Immune System Overview

Immune System

• The immune system protects against infection, mutant cells, tumour cells, and foreign substances.
• Immune deficiencies lead to increased susceptibility to infections and diseases.
• The immune system can also cause tissue damage and disease, such as hypersensitivity reactions and autoimmune diseases.

Antigens & Antibodies

• Antigens are substances, usually proteins, that stimulate antibody production.
• A hapten is a small molecule that requires a carrier molecule to elicit an immune response.
• Antibodies (immunoglobulins) are proteins produced in response to antigenic stimulation.
• There are five classes of immunoglobulins: IgG, IgA, IgM, IgE, and IgD.

Immune Response Mechanisms

• The immune system can be divided into innate (natural) and adaptive (acquired) immunity.

Innate Immunity

• Provides the first line of defense against pathogens.
• Components include:
  • Epithelia (skin, GIT, respiratory tract): act as mechanical barriers.
  • Phagocytes (monocytes, macrophages, neutrophils): engulf and destroy pathogens.
  • Dendritic cells: present antigens to adaptive immune cells.
  • Natural killer cells: kill infected cells without prior sensitization.
  • Innate lymphoid cells: contribute to early defense against microbes.
  • Soluble proteins (complement, C-reactive protein, mannose-binding lectin): enhance immune responses.
• Innate immunity mechanisms:
  • Triggers inflammation by releasing cytokines, complement products, and mediators.
  • Releases type I interferons: activate enzymes that degrade viral nucleic acids and inhibit viral replication.
  • Stimulates a stronger adaptive immune response.
• Innate immunity lacks memory and fine antigen specificity, unlike adaptive immunity.

Adaptive Immunity

• Mediated by lymphocytes and their products (antibodies, cytokines), antigen-presenting cells (macrophages, dendritic cells, B-cells), mast cells/basophils, and eosinophils.
• Divided into:
  • Humoral immunity: mediated by B lymphocytes and protects against extracellular microbes and toxins.
  • Cell-mediated immunity: mediated by T lymphocytes and protects against intracellular microbes.

Lymphoid Organs

• Categorized into primary and secondary lymphoid organs.
• Primary (generative):
  • Bone marrow: site of B cell development.
  • Thymus: site of T cell development.
• Secondary (peripheral):
  • Lymph nodes, spleen, mucosa-associated lymphoid tissue (MALT) of GIT and respiratory tract.

Natural Killer (NK) Cells

• Also known as large granular lymphocytes due to cytoplasmic granules.
• Make up 5-10% of peripheral blood lymphocytes.
• Do not express T cell receptors (TCRs) or immunoglobulins.
• Inherently capable of killing tumor cells and virus-infected cells without prior sensitization (innate immunity).
• Express CD16 and CD56 markers.
• CD16 is an Fc receptor for IgG, enabling antibody-dependent cell-mediated cytotoxicity (ADCC).
• Function is regulated by the balance between activating and inhibitory receptors.
• Activating receptors recognize molecules on target cells and stimulate killing.
• Inhibitory receptors recognize MHC class I molecules and suppress killing.
• NKG2D is an activating receptor whose expression increases with viral infections and neoplastic transformation, both of which also decrease MHC class I expression.

Major Histocompatibility Complex (MHC)

• MHC molecules are essential for T cell recognition of antigens.
• They display peptide fragments of protein antigens for recognition by antigen-specific T cells.
• Determine tissue compatibility between individuals.
• Also known as human leukocyte antigens (HLA).
• Genes encoding MHC molecules are located on chromosome 6.
• MHC genes are polymorphic, meaning there are many alleles in the population.
• This allelic variation poses a challenge in organ transplantation.

MHC Class I Molecules

• Expressed by all nucleated cells.
• Present endogenous antigens, such as viral proteins, to CD8+ cytotoxic T lymphocytes (CTLs).
• Composed of a heavy α chain and a light β2-microglobulin chain.
• The α1 and α2 domains form the antigen-binding groove.
• The α3 domain binds to CD8 on CTLs.

MHC Class II Molecules

• Expressed by antigen-presenting cells (macrophages, dendritic cells, B cells).
• Present exogenous antigens (proteins taken up from the environment) to CD4+ helper T lymphocytes.
• Composed of an α chain and a β chain.
• The α1 and β1 domains form the antigen-binding groove.
• The β2 domain binds to CD4 on helper T cells.

HLA and Disease

• Certain HLA alleles are associated with specific diseases:
  • Ankylosing spondylitis and HLA-B27: increased risk of developing the disease.
  • Inherited errors of metabolism (e.g., 21-hydroxylase deficiency) and specific HLA alleles (e.g., HLA-B47).
  • Autoimmune diseases (e.g., endocrinopathies) and specific HLA-DR locus alleles.

Activation of T Lymphocytes and Elimination of Intracellular Microbes (Cell-Mediated Immunity)

• Naive T lymphocytes are activated in peripheral lymphoid organs by antigens and co-stimulators (CD28 on T cells and B7 proteins on APCs).
• Activated T cells proliferate and differentiate into effector and memory cells.
• Effector cells migrate to sites of antigen presence.
• CD4+ T cells differentiate into various effector cells (TH1, TH2, TH17) that secrete different cytokines with specific functions.

Type I Hypersensitivity Reactions

• Allergic reactions mediated by IgE antibodies.
• Triggered by allergens, which elicit strong TH2 responses.
• Involve the following steps:
  • Sensitization: Initial exposure to allergen leads to production of IgE antibodies.
  • Mast cell sensitization: IgE antibodies bind to FcεRI receptors on mast cells.
  • Re-exposure: Subsequent exposure to allergen crosslinks IgE on mast cells.
  • Mast cell degranulation: Release of preformed mediators (histamine, proteases) and synthesis of secondary mediators (leukotrienes, prostaglandins).
  • Clinical manifestations: Immediate hypersensitivity reactions due to mediator release.

Mast Cells

• Marrow-derived cells found in subepithelial tissues.
• Contain granules with various mediators.
• Express FcεRI receptors, which bind IgE.
• Sensitized mast cells release mediators upon allergen exposure.
• Mediator release triggers clinical features of immediate hypersensitivity reactions.

Type I Hypersensitivity Reaction Triggers

• Multivalent allergens crosslinking IgE on mast cells.
• Other stimuli: C3a and C5a anaphylatoxins, IL-8, bee sting, drugs (mellitin, codeine), physical stimuli (temperature extremes).

Mediator Release

• Degranulation of mast cells releases preformed mediators (primary mediators).
• De novo synthesis and release of secondary mediators.

Primary Mediators

• Preformed and stored in granules:
  • Histamine: causes vasodilation, increased vascular permeability, bronchoconstriction.
  • Proteases: degrade tissue proteins, contribute to inflammation.

Secondary Mediators

• Synthesized upon mast cell activation:
  • Leukotrienes: potent bronchoconstrictors, increase vascular permeability.
  • Prostaglandins: cause vasodilation, increase vascular permeability.
• Contribute to the development of late-phase allergic reactions.