoglobulin synthesis

  • A marked deficiency of T cell immunity and varying degrees of deficiency of B cell immunity occurs in this condition
  • Abundant plasma cells are seen in the spleen, lymph nodes, intestines and elsewhere in the body
  • Patients are susceptible to all types of infection
• Ataxia telangiectasia


  • Ataxia-telangiectasia /AT syndrome or Louis–Bar syndrome
  • Rare, neurodegenerative, autosomal recessive disease causing severe disability
  • Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease
  • It impairs certain areas of the brain including the cerebellum, causing difficulty with movement and coordination
  • It weakens the immune system, causing a predisposition to infection
  • It prevents repair of broken DNA, increasing the risk of cancer
  • Majority of patients lack serum & secretory IgA and IgE deficiency is also frequent
  • CMI is also defective
• Wiskott-Aldrich syndrome


  • WAS is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea
  • The CMI undergoes progressive deterioration of lymph-nodes
  • Serum IgM level is low But IgG & IgA levels are normal and a reduced ability to form blood clots
  • Petechiae, bruising (resulting from a low platelet count), Spontaneous nose bleeds and bloody diarrhoea are common
  • Eczema develops within the first month of life
  • Recurrent bacterial infections develop by three months
• Lymphopenia with lymphotoxin


  • Profound depressions of T cell function by the action of a circulating complement dependent lymphotoxin
  • The toxin affects memory cells
  • So the patients lack immunological memory so secondary antibody response is abolished
  • The disease is familial
• Immunodeficiency with short limbed dwarfism


  • The features of this condition are a distinctive form of Short limbed dwarfism, Ectodermal dysplasia, Thymic defects and Enhanced susceptibility to infection
• Severe combined immunodeficiency diseases (SCID)

  • Several different genetic abnormalities causes severe combined immunodeficiencies (SCID)
  • About half of these are X- linked affecting only male children
• 1. Linked SCID


  • X-linked SCID are caused by mutations in a signalling subunit of a receptor for cytokines
  • The subunit receptor acts for numerous cytokines – IL2, IL-4, IL-7, IL-9 & IL-15
  • If no receptor subunit, the immature pro T & B cells cannot proliferate and mature
• Autosomal SCID


  • Caused by mutations in the enzyme - Adenosine deaminase (ADA)
  • It is involved in the breakdown of purine, the deficiency of ADA leads to accumulation of toxic purine metabolites in cells
  • Stop DNA synthesis in the actively proliferating mature B & T cells
• Disorders of Complement


  • Complement component deficiencies
• Complement component deficiencies have been frequently associated with SLE
• C1, C3, or C5 deficiencies in the cascade

  • Have an increased susceptibility to bacterial infections
• Patients with C3 deficiency

  • Are particularly susceptible to sepsis with pyogenic bacteria such as Staphylococcus aureus
• Those with reduced levels of C6, C7, or C8, which form the MAC


  • Are especially prone to bacteraemia
• Short limbed dwarfism


  • Distinctive form
  • Ectodermal dysplasia
  • Thymic defects
  • Enhanced susceptibility to infection
• Severe combined immunodeficiency diseases (SCID)

  Several different genetic abnormalities causes severe combined immunodeficiencies
• About half of SCID cases are X-linked affecting only male children
• 1. Linked SCID


  Caused by mutations in a signalling subunit of a receptor for cytokines
• 1. Linked SCID


  • Subunit receptor acts for numerous cytokines - IL2, IL-4, IL-7, IL-9 & IL-15
  • If no receptor subunit, the immature pro T & B cells cannot proliferate and mature
• Autosomal SCID


  • Caused by mutations in the enzyme Adenosine deaminase (ADA)
  • Deficiency of ADA leads to accumulation of toxic purine metabolites in cells
  • Stops DNA synthesis in the actively proliferating mature B & T cells
• Complement component deficiencies


  • Defects are transmitted as autosomal recessive traits
  • Frequently associated with SLE
  • C1, C3, or C5 deficiencies have increased susceptibility to bacterial infections
  • C3 deficiency are susceptible to sepsis with pyogenic bacteria
  • C6, C7, or C8 deficiency are prone to bacteraemia with Neisseria meningitidis or N. gonorrhoeae
• Phagocytosis


  • May be impaired by either intrinsic or extrinsic defects
  • Intrinsic disorders may be due to defects within the phagocytic cell, such as enzyme deficiency
  • Extrinsic disorders may be due to a deficiency of opsonic antibody, complement or other factors promoting phagocytosis or drugs or antineutrophil autoantibodies
• Chronic granulomatous disease


  • Phagocytic cells do not undergo degranulation following phagocytosis
  • Due to diminished H2O2 production to be the major reason for bactericidal defects
  • More common X-linked type seen in boys
  • Rare autosomal recessive type seen in girls
• Nitroblue tetrazolium reduction test (NBT)


  Used as screening test to detect deficiency of NADPH oxidase activity