immunodeficiencies

• Immunodeficiency


  The state in which the immune system's ability to fight infectious disease is compromised or entirely absent
• Types of immunodeficiency


  • Primary Immunodeficiency (PID)
  • Secondary Immunodeficiency (SID)
• Classification of Primary Immunodeficiency Diseases

  • Humoral Immunodeficiencies
  • Cellular Immunodeficiencies
  • Combined Immunodeficiencies
  • Disorders of Complement
  • Disorders of Phagocytosis
• Humoral Immunodeficiencies


  • IgA deficiency
  • IgG subclass deficiency
  • Immunodeficiency with increased IgM
  • Common variable immunodeficiency
  • Transient hypogammaglobulinaemia of infancy
  • X-linked agammaglobulinemia
• 1. linked agammaglobulinemia


  • Early maturation of B cells fails
  • Affects males
  • Few or no B cells in blood
  • Very small lymph nodes and tonsils
  • No Ig
  • Small amount of IgG in early age
  • Recurrent pyogenic infection
• IgA deficiency


  • Most common
  • Patients tend to develop immune complex disease
  • About 20% lack IgG2 and IgG4
  • Susceptible to pyogenic infection
  • Result from failure in terminal differentiation of B cells
• Immunodeficiency with increased IgM


  • Results in patients with IgA and IgG deficiency
  • Production of large amount of IgM >200mg/dl of polyclonal IgM
  • Susceptible to pyogenic infection
  • Formation of IgM to neutrophils, platelets and other blood components
  • Due to inability of B cells to isotype switching
• hypoglobulinemia of infancy

  • Due to delay in IgG synthesis approximately up to 36 months
  • In normal infants synthesis begins at 3 months
  • Normal B lymphocytes
  • Probably lack help of T lymphocytes
• DiGeorge's Syndrome


  • Most understood T-cell immunodeficiency
  • Also known as congenital thymic aplasia/hypoplasia
  • Associated with hypoparathyroidism, congenital heart disease, fished shaped mouth
  • Defects results from abnormal development of fetus during 6th-10th week of gestation when parathyroid, thymus, lips, ears and aortic arch are being formed
• Ataxia-telangiectasia


  • Associated with lack of coordination of movement (ataxis) and dilation of small blood vessels of the facial area (telangiectasis)
  • T cells and their functions are reduced to various degrees
  • B cell numbers and IgM concentrations are normal to low
• Wiskott-Aldrich Syndrome


  • Associated with normal T cell numbers with reduced functions, which get progressively worse
  • IgM concentrations are reduced but IgG levels are normal
  • Both IgA and IgE levels are elevated
  • Boys with this syndrome develop severe eczema
  • They respond poorly to polysaccharide antigens and are prone to pyogenic infections
• MHC Deficiency (Bare Leukocyte Syndrome)


  • Due to defect in the MHC Class II transactivator (CIITA) protein gene, which results in a lack of class-II MHC molecule on APC
  • Patients have fewer CD4 cells and are infection prone
  • There are also individuals who have a defect in their transport associated protein (TAP) gene and hence do not express the class-I MHC molecules and consequently are deficient in CD8+ T cells
• Defects of Phagocytic System

  • Cyclic Neutropenia
  • Chronic Granulomatous Disease (CGD)
  • Leukocyte Adhesion Deficiency
  • Chediak-Higashi Syndrome
• Cyclic Neutropenia


  • Marked by low numbers of circulating neutrophil approximately every three weeks
  • The neutropenia lasts about a week during which the patients are susceptible to infection
  • The defect appears to be due to poor regulation of neutrophil production
• Chronic Granulomatous Disease (CGD)


  • Characterized by marked lymphadenopathy, hepato-splenomegaly and chronic draining lymph nodes
  • In majority of patients, the deficiency is due to a defect in NADPH oxidase that participate in phagocytic respiratory burst
• Leukocyte Adhesion Deficiency


  • Leukocytes lack the complement receptor CR3 due to a defect in CD11 or CD18 peptides and consequently they cannot respond to C3b opsonin
  • Alternatively, there may be a defect in integrin molecules, LFA-1 or mac-1 arising from defective CD11a or CD11b peptides, respectively
  • These molecules are involved in diapedesis and hence defective neutrophils cannot respond effectively to chemotactic signals
• Chediak-Higashi Syndrome


  • Marked by reduced (slower rate) intracellular killing and chemotactic movement accompanied by inability of phagosome and lysosome fusion and proteinase deficiency
  • Respiratory burst is normal
  • Associated with NK cell defect, platelet and neurological disorders
• Disorders of Complement System

  • Complement abnormalities also lead to increased susceptibility to infections
  • There are genetic deficiencies of various components of complement system, which lead to increased infections
  • The most serious among these is the C3 deficiency which may arise from low C3 synthesis or deficiency in factor I or factor H
• Severe Combined Immunodeficiency (SCID)


  • In about 50% of SCID patients the immunodeficiency is x-linked whereas in the other half the deficiency is autosomal
  • They are both characterized by an absence of T cell and B cell immunity and absence (or very low numbers) of circulating T and B lymphocytes
  • Patients with SCID are susceptible to a variety of bacterial, viral, mycotic, and protozoan infections
  • The x-linked SCID is due to a defect in gamma-chain of IL-2 also shared by IL-4, -7, -11 and 15, all involved in lymphocyte proliferation and/or differentiation
  • The autosomal SCIDs arise primarily from defects in adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) genes which results is accumulation of dATP or dGTP, respectively, and cause toxicity to lymphoid stem cells

  
• Secondary Immunodeficiency


  The loss of immune function and results from exposure to various agents (not a genetic or developmental problem)
• Stages of HIV infection

  1. Incubation Period

  2. Acute Infection

  3. Latency stage

  4. AIDS
• 0.5% of HIV-1 infected individuals retain high levels of CD4 T-cells and a low or clinically undetectable viral load without anti-retroviral treatment. These individuals are classified as HIV controllers or long-term non progressors (LTNP)
• Helper T-cells


  The T-helper population is further divided into those which help B cells (Th2) and those which help cytotoxic T-cells (Th1)
• Effect of HIV on the immune system


  Gradual (usually) elimination of the Th1 and Th2 helper T-cell sub-populations
• Effects of corticosteroids


  • Cause changes in circulating leukocytes
  • Depletion of CD4 cells
  • Monocytopenia
  • Decreased in circulating eosinophils and basophils
  • Inhibition of T cell activation and B cell maturation
  • Inhibit cytokine synthesis
• Methotrexate


  • Structural analogue of folic acid
  • Blocks folic acid dependent synthetic pathways essential for DNA synthesis
  • Prolonged use for treatment reduces immunoglobulin synthesis
• Effects of methotrexate


  • Have severe effects on T cell signaling and functions
  • It binds to immunophilins which are believed to have a critical role in signal transduction
  • Also inhibit IL2 dependent signal transduction
• Other causes of immunodeficiency

  • Malnutrition
  • Minerals
  • Vitamins
  • Obesity