L7 Immunodeficiency and Disease

• Immunodeficiency is impaired function of the immune system, caused by a deficiency of immune cells or immune mediators, or reduced function of these cells or mediators

  
• Outcomes of Immunodeficiency


  • Increased susceptibility to infections, potentially opportunistic infections
  • Poor healing
  • Increased susceptibility to malignancy

  
• Outcomes of Immune Dysfunction

  • Hypersensitivity/hyperfunction
  • Autoimmunity

  
• Newborns more susceptible to infections


  Newborn immune system is still in development with some immature function, particularly in premature infants
• Reasons for newborns' impaired immunity

  • Neutrophils have impaired phagocytosis and chemotaxis, and reduced endothelial adhesion
  • Lymphocytes give a weak response to antigen stimuli
  • Monocytes/Macrophages are still immature with reduced function

  
• Maternal antibodies


  IgG from transplacental transfer, and IgA from breast-feeding, can provide some passive protection against infections
• Aged community more susceptible to infections


  Aetiology of immunodeficiency in the aged community: Comorbidities, Medication (e.g. steroidal anti-inflammatory), Poor nutrition, Reduced antibody titres from vaccines/boosters
• Immunosenescence


  Age-related reduced function of immune cells due to shortening telomeres and reduced activity of the thymus
• Types of Immunodeficiency


  • Primary Immunodeficiency (congenital, present from birth, caused by genetic abnormalities)
  • Secondary Immunodeficiency (acquired, caused by an underlying pathology)

  
• Primary Immunodeficiency


  • Aetiology: Congenital, present from birth, caused by genetic abnormalities
  • Pathogenesis: Dependant on the abnormality, examples include loss of T and/or B cells, impaired phagocytosis, complement deficiency

  
• Examples of primary immunodeficiency affecting the innate immune system

  • Leukocyte adhesion deficiency
  • Chediak-Higashi syndrome
  • Primary myeloperoxidase deficiency
  • Primary C3 Deficiency

  
• Examples of primary immunodeficiency affecting the adaptive immune system

  • DiGeorge Syndrome
  • X-linked Agammaglobulinaemia

  
• DiGeorge Syndrome (DGS)


  Also known as third and fourth pharyngeal pouch syndrome or 22q11.2 deletion syndrome, DGS is a germline congenital condition involving thymic hypoplasia
• Pathogenesis of DiGeorge Syndrome

  • Impaired development of the third and fourth pharyngeal pouches, causing thymic hypoplasia, parathyroid hypoplasia, heart/blood vessel defects, craniofacial defects
  • Aetiology: Caused by germline deletions in the region of 22q11, notably the loss of the TBX1 gene

  
• Immunodeficiency in DiGeorge Syndrome

  Impaired patterning of cardiac neural crest cells results in thymic hypoplasia, or even complete athymia in some cases, causing a deficiency in T lymphocytes and increased susceptibility to infections

  
• 1. linked Agammaglobulinaemia (XLA)


  Also known as Bruton agammaglobulinaemia, XLA is a X-linked hereditary condition characterised by the failure to produce mature B lymphocytes, and failure of immunoglobulin heavy chain rearrangement

  
• Pathogenesis of X-linked Agammaglobulinaemia

  • Mutations in the BTK gene prevents maturation of B lymphocytes, causing marked reduction in circulating B lymphocytes and serum levels of all classes of immunoglobulins, and underdeveloped lymphoid tissue
  • Aetiology: Caused by mutations in the BTK gene located at Xq21.22, X-linked inheritance (i.e. almost exclusively affects males)

  
• Immunodeficiency in X-linked Agammaglobulinaemia

  Impaired maturation of B lymphocytes impairs the development of lymphoid tissue in lymph nodes, gut/appendix, and tonsils, and without B lymphocytes, immunoglobulins (antibodies) cannot be produced, leading to susceptibility to infections

  
• Secondary Immunodeficiency


  • Aetiology: Acquired, caused by an underlying pathology (e.g. HIV infection, malnutrition, diabetes)
  • Pathogenesis: Often secondary to an underlying pathology, so dependant on the mechanism of the causative disease
• Acquired Immunodeficiency Syndrome (AIDS)


  AIDS is the final phase of human immunodeficiency virus (HIV) infection, characterised by a CD4+ T cell count <200 cells/mm3 or <0.2 x 109 cells/L
• Pathogenesis of AIDS


  • Progressive CD4+ T lymphocyte deficiency, causing susceptibility to infection, including opportunistic infections, Kaposi sarcoma, and increased incidence of B cell lymphoma, cervical cancer, and anal cancer
  • Aetiology: HIV infection, causing depletion of CD4+ T lymphocytes

  
• Immunological abnormalities and their effects in patients with AIDS

  • Lymphocytopenia (low CD4+ T cell count)
  • Decreased/altered T cell function in vivo
  • Altered/impaired B cell activation in vivo
  • Abnormal macrophage function

  
• AIDS-Defining Opportunistic Infections


  • Fungi: Cryptococcus neoformans, Candida albicans, Pneumocystis jirovecii, Histoplasma capsulatum, Coccidioidomycosis immitis
  • Bacteria: Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, Nocardia asteroides
  • Viruses: Cytomegalovirus, Herpes simplex virus, Varicella-zoster virus
  • Protozoa: Cryptosporidium spp., Toxoplasma gondii
• Immunodeficiency in Malnutrition


  Worldwide, a protein/calorie malnutrition is the most common cause of immunodeficiency, causing hypoproteinaemia which decreases T cell production and function, impairs phagocytosis, and reduces production of cytokines and other immune mediators, as well as deficiencies in zinc, iron, vitamin C, and vitamin D
• Immunodeficiency in Obesity


  Obesity is a risk factor for post-surgical infections, susceptibility to viral infections such as influenza and COVID, and periodontal disease
• Immunodeficiency in Diabetes Mellitus

  Chronic hyperglycaemia in diabetes mellitus causes defective phagocytosis and macrophage chemotaxis, T cell anergy, and poor lymphoproliferative response to mitogens, contributing to diabetic foot ulceration and gangrene

  
• Examples of drug-induced immunodeficiency

  • Glucocorticoids (autoimmune diseases)
  • Methotrexate (rheumatoid arthritis)
  • Phenytoin (epilepsy)
  • Cyclophosphamide (cancer)
• Immunodeficiency Post-Splenectomy


  The spleen filters phagocytic cells, produces antibodies, and deals with blood-borne microorganisms, so post-splenectomy patients have increased susceptibility to encapsulated bacteria and decreased antibody production

  
• Radiation-induced Immunodeficiency


  Ionizing radiation can induce genetic aberrations that particularly affect dividing cells, such as the haematopoietic stem cells in the bone marrow, causing pancytopenia or aplastic anaemia, and weakened T cell-mediated immunity
• Stress-induced Immunodeficiency


  Chronic stress imbalances stress hormone levels, induces pro-inflammatory cytokines, and interferes with normal immune responses, leading to reactivation of latent infections, influencing disease severity, slowing wound healing, and impairing vaccine responses
• Cold weather and Immunodeficiency

  Immune function is reduced at low temperatures, nasal mucosal cells are more susceptible to viral infection at low temperatures, and seasonal depression may impair immune function, though confounding factors like people gathering indoors and viruses surviving better in cold dry environments also play a role