Paediatric Immunology

Definitions

• Immune system consists of cells, tissues, and molecules that mediate resistance to infections
• Immunology is the study of the structure and function of the immune system
• Immunity is the resistance of a host to pathogens and their toxic effects
• Immune response:
  • Collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules of the immune system

Role of the Immune System

• Defense against microbes
• Defense against the growth of tumor cells:
  • Kills the growth of tumor cells
• Homeostasis:
  • Destruction of abnormal or dead cells (e.g. dead red or white blood cells, antigen-antibody complex)

Immune System

• Organs that play vital roles in immune responses.
• Various types of Cells that execute immune functions.
• Special Molecules responsible for immune processes.

Immune System: Organs

• Tonsils and adenoids - Guard the entry of pathogens through the mouth and nose.
• Thymus - Where T-cells mature and become functional.
• Lymph nodes - Act as hubs for immune cell interaction and response.
• Spleen - Filters blood and monitors for harmful substances.
• Peyer's patches - Found in the small intestine to prevent infection.
• Appendix - Houses immune cells and contributes to gut immunity.
• Lymphatic Vessels - Transport immune cells and fluids.
• Bone Marrow - Produces various blood cells, including immune cells.

Immune System: Cells

• Lymphocytes
  • T-lymphocytes - Regulate immune responses and directly attack infected cells.
  • B-lymphocytes, plasma cells - Produce antibodies to neutralize pathogens.
  • Natural killer lymphocytes - Recognize and destroy infected or cancerous cells.
• Monocytes, Macrophage - Engulf and digest pathogens and debris.
• Granulocytes
  • Neutrophils - First responders to infections, neutralize pathogens.
  • Eosinophils - Defend against parasites and modulate allergic responses.
  • Basophils - Release histamines and contribute to immune responses.

Immune System: Molecules

• Antibodies - Y-shaped proteins that bind to and neutralize specific antigens.
• Complement - Group of proteins that enhance immune responses.
• Cytokines - Signaling molecules that regulate immune cell communication.
• Interleukins - Specific type of cytokines that mediate immune responses.
• Interferons - Warn nearby cells of viral infections, aiding antiviral defense.

• Innate (non-adaptive)
  • First line of immune response, providing immediate defense.
  • Relies on mechanisms that exist before infection, like physical barriers.
• Acquired (adaptive)
  • Second line of response if innate immunity fails to contain the threat.
  • Relies on mechanisms that adapt after infection or exposure.
  • Handled by T- and B-lymphocytes, specialized immune cells.
  • Each T- or B-lymphocyte recognizes a specific antigenic determinant.

Innate Immunity

• Based on genetic make-up, present from birth.
• Relies on pre-formed components for immediate defense.
• Rapid response: Within minutes of infection or threat.
• Non-specific defense mechanism.
• Same molecules/cells respond to a range of pathogens.
• No memory or adaptation to specific threats.
• Does not lead to clonal expansion of immune cells.

Innate Immunity: Mechanisms

• Mechanical barriers/surface secretion
  • Skin acts as a physical barrier.
  • Acidic pH in the stomach hinders microbial growth.
  • Cilia in the respiratory tract help trap and expel pathogens.
• Humoral mechanisms
  • Lysozymes break down bacterial cell walls.
  • Basic proteins have antimicrobial properties.
  • Complement proteins enhance immune responses.
  • Interferons signal other cells to defend against viruses.
• Cellular defense mechanisms
  • Natural killer cells identify and eliminate virus-infected cells.
  • Neutrophils are rapid responders to bacterial infections.
  • Macrophages engulf and destroy pathogens.
  • Mast cells, basophils, and eosinophils contribute to various immune reactions.

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Adaptive Immunity: Second Line of Response

• Based upon resistance acquired during an individual's life.
• Relies on genetic events and cellular growth to generate specific responses.
• Responds more slowly, typically over the course of a few days.
• Specific defense mechanism, targeting distinct antigens.
• Each immune cell responds to a single epitope on an antigen.
• Exhibits anamnestic (non-forgetting) memory.
• Repeated exposure leads to a quicker and stronger immune response.
• Results in clonal expansion of specific immune cells.

Adaptive Immunity: Active and Passive

Immunity Type	Active Immunity	Passive Immunity
Natural	Clinical or sub-clinical infection: Results from encountering a pathogen and developing an immune response.	Via breast milk or placenta: Immune components from the mother provide temporary protection to the offspring.
Artificial	Vaccination: Using live, killed, or purified antigen vaccines to stimulate an immune response.	Immune serum or immune cells: Direct introduction of immune components, providing immediate but temporary protection.

Adaptive Immunity: Mechanisms

• Cell-mediated immune response (CMIR)
  • T-lymphocytes are key players.
  • They eliminate intracellular microbes surviving within infected cells.
• Humoral Immune Response (HIR)
  • B-lymphocytes are central.
  • Mediated by antibodies produced by B-cells.
  • Effective against extracellular microbes and their toxins.

Cell-Mediated Immune Response

• T-cell
  • Recognizes peptide antigens presented by macrophages, bound to major histocompatibility complex (MHC) class molecules.
  • Identifies specific molecules on cell surfaces, aiding in distinguishing self from non-self.
  • Goes into effector cell stage, becoming capable of killing infected cells.

T Lymphocytes

There are two types of T lymphocytes:

• Helper T-lymphocytes (CD4+):
  • CD4+ T cells play a vital role in activating phagocytes to eliminate microbes.
• Cytolytic T-lymphocytes (CD8+):
  • CD8+ T cells are responsible for the destruction of infected cells containing microbes or microbial proteins.

Cell Mediated Immune Response

Primary Response:

• Specific clones of effector T cells and memory clones are produced.
• Develops over several days after initial exposure to an antigen.
• Does not significantly limit the infection initially.

Secondary Response:

• More pronounced and faster than the primary response.
• More effective in limiting the infection.
• Examples include cytotoxic reactions against intracellular parasites, delayed hypersensitivity (e.g. Tuberculin test), and allograft rejection.

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Humoral Immune Response

• B lymphocytes recognize specific antigens.
• Proliferate and differentiate into antibody-secreting plasma cells.
• Antibodies bind to specific antigens on microbes and destroy them through specific mechanisms.
• Some B lymphocytes evolve into a resting state known as memory cells.

Antibodies (Immunoglobulins)

• Belong to the gamma-globulin fraction of serum proteins.
• Have Y-shaped or T-shaped polypeptide structures.
• Composed of 2 identical heavy chains and 2 identical light chains.
• Not all immunoglobulins are antibodies.
• Five types of antibodies exist: IgG, IgM, IgA, IgD, IgE.

IgG

• Constitute 70 – 75% of total immunoglobulin.
• Secreted in high quantities in secondary exposures.
• Capable of crossing the placenta.
• Major functions/applications include neutralizing microbes and toxins, opsonizing antigens for phagocytosis, activating the complement, and protecting the newborn.
• A 4-fold rise or fall in antibody titer indicates an active infection.
• A single positive sample indicates past exposure.

IgM

• Initially secreted during primary infection.
• Cannot cross the placenta.
• Functions include activating the complement and serving as a marker of recent infection.
• Presence in newborn indicates infection.
• A single positive sample in serum or CSF indicates recent or active infection.
• Used to detect the early phase of infection.

IgA

• Exists as monomeric in serum and dimeric with secretory component in the gastrointestinal and respiratory tracts.
• Major function/application is neutralizing microbes and toxins.
• Sero-diagnosis of tuberculosis.
• Synthetic respiratory virus tests.

IgD

• Exists as monomeric.
• Functions as a membrane receptor on the surface of B lymphocytes and has a role in antigen-stimulated lymphocyte differentiation.

IgE

• Mediates type I hypersensitivity.
• Exists as monomeric.
• Functions include mediating anaphylaxis and playing a role in immunity to helminthic parasites.
• Serodiagnosis of infectious and non-infectious allergies (e.g. allergic bronchopulmonary aspergillosis, parasitic diseases).

Sequential IgM – IgG Humoral Response

IgM:

• Produced as a first response to many antigens.
• Levels remain high transiently.

IgG:

• Produced after IgM in response to an antigen.
• Higher levels persist in small amounts throughout life.
• Produced in large amounts during the secondary response due to the persistence of antigen-sensitive 'memory cells' after the primary response.

• Immune response helps individuals defend against:
  • Microbes
  • Some cancers
• Immune response can fail due to:
  • Hypersensitivity reactions
  • Immunodeficiency

Hypersensitivity Reactions

• Cause cell damage through excessive immune response to antigens.
• Hypersensitivity:
  • Overreaction to infectious agents.
• Allergy:
  • Overreaction to environmental substances.
• Autoimmunity:
  • Overreaction to self.

Immunodeficiency

• Loss or inadequate function of various components of the immune system.
• Can occur in any part or state of the immune system:

• Physical barrier, phagocytes, B lymphocytes, T lymphocytes, complement, natural killer cells.

• The immune-compromised host:
• Has impaired immune system function.
• Is at a high risk of infection.
• Congenital (primary) immunodeficiency:
  • Results from genetic abnormalities.
  • Defect in lymphocyte maturation.
• Acquired (secondary) immunodeficiency:
  • Results from infections, nutritional deficiencies, or treatments.
  • AIDS, chronic leukemia.

• Innate Immunity:
  • Relies on mechanisms existing before microbe infects host.
  • First line of defense.
  • No memory for subsequent exposure.
  • Relies on non-specific mechanisms.
• Adaptive Immunity:
  • Develops following entry of microbe into the host.
  • Activated after innate immunity fails to eliminate microbe.
  • Has memory for subsequent exposure.
  • Occurs through specific cells:
  • T cells (cell-mediated)
  • B cells (antibody-mediated)
• Primary Immune Response:
  • Short-lasting.
  • Smaller in magnitude.
• Secondary Immune Response:
  • Longer in duration.
  • Larger in magnitude.
  • Develops 'memory cells' following primary response.
• Failure of Immune Response can result in:
  • Hypersensitivity.
  • Immunodeficiency.