Immunodeficiencies Notes

Immunodeficiencies

Definition

Immunodeficiency is defined as the absence or failure of normal function in one or more components of the immune system. It can be categorized into:

  • Specific Immunodeficiencies: Affecting B or T cells.

  • Non-specific Immunodeficiencies: Affecting complement or phagocytes.

  • Primary Immunodeficiency: Generally genetically determined and uncommon.

  • Secondary Immunodeficiency: Due to infection or environmental factors (e.g., HIV, malignancy, nutrition, X-rays, or drugs), and is more prevalent.

Primary Immunodeficiencies

Deficiencies in Innate Immune Mechanisms

These include phagocytic defects, such as:

  • Impaired neutrophil migration

  • Dysfunctional NK, T cells, and neutrophils: leading to poor phagocytosis and lysosomal trafficking.

  • Impaired IFN-γ: A key component as an endoplasmic reticulum protein, resulting in poor interaction with intracellular TLRs.

  • Common TLR signaling defects

  • Generation of reactive oxygen species defects

Chronic Granulomatous Disease

Involves a defective NADPH pathway, which normally produces reactive oxygen species when activated by phagocytosis. This leads to a defective respiratory burst in neutrophils.

Defects in Complement Pathway

Deficiencies in various complement pathways can occur, affecting the membrane attack complex.

Primary B Cell Deficiencies

Characterized by defects affecting B-lymphocytes and checkpoints in B cell development.

X-linked Agammaglobulinemia (XLA)

  • Maps to the X chromosome.

  • Affects B cell maturation at the pre-B cell stage, severely decreasing Ig levels in males.

  • Caused by a mutation in the Bruton’s tyrosine kinase gene (Btk).

  • Individuals are susceptible to pyogenic infections.

  • Treatment involves intravenous immunoglobulin every 3 weeks.

Selective IgA Deficiency

  • Most common immunodeficiency.

  • Affects circulating and secretory dimeric IgA.

  • Absence or low levels of IgA.

  • Most individuals are unaware due to lack of symptoms.

Primary T Cell Deficiencies

Di George Syndrome

  • Caused by a mutation in the TBX transcription factor involved in embryonic development.

  • Results in failure of the thymus to develop properly, preventing hematopoietic stem cells from becoming T cells.

  • Affected infants have distinctive facial features (wide-set eyes, low-set ears, shortening of the upper lip).

  • Congenital heart malformations are common.

  • Leads to undetectable CMI (cell-mediated immunity) and poor antibody responses (dependent on T cell help).

  • Patients can be overwhelmed by live attenuated vaccines.

Severe Combined Immunodeficiency (SCID)

  • Complete failure in T cell development.

  • Occurs in approximately 1 in 80,000 live births.

  • Causes profound defects in cellular and humoral immunity.

  • Infants develop recurrent opportunistic infections early in life and typically die within 1 year without a bone marrow transplant.

  • Symptoms include prolonged diarrhea due to bacterial infections of the GIT, pneumonia, and Candida albicans (yeast) infections.

  • Vaccination with live organisms (e.g., polio and BCG for tuberculosis) can lead to death.

  • Caused by mutations in several genes, blocking T cell development or causing direct/indirect B cell/NK cell deficiency.

Bubble Boy Disease

  • Also known as Bubble boy disease, necessitating a sterilized environment from birth.

  • Example: David Vetter (1971-1984), who died as a result of an unmatched bone marrow transplant from his sister, leading to Burkitt’s lymphoma caused by Epstein-Barr virus (EBV).

  • Raises ethical issues regarding the quality of life, cost (USD $1-3 million), and mental health issues associated with the condition. The parents lost a previous baby at 7 months and knew they had a 50% chance of having another baby with SCID.

Secondary Immunodeficiencies

Examples of Secondary Immunodeficiency

Drugs and Immunodeficiency

  • Steroids

    • Alter white blood cell population numbers.

    • Reduce T cells and monocytes.

    • Increase neutrophil numbers.

    • Inhibit T cell activation and proliferation.

    • Reduce cytokine production.

    • Increase the release of immature cells from bone marrow.

  • Cancer Treatments

    • Cyclophosphamide: An alkylating agent that cross-links DNA, affecting both B and T cell function.

    • Methotrexate: Blocks cell growth and affects B cells.

  • Anti-rejection Drugs

    • Mycophenolate mofetil: Blocks B and T cell proliferation.

    • Cyclosporin: Inhibits T cell signaling and function.

Human Immunodeficiency Virus (HIV)

  • Discovered in 1983.

  • Retrovirus with an RNA genome (2 copies of ssRNA, 9kb) that replicates through reverse transcriptase.

  • Globally, approximately 33.4 (31.1–35.8) million individuals are infected with HIV (as of 2008).

HIV Genome

Consists of 9 genes.

Life Cycle of HIV

Attacks cells needed to control the virus, utilizing CXCR4.

Typical Course of HIV Infection

Involves CD4+ T cell apoptosis.

Primary HIV Syndrome

  • Mononucleosis-like, cold, or flu-like symptoms occur 2-4 weeks (up to 12 weeks) after infection.

    • Symptoms include lymphadenopathy, fever, rash, headache, fatigue, diarrhea, sore throat, and neurologic manifestations.

    • Some individuals may be asymptomatic.

    • Seroconversion occurs 3-6 months post-infection.

    • Characterized by rapid CD4 T cell loss.

Clinical Latency Period

  • Asymptomatic HIV infection or chronic HIV infection.

  • HIV reproduces at very low levels and can last up to 8 years.

  • CD4 counts gradually decline, and viremia increases (normal range: 500-1600 cells per cubic millimeter).

  • Opportunistic infections become a risk when CD4 counts drop below 500 cells per cubic millimeter.

  • Predictive diseases of progression to AIDS include persistent herpes-zoster infection (shingles), oral candidiasis (thrush), oral hairy leukoplakia, and Kaposi’s sarcoma (KS).

AIDS

  • Diagnosed when the CD4 count drops below 200 cells per cubic millimeter.

  • Without preventative medications, life expectancy is approximately 3 years.

  • Severe opportunistic infections reduce life expectancy to 1 year.

  • Most deaths occur with CD4 counts below 50 cells per cubic millimeter.

Pre-exposure Prophylactics (PrEP)

Reduces the risk of HIV infection by 99% after sex. Available on PBS (Pharmaceutical Benefits Scheme) from 2018.