Human Immune System Basics

Introduction to the Human Immune System

• The human immune system protects us from pathogens and microbes in the environment.

• We encounter bacteria, fungal pathogens, and spores every time we breathe.

• The immune system patrols our body, preventing infections.

Key Concepts and Terminology

• Immunology involves learning a new set of terms, which can initially be confusing.

• Examples of easily confused terms: antibody, antigen.

• The British Society for Immunology offers a section called "bite-sized immunology" with articles on various cells, proteins, and immune organs, written in accessible language.

Overview of the Human Immune System

• The human immune system primarily consists of white blood cells circulating in the blood.

• Some white blood cells migrate from the blood into tissues.

• Specialised organs of the immune system include:

  • Thymus:

    • A primary lymphoid organ.

    • Involved in the creation of new blood cells.

  • Bone Marrow:

    • A primary lymphoid organ.

    • Involved in the creation of new blood cells.

  • Secondary Lymphoid Organs: Discussed in a later lecture.

Blood Composition and Immune Cells

• Blood separates into cellular and liquid components when centrifuged.

  • The liquid component of blood is called plasma.

  • Red blood cells:

    • Very dense and sinks to the bottom.

    • Comprises about 45% of the blood.

  • White blood cells:

    • Immune cells.

    • Less than 1% of the blood.

    • Form a fine layer on top of the red blood cells.

• Blood plasma:

  • Delivers nutrients and gases throughout the body.

  • Contains:

    • Albumin.

    • Fibrinogen (a clotting factor).

    • Water.

    • Specialist immune proteins like antibodies and complement.

    • Chemicals that buffer and regulate blood pH.

Blood Cell Types and Functions

• Each drop of blood contains:

  • 4 to 6 million red blood cells.

  • Numerous platelets (important for clotting).

  • Various white blood cells (leukocytes), including:

    • Neutrophils (60-70% of white blood cells in most people).

    • Eosinophils.

    • Monocytes.

    • Basophils.

    • Lymphocytes.

Red Blood Cells (Erythrocytes)

• Deliver oxygen from the lungs to tissues.

• Take carbon dioxide back to the lungs for exhalation.

• Approximately 5 million per microliter of blood.

• The proportion of blood made up of red cells is called hematocrit, which is an important clinical test for diseases affecting cell formation.

• In mammals, erythrocytes lack a nucleus.

White Blood Cells (Leukocytes)

• Also known as leukocytes.

• 'Leukos' (Greek) means white, and 'cyte' means cell.

• Make up less than 1% of blood cells.

• About ten microns across, larger than red blood cells.

• Circulate in the body and can squeeze through blood vessel walls to migrate into tissues during infections.

Granulocytes vs. Agranular Leukocytes

• Granulocytes:

  • Have a granular or speckled cytoplasm (e.g., neutrophils, eosinophils, basophils).

• Agranular leukocytes:

  • Have a smoother cytoplasm (e.g., monocytes, lymphocytes).

• Neutrophils:

  • Have a dark, condensed, polymorphic (multi-lobed) nucleus.

  • Cytoplasm contains granules with cytotoxic molecules for killing microorganisms.

• Lymphocytes:

  • Have a large nucleus.

  • Smooth cytoplasm without intracellular granules.

  • High gene expression activity, with less tightly wound DNA.

Hematopoiesis: Blood Cell Formation

• Hematopoiesis occurs in the bone marrow. All blood cells derive from pluripotent stem cells.

• Pluripotent stem cells differentiate into:

  • Myeloid stem cells

  • Lymphoid stem cells

• Differentiation is permanent; cells cannot switch from myeloid to lymphoid lineages.

• Myeloid Stem Cells:

  • Differentiate into:

    • Erythrocytes (red blood cells).

    • Platelets (from megakaryocytes).

    • Myeloblasts (giving rise to granulocytes like eosinophils and neutrophils).

    • Monoblasts (giving rise to monocytes).

• Lymphoid Stem Cells:

  • Differentiate into:

    • B lymphocytes.

    • T lymphocytes.

Regulation of Hematopoiesis

• Governed by:

  • Cytokines (signalling molecules).

  • Growth factors.

  • Oxygen concentration.

• Hypoxia (low oxygen) in the centre of the bone marrow, while areas near the blood supply have high oxygen levels.

• Cytokines:

  • Signalling molecules secreted by cells.

  • Bind to receptors on target cells, initiating gene activation and protein expression.

  • Can work through:

    • Autocrine activation: Cytokine binds to receptors on the same cell.

    • Paracrine activation: Cytokine activates nearby cells.

    • Endocrine activation: Cytokine activates distant cells via the bloodstream.

• Examples of cytokine families:

  • Interleukins.

  • Chemokines.

  • Interferons.

  • Colony-stimulating factors.

  • Tumour necrosis factors.

Blood Smear Analysis and Cell Identification

• Blood smears are prepared by spreading a drop of blood on a slide and staining it to observe cell morphology.

• Red blood cells: Pink doughnuts without a nucleus.

• Neutrophils: Polymorphic nucleus (smiley face) and faintly stained cytoplasm; condense their nucleus to squeeze out of the bloodstream.

• Eosinophils: Polymorphic nucleus and cytoplasm that picks up pink (acidic) dye (eosinophilia), and granules containing cytotoxic killing molecules.

• Basophils: Very rare granulocytes.

• Monocytes: Smoother cytoplasm and horseshoe-shaped nucleus.

• Lymphocytes: T cells or B cells (naive lymphocytes).

Leukocyte Circulation and Migration

• Leukocytes circulate in the blood and migrate into tissues when activated.

• Neutrophils squeeze through gaps in the blood vessel walls into tissues to kill bacteria.

• Some white blood cells reside permanently in tissues (tissue-resident).

• Others live within secondary organs like the spleen.

The Need for an Immune System

• We are exposed to a wide range of microbes, including viruses, bacteria, fungi, and parasites.

• Microorganisms have different surface properties, requiring diverse killing capacities by the immune system.

• The immune system must distinguish between self and non-self.

• Some pathogens are small enough to be eaten (phagocytosis), while others are too large and require the secretion of toxic molecules.

• Extracellular pathogens are easier to target than intracellular pathogens, which hide within host cells (e.g., viruses).

• The immune system sometimes needs to kill infected cells to eliminate intracellular pathogens.

Size and Range of Pathogens

• Tapeworms can be over a meter long.

• Malaria parasites live within red blood cells.

• Fungi include Aspergillus and Candida.

• Viruses, such as poliovirus and SARS-Cov-2, are incredibly small.

Global Impact of Infectious Diseases

• In developed countries, about 2% of deaths are caused by infections, mainly affecting newborns and the elderly.

• In developing countries, parasitic and waterborne diseases affect people of all ages, causing a significant number of deaths.

Layers of Protection Against Pathogens

• Physical Barriers:

  • The skin is a virtually impenetrable barrier in healthy individuals.

  • Lysozyme in sweat breaks down bacterial cell walls.

  • Acidic pH on skin inhibits pathogen growth.

  • Normal flora (friendly bacteria) provide a protective layer.

• Innate Immune System: Very old and conserved across species.

• Adaptive Immune System: Highly specific.

Physical Barriers in Detail

• The skin is the largest barrier, but we are not entirely covered in skin.

• Potential sources of infection:

  • Digestive system.

  • Respiratory system.

  • Human genital tract.

• The hand of a six-year-old child incubated on a petri dish overnight demonstrates the range of bacterial species on the skin.

Special Adaptations in Different Systems

• Digestive Tract:

  • Enzymes in saliva break down bacteria.

  • Acidic pH in the stomach (pH 2.4) is hostile to pathogens.

  • Normal flora in the gut provides a layer of protection.

• Urogenital Tract:

  • Acidic urine provides protection.

  • Normal flora in the vagina.

• Respiratory Tract:

  • Epithelial cells with cilia (finger-like protrusions) beat in time to lift mucus up and out of the lungs.

  • Mucus traps bacteria and fungal pathogens, which are then swept out.

Designing an Effective Immune System

• Must distinguish between self and non-self.

• Needs to be activated rapidly.

• Must have cytotoxic potential against a range of pathogens.

Two Arms of the Immune System

• Innate Immune System:

  • Recognises patterns in invading pathogens.

  • Activated quickly, makes use of soluble antimicrobial proteins.

• Adaptive Immune System.

  • Highly specific and slow to activate.

Innate Immunity: Recognising Pathogens

• Recognises molecular patterns on pathogens.

• Bacteria have cell walls with molecules like lipopolysaccharide and peptidoglycan, recognised by the innate immune system.

• Pathogen-associated molecular patterns (PAMPs): Conserved molecular shapes recognised by cells of the innate immune system.

• Pattern recognition receptors (PRRs):

  • Receptors on innate immune cells that recognise PAMPs.

  • Toll-like receptors (TLRs) are a family of PRRs.

  • Different TLR combinations recognise different patterns (e.g., tri-acylated lipoprotein, di-acylated lipoproteins, polysaccharides, viral RNA, and viral DNA).

• Activation of Pattern Recognition Receptors:

  • Engagement with PAMPs activates the receptor.

  • Activates signal transduction.

  • Activates the innate immune cell.

  • Production of broad-spectrum cytotoxic molecules, inflammatory response, and complement.

Opsonisation

• Pathogens coated with serum proteins (complement, antibodies) are recognised by immune cells.

• Opsonisation: Coating of pathogens with immune proteins to enhance recognition and phagocytosis.

• Immune proteins form a bridge between the pathogen and the neutrophil, enabling capture and killing.

Phagocytosis Process

• Neutrophils capture and kill bacteria through phagocytosis.

• Process:

  1. Opsonised bacteria touch the plasma membrane of a neutrophil.

  2. Receptors on the neutrophil bind to molecules on the bacteria.

  3. The plasma membrane creeps around the bacteria, forming pseudopodia.

  4. Arms close and bring the bacteria into the cytoplasm in a phagosome (an organelle with a lipid membrane).

  5. Granules containing cytotoxic molecules migrate toward the phagosome.

  6. The membrane of the granule fuses with the membrane of the phagosome.

  7. Toxic content is released onto the surface of the bacteria.

  8. The bacteria are lysed, and their DNA is released.

Neutrophil Extracellular Traps (NETs)

• NETs: DNA of the neutrophil is thrown out like a fishing net to capture extracellular pathogens.

• If an infection is overwhelming, neutrophils dismantle their DNA and stick cytotoxic molecules on it.

• NETs capture and deactivate bacteria, preventing reproduction.

• Neutrophils produce reactive oxygen species (ROS) like hydrogen peroxide or hydrochloric acid, which are cytotoxic and stimulate NET production.

Eosinophils

• Granulocytes are filled with cytotoxic molecules.

• Provide protection against parasites (e.g., nematode infections) and fungal pathogens.

• Attack pathogens too big to be phagocytosed.

• Work as a community to kill parasitic worms, responding to chemical signals.
  Monocytes and Macrophages

• Monocytes circulate in the blood with a horseshoe-shaped nucleus. They migrate to tissues and mature into macrophages.

• Macrophages provide long-term protection in tissues.

• The tissue in which the macrophages are located determines their properties.

Natural Killer (NK) Cells

• Deal with viruses that infect our cells.

• Initiate cytotoxic killing of infected host cells.

• Process:

  1. Infected cells send out signals.

  2. NK cells bind to the surface of the infected cell.

  3. Secretes two important proteins: Perforin and Granzymes.

Whole Body Response to Infection: Inflammatory Response

• Inflammation is a comprehensive response involving various body systems to identify and combat pathogens.

• Injured cells release chemical alarm signals, activating nearby cells to produce histamine and prostaglandins.

• These mediators cause swelling and increased permeability of blood vessels, facilitating immune cell access to the infection site.

• Neutrophils move from the bloodstream into infected tissue, initiating phagocytosis and clearing bacterial infections.

• Signs of inflammation include redness, warmth, swelling, and potentially loss of function.

• Pus formation indicates a severe infection and is actually neutrophils.

• Neutrophils contain myeloperoxidase, which produces hydrochloric acid and chlorine, giving pus its greenish-yellow colour.

Inflammatory Response Mechanism

• A splinter in the finger introduces bacteria into the tissue.

• Chemical signals (including histamine) cause endothelial gaps to appear.

• Neutrophils squeeze through these gaps and perform phagocytosis.

• Monocytes follow, differentiating into macrophages to continue the clearing process.

• Neutrophils are short-lived and undergo apoptosis after 24 hours, with macrophages clearing both bacteria and dead neutrophils.

Acute Phase Response

• A whole-body response to infection.

• Includes:

  • Fever: The Hypothalamus raises body temperature to inhibit the growth of viruses and bacteria.

  • Cytokine release: Neutrophils and macrophages release cytokines like interleukin-6 and tumour necrosis factor.

  • Acute phase proteins: Production of proteins involved in activating phagocytes (e.g., complement and CRP).

The Inflammatory Response as a Non-Specific Defence

• Process:

  1. Injured tissue releases chemical signals.

  2. Endothelial cells of nearby capillaries are activated.

  3. Adhesion molecules called selectins are displayed on endothelial cells, attracting neutrophils.

  4. Neutrophils roll along the endothelium and encounter chemicals that activate integrins.

  5. Integrins tightly attach to receptor molecules, causing neutrophils to stick to the endothelium (margination).

  6. Inflammatory mediators cause mast cells to release histamine, leading to vascular dilation and opening of junctions between endothelial cells.

  7. Fluid and leukocytes then leave the capillary and enter the infected tissue.

  8. Neutrophils undergo changes in shape and squeeze through the endothelial wall into the tissue fluid (extravasation).

  9. Neutrophils, followed by other phagocytes, are attracted to the damage site by chemotactic substances and ingest and destroy invading bacteria.

Complement System

• Ancient protein family involved in innate immunity.

• About 30 proteins are circulating in an inactive form.

• Activated through a cascade reaction, amplifying the signal quickly.

• Involved in:

  • Opsonization

  • Chemotaxis: Attracting cells to sites of infection.

  • Killing pathogens: Proteins insert themselves into the membrane of a pathogen to cause lysis (membrane attack complex).

Adaptive Immunity

• If the adaptive immune system gets a serious infection, it will call on the aid of the adaptive immune response.

• The adaptive immune response is highly specific to infections.

Antigens and Epitopes

• Antigen: A molecule able to activate the adaptive immune system (e.g., on the surface of a bacteria, fungi, or virus).

• Epitope: A specific three-dimensional shape on an antigen that binds to a receptor on an adaptive immune cell.

• Each epitope can stimulate a different immune response.

• Soluble Proteins: Act as Antigens and molecular residues form the epitopes that are able to bind receptors on the adaptive Immune cells.

Types of Adaptive Immunity

• Active Immunity: Activation of your own adaptive immune cells.

• Passive Immunity: Obtaining antibodies from the mother across the placenta or in breast milk.
  *Breast milk transfers antibodies that are not digested, thus being able to be passed into the circulation and forming an initial layer of protection for the newborn Infant.

Lymphocytes and Receptors

• Key aspect of Adaptive Immunity!

• Adaptive immunity involves lymphocytes that are able to recognise the vast amount of epitopes through genetic rearrangements and generate memory cells so that if we have seen infectious agents before, we already have an immune response that is ready to go.

• Vaccines Work by showing the immune system highly specific proteins on a pathogen to ensure an effective immune response. This ensures that memory is built up for the infectious agent.

• 100,000 receptors circulate on lymphocytes. This specific number is important to allow for genetic rearrangements that have the specific molecular shape to bind to a particular epitope.