Immune disorders Knowledge-Based Study

Study notes

1. Overview of Immune Malfunctions

   The immune system is evolved to protect the host against infectious pathogens while maintaining self-tolerance and avoiding harmful reactivity to benign environmental substances. However, functional defects in discrimination, regulation, or activation can lead to pathology. Immune disorders generally fall into three primary categories:

   • Hypersensitivity reactions (Allergies): Inappropriate or hyperactive immune responses against harmless non-self environmental antigens.
   • Autoimmune disorders: Loss of self-tolerance leading to immune-mediated destruction of the body's own cells and tissues.
   • Immunodeficiency disorders: Partial or complete impairment in one or more components of the immune system, leading to heightened vulnerability to infections.

   Allergic Responses and Anaphylaxis

   An allergy is an exaggerated immune response to an otherwise harmless environmental antigen known as an allergen (e.g., pollen, pet dander, insect venom, or specific foods).

   Mechanism of Type I (Immediate) Hypersensitivity

   1. Sensitization: Initial exposure to an allergen stimulates B lymphocytes to differentiate into plasma cells that secrete large quantities of allergen-specific Immunoglobulin E (IgE) antibodies.
   2. Binding to Effectors: The constant (Fc) regions of these IgE antibodies bind with high affinity to Fc receptors located on the surfaces of tissue-resident mast cells and circulating basophils.
   3. Secondary Exposure: Upon subsequent exposure, allergen molecules cross-link adjacent membrane-bound IgE molecules on sensitized mast cells.
   4. Degranulation: Cross-linking triggers rapid exocytosis of cytoplasmic granules, releasing chemical mediators such as histamine, leukotrienes, and prostaglandins.

   These chemical mediators cause local vasodilation, increased capillary permeability, and smooth muscle contraction. A severe, systemic release of mediators can cause anaphylaxis, characterized by sudden airway constriction, widespread vascular leakage, and a severe drop in blood pressure (anaphylactic shock), requiring immediate treatment with epinephrine.

   Failure of Self-Tolerance

   Normally, developing lymphocytes that react against self-antigens undergo deletion via central tolerance (in the thymus for T cells and bone marrow for B cells) or inactivation via peripheral tolerance mechanisms. In autoimmune diseases, self-tolerance fails, causing autoantibodies and autoreactive cytotoxic T lymphocytes (CTLs) to attack healthy self-tissues.

   Major Examples of Autoimmune Conditions

   • Type 1 Diabetes Mellitus: Cytotoxic T cells selectively target and destroy insulin-producing beta cells within the pancreatic islets of Langerhans, eliminating endogenous insulin production.
   • Rheumatoid Arthritis: Chronic inflammation of the synovial membrane lining movable joints, driven by immune complexes and cytokine release (such as TNF-alpha), resulting in cartilage destruction and joint deformity.
   • Multiple Sclerosis (MS): Autoreactive T cells cross the blood-brain barrier and coordinate the destruction of myelin sheaths surrounding axons in the central nervous system, impairing nerve impulse conduction.
   • Systemic Lupus Erythematosus (SLE): Autoantibodies form against ubiquitous intracellular antigens, including double-stranded DNA and histones. Circulating immune complexes deposit in kidneys, skin, and blood vessels, provoking widespread systemic inflammation.

   Primary and Secondary Immunodeficiencies

   An immunodeficiency occurs when the immune system fails to provide adequate protective capability, resulting in persistent, recurrent, or life-threatening infections by opportunistic pathogens.

   1. Primary (Congenital) Immunodeficiencies

   These disorders result from inherited genetic mutations that disrupt immune cell development or function:

   • Severe Combined Immunodeficiency (SCID): A group of rare disorders typically caused by genetic defects (such as adenosine deaminase deficiency or IL-2 receptor subunit mutations) that block the maturation of both functional T cells and B cells. Without stem cell transplantation or gene therapy, SCID is uniformly fatal in infancy.
   • X-linked Agammaglobulinemia: Caused by a defect in Bruton's tyrosine kinase (Btk), preventing B cell maturation and producing an absence of functional antibodies.

   2. Secondary (Acquired) Immunodeficiencies

   Secondary immunodeficiencies arise from external factors encountered during life:

   • Human Immunodeficiency Virus (HIV/AIDS): HIV preferentially infects and destroys helper T cells (CD4+ T lymphocytes) by binding the CD4 surface receptor and co-receptors (such as CCR5). Over time, depletion of helper T cells collapses both cell-mediated and humoral adaptive responses, leading to Acquired Immunodeficiency Syndrome (AIDS).
   • Iatrogenic Causes: Chemotherapy, ionizing radiation, and therapeutic immunosuppressive medications given to prevent organ transplant rejection actively suppress leukocyte proliferation.
   • Severe Malnutrition: Deficiencies in protein, calories, and micronutrients such as zinc directly reduce lymphocyte numbers and lymphoid organ integrity.