Congenital and Acquired Immunodeficiencies

Core Definitions

• Immunodeficiency: A full or partial defect in the development or function of the immune system.
• Immunodeficiency Disorder/Disease: A health condition resulting from defective immunity.
• Congenital (Primary) Immunodeficiency: A genetically defined abnormality present at birth.
• Acquired (Secondary) Immunodeficiency: A defect developed over time due to environmental factors (e.g., malnutrition, $HIV$, or medical therapies).
• Immunocompromised Person: An individual living with an ineffective immune response.

Clinical Manifestations of Deficiencies

• B Cell Deficiencies: Characterized by absent or reduced follicles and germinal centers in lymph nodes, and reduced serum antibody levels ($Ig$). Results in increased risk of infection and inability to neutralize or opsonize pathogens.
• T Cell Deficiencies: Characterized by reduced $CD3$ T cell zones in lymph nodes and reduced reactions to antigens. Leads to increased susceptibility to viruses, intracellular pathogens, and cancers.
• Innate Immune Deficiencies: Results in the inability to contain or clear pathogens, placing a heavy burden on the adaptive immune response.

Congenital (Primary) Immunodeficiencies

• Chronic Granulomatous Disease: A genetic mutation preventing the production of reactive oxygen species in the phagolysosome, leading to recurrent bacterial and fungal infections.
• Leukocyte Adhesion Deficiency (LAD) Types 1 and 2: Defective integrins or selectin ligands prevent leukocytes from adhering and extravasating to infection sites. Clinical signs include elevated phagocyte counts in the blood but an absence of pus at infection sites.
• Chediak-Higashi Syndrome: A defect in vesicle fusion (phagolyosome formation) affecting the ability to kill pathogens.
• Severe Combined Immunodeficiency (SCID): A group of rare, serious conditions affecting both T and B cell function (e.g., $X$-linked $SCID$ or $ADA$/$PNP$ deficiency). Often requires hematopoietic stem cell transplantation.
• DiGeorge Syndrome: A deletion at chromosome $22$ resulting in thymic hypoplasia (reduced thymus size), which impairs T cell maturation.
• X-linked Agammaglobulinemia: A B cell maturation defect (linked to the gene $BTK$) resulting in a total absence of antibodies in the blood ($emia$).
• Hyper IgM Syndrome: Caused by mutations in $CD40$, $CD40$ ligand, or the enzyme $AID$. B cells cannot receive signals to class switch, resulting in high levels of $IgM$ but deficiencies in $IgG$, $IgA$, and $IgE$.
• Hemophagocytic Lymphohistiocytosis: A defect in the perforin gene that prevents Cytotoxic T Lymphocytes ($CTL$) from delivering their cytotoxic payload to target cells.

Acquired (Secondary) Immunodeficiencies

• These are more common than primary deficiencies and are often reversible if the underlying cause (external factor) is addressed.
• Common Causes:
  • Malnutrition (specifically protein-calorie malnutrition).
  • Infections such as $HIV$ (targeting $CD4$ T cells).
  • Cancers of the bone marrow.
  • Splenectomy (asplenia).
  • Immunosuppressive drug treatments (chemotherapy or therapy for autoimmune diseases).

Immune System Changes Across the Lifespan

• Neonatal Period: The immune system is immature at birth. Protection is provided by maternal antibodies transferred across the placenta and via breast milk (colostrum).
• Thymic Involution: The thymus is large and highly active in early life to produce naive T cells for new antigen exposure; it shrinks (involutes) over time as the body relies more on memory T cells.
• Immunosenescence and Inflammaging: In older age, the immune system becomes "exhausted." There is a shift toward a chronic, low-grade pro-inflammatory state (inflammaging) and a reduced ability to respond to new infections or vaccinations.
• Sex Differences: Biological sex influences immune responses. For example, female children often show increased $CD4$ to $CD8$ ratios, and adult females typically show higher inflammatory pathways and antibody responses compared to males.

Questions & Discussion

Question (Lecturer to Audience): What do you think are the four top things you can do to live a long and healthy life (according to centenarians)?

Response/Discussion:

• Vaccination: Good for maintaining protection across the lifespan.
• Diet: Essential for providing the nutrition required for immune cell function.
• Exercise: Supports overall physiological health and immune balance.
• Sleep: Crucial for immune regulation and recovery.
• Social Connection: Highlighted as a major factor for longevity.
• Lifestyle choices: Avoid smoking and excessive alcohol use; manage medication and spend time outdoors ("touch grass").