Immunodeficiencies LO1

Learning Objectives

  1. Distinguish between primary and secondary immunodeficiencies and analyze how environmental factors compromise the immune system.

  2. Analyze key concepts in primary immunodeficiencies and examine diverse genetic mutations leading to varied clinical outcomes.

  3. Compare and contrast genes, clinical outcomes, and treatments for innate immune system immunodeficiencies.

  4. Dissect mechanisms of X-linked severe combined immunodeficiency (SCID) and explain how mutations influence lymphocyte development.

  5. Compare genes, clinical outcomes, and treatments concerning deficiencies in lymphocyte activation.

Discussion on Immunodeficiencies

Definition

  • Immunodeficiency: A state wherein the immune system's ability to fight infectious diseases or cancer is either compromised or entirely absent.

Types of Immunodeficiencies

Primary Immunodeficiencies

  • Characteristics:

    • Rare genetic diseases.

    • Manifestation typically occurs early in life.

    • Repeated infections with the same pathogens.

    • Caused by opportunistic pathogens, which are usually harmless but can cause disease in those with non-functional immune systems.

  • Genetic Mutations:

    • Primarily caused by mutations in recessive genes, often loss of function mutations.

    • X-linked diseases more common due to the male genetic make-up (only one X chromosome).

  • Historical Note:

    • First description by Ogden C. Bruton in 1952, considered recent due to the prior unavailability of antibiotics.

Secondary Immunodeficiencies

  • Characteristics:

    • Acquired conditions due to extrinsic or environmental factors, typically manifesting later in life.

    • Associated with a history of diverse clinical manifestations.

Environmental Factors Leading to Secondary Immunodeficiency

  1. Infectious Agents:

    • HIV: Major cause of secondary immune deficiency (to be discussed in detail).

    • Measles: Known to cause immunodeficiency.

    • Helminths: Induce malnutrition and skew immune responses.

  2. Medical Treatments:

    • Radiation and Chemotherapy:

      • Ablate rapidly proliferating cells including immune cells.

      • Cancer treatments also affect the immune system, leading to secondary deficiencies.

    • Splenectomy:

      • Removal of the spleen increases susceptibility to infections, particularly malaria.

    • Statistics for Travelers:

      • Normal travelers: 5-10% death rate from severe malaria.

      • Splenectomized patients: Death rate of 48-28% from severe malaria.

  3. Nutritional Deficiencies:

    • Protein deficiency leads to T cell deficiencies, a significant issue in developing regions.

    • Example: Protein deficiency (kwashiorkor) manifesting in children.

    • Shingles reemergence in individuals with low immune system functionality, potentially due to deficient protein intake in vegan diets.

Life Cycle of Human Immunodeficiency Virus (HIV)

  • Binding and Fusion:

    • HIV virion binds specifically to CD4+ T cells and chemokine receptors.

    • Viral envelope fuses with the host cellular membrane, depositing viral contents.

  • Viral Replication:

    • The RNA genome is reverse-transcribed into DNA and integrated into the host cell genome.

    • Upon cell activation, the HIV genome transcribes into viral proteins and new virions.

    • New viruses bud off from the host cell, resulting in cell death.

Clinical Course of HIV Infection

  • Initial Stage:

    • Mild viral syndrome lasts 2-3 weeks, followed by recovery.

  • Clinical Latency:

    • Integrated viral genome without significant production of virions; CD4 levels initially drop but stabilize.

  • Increased Viremia:

    • As the immune system is reactivated, viral load rises.

    • CD4+ T cell count decreases, leading to immunodeficiency, opportunistic infections, and possible death.

  • Immune Response:

    • Initial strong immune responses consist of antibodies and cytotoxic T cells.

    • Over time, viral mutations allow HIV to evade the immune response, leading to increased viremia and depletion of CD4+ T cells.

Treatment of HIV

  • Modern Advances (2023):

    • HIV infection is less severe with Highly Active Antiretroviral Therapy (HAART).

    • HAART includes various drug classes targeting different viral life stages, effectively maintaining low viral loads and preventing progression to AIDS.

  • Challenges in the Developing World:

    • Continued high prevalence of HIV in areas like Sub-Saharan Africa due to economic constraints preventing access to treatment.

    • Correlation with high tuberculosis incidence due to compromised immune systems (lack of CD4+ Th1 cells).

  • Future Considerations:

    • Development of a vaccine against HIV is essential for long-term management, although challenging due to rapid viral mutation.

Conclusion

  • Summary of discussed points: Primary and secondary immunodeficiencies, their causes, HIV lifecycle, and the global challenges associated with immunodeficiencies.

  • Transition to focus on primary immunodeficiencies in the next session.