Unit 1: Fundamentals of the immune system - Subjective Questions

Immunity refers to the ability of an organism to resist and defend against pathogens, foreign substances, and abnormal cells.

Innate (Non-specific) Immunity:

• Present from birth; the first line of defense.
• Acts immediately or within hours of infection.
• Non-specific — responds the same way to all pathogens.
• No immunological memory.
• Components: physical barriers (skin, mucous membranes), phagocytes (neutrophils, macrophages), NK cells, complement system, inflammation.
• Example: Skin acting as a barrier, macrophages engulfing bacteria.

Adaptive (Specific/Acquired) Immunity:

• Develops after exposure to a specific antigen.
• Slower response (days) on first exposure.
• Highly specific to particular antigens.
• Exhibits immunological memory — faster, stronger response on re-exposure.
• Components: T lymphocytes (cell-mediated) and B lymphocytes (humoral).
• Example: Antibody production against measles virus after vaccination.

Key Difference: Innate immunity is generalized and immediate, while adaptive immunity is specific and develops memory.

Acquired (Adaptive) Immunity can be classified into two main types:

1. Active Immunity — the host's own immune system produces antibodies.

• Natural Active: Acquired through actual infection (e.g., recovery from chickenpox).
• Artificial Active: Acquired through vaccination (e.g., polio vaccine).
• Features: Long-lasting, memory develops, slow onset.

2. Passive Immunity — ready-made antibodies are transferred to the host.

• Natural Passive: Antibodies transferred from mother to fetus via placenta or through breast milk (IgA).
• Artificial Passive: Injection of pre-formed antibodies/antiserum (e.g., anti-tetanus serum, anti-snake venom).
• Features: Immediate protection, short-lived, no memory.

Classification Chart:

Acquired Immunity
├── Active Immunity
│ ├── Natural (infection)
│ └── Artificial (vaccine)
└── Passive Immunity
├── Natural (mother to child)
└── Artificial (antiserum)

Comparison: Active immunity is durable but slow; passive immunity is instant but temporary.

Hematopoiesis is the process of formation, development, and differentiation of all blood cells from pluripotent hematopoietic stem cells (HSCs) in the bone marrow.

Properties of HSCs:

• Self-renewal — maintain the stem cell pool.
• Multipotency — differentiate into all blood cell types.

Differentiation Pathway:

Pluripotent HSC gives rise to two main progenitors:

1. Common Myeloid Progenitor (CMP):

• Erythrocytes (RBCs)
• Megakaryocytes → Platelets
• Granulocytes — Neutrophils, Basophils, Eosinophils
• Monocytes → Macrophages, Dendritic cells
• Mast cells

2. Common Lymphoid Progenitor (CLP):

• B lymphocytes
• T lymphocytes
• NK cells
• Dendritic cells (some)

Regulation: The process is controlled by cytokines and growth factors such as:

• Erythropoietin (EPO) — RBC production
• Thrombopoietin (TPO) — platelet production
• Colony Stimulating Factors (CSFs) — leukocyte production
• Interleukins (IL-3, IL-7)

Site: In adults, occurs mainly in the red bone marrow; in the fetus, it occurs in the liver and spleen.

Macrophages are large phagocytic cells derived from monocytes that migrate from blood into tissues.

Origin: Monocytes (from Common Myeloid Progenitor) enter tissues and differentiate into macrophages.

Structure:

• Large cells (10–30 µm) with abundant cytoplasm.
• Contain numerous lysosomes and phagosomes.
• Irregular shape with pseudopodia for movement.

Tissue-specific names:

• Kupffer cells — liver
• Alveolar macrophages — lungs
• Microglia — brain/CNS
• Osteoclasts — bone
• Histiocytes — connective tissue

Functions:

• Phagocytosis — engulf and destroy pathogens, dead cells, and debris.
• Antigen Presentation — act as Antigen Presenting Cells (APCs), presenting antigens via MHC-II to T cells.
• Cytokine secretion — release IL-1, TNF-α, IL-6 to trigger inflammation.
• Initiation of adaptive immunity by activating T-helper cells.
• Tissue repair and wound healing.

Macrophages thus bridge innate and adaptive immunity.

Both B and T lymphocytes originate from the Common Lymphoid Progenitor but differ in maturation and function.

B cell function: Differentiate into plasma cells that secrete antibodies against extracellular pathogens.

T cell function:

• Helper T (CD4+): Activate B cells, macrophages, and cytotoxic T cells.
• Cytotoxic T (CD8+): Kill infected/tumor cells.
• Regulatory T: Suppress immune responses.

Summary: B cells provide antibody-based defense; T cells provide cellular defense and regulation.

Granulocytes are white blood cells characterized by the presence of cytoplasmic granules and multilobed nuclei. They arise from the Common Myeloid Progenitor.

1. Neutrophils (50–70% of WBCs):

• Most abundant granulocyte; first responders to infection.
• Highly phagocytic — engulf bacteria and fungi.
• Multilobed nucleus (3–5 lobes).
• Form pus and undergo NETosis (release Neutrophil Extracellular Traps).

2. Eosinophils (1–4%):

• Bilobed nucleus with red-staining granules.
• Combat parasitic infections (helminths/worms).
• Involved in allergic reactions and asthma.
• Release toxic proteins like major basic protein.

3. Basophils (<1%):

• Least abundant; bilobed nucleus with blue-staining granules.
• Release histamine and heparin.
• Mediate allergic and inflammatory responses.
• Involved in hypersensitivity reactions.

Mast Cells (tissue-resident, similar function to basophils):

• Release histamine causing vasodilation and inflammation.

Summary: Neutrophils fight bacteria, eosinophils target parasites, and basophils/mast cells mediate allergy and inflammation.

Natural Killer (NK) cells are large granular lymphocytes belonging to the innate immune system, derived from the Common Lymphoid Progenitor.

Characteristics:

• Do not require prior sensitization (unlike T/B cells).
• Lack antigen-specific receptors (no TCR or BCR).
• Contain cytoplasmic granules with perforin and granzymes.
• Markers: CD16 and CD56 (CD3 negative).

Mechanism of Action — 'Missing Self' Hypothesis:

• Normal cells display MHC class I molecules → inhibitory signal → NK cell does NOT kill.
• Virus-infected or tumor cells often downregulate MHC-I → loss of inhibition → NK cell activated → kills the cell.

Killing Mechanisms:

1. Perforin-Granzyme pathway: Perforin creates pores; granzymes enter and trigger apoptosis.
2. Antibody-Dependent Cell-mediated Cytotoxicity (ADCC): NK cells bind antibody-coated cells via CD16 (Fc receptor) and destroy them.
3. Fas-FasL pathway: Induces apoptosis via death receptors.

Functions:

• Destroy virus-infected cells and tumor cells.
• Secrete IFN-γ to activate macrophages.
• Provide early defense before adaptive immunity develops.

Bone marrow is the soft, spongy tissue found in the cavities of bones and is a primary lymphoid organ.

Types:

• Red bone marrow: Site of active hematopoiesis (in flat bones like sternum, ribs, pelvis, vertebrae).
• Yellow bone marrow: Contains fat cells; can convert to red marrow when needed.

Structure:

• Contains hematopoietic stem cells (HSCs).
• Stromal cells provide a supportive microenvironment (niche).
• Rich network of sinusoids (blood vessels) for cell release.
• Reticular connective tissue framework.

Functions:

• Site of hematopoiesis — production of all blood cells (RBCs, WBCs, platelets).
• B-cell maturation — B lymphocytes mature here and undergo selection.
• Origin of all immune cells including T cell precursors (which mature in the thymus).
• Provides growth factors and cytokines for cell differentiation.
• Negative selection of self-reactive B cells (central tolerance).

Significance: Bone marrow is the source of all immune cells and the maturation site for B lymphocytes, making it central to immune function.

The thymus is a bilobed primary lymphoid organ located in the thoracic cavity behind the sternum. It is most active during childhood and undergoes involution (shrinks) after puberty.

Structure:

• Divided into lobules, each with an outer cortex and inner medulla.
• Cortex: Densely packed immature thymocytes (developing T cells).
• Medulla: Fewer, mature thymocytes; contains Hassall's corpuscles.
• Contains thymic epithelial cells, macrophages, and dendritic cells.

T-cell Maturation Process:
Immature T cells (thymocytes) migrate from bone marrow to the thymus and undergo:

1. Positive Selection (in cortex):

• Thymocytes that can recognize self-MHC molecules survive.
• Cells unable to bind MHC undergo apoptosis (death by neglect).

2. Negative Selection (in medulla):

• Thymocytes that bind too strongly to self-antigens are eliminated (apoptosis).
• Prevents autoimmunity by removing self-reactive T cells.

Outcome:

• Only ~2% of thymocytes survive and become mature CD4+ or CD8+ T cells.
• These enter circulation as immunocompetent T cells.

Functions:

• Site of T-cell maturation and education.
• Establishes central tolerance.
• Secretes hormones like thymosin and thymopoietin.

The lymphatic system is a network of vessels, organs, and tissues that transports lymph, maintains fluid balance, and plays a crucial role in immune defense.

Components:

1. Lymphatic Vessels:

• Thin-walled vessels that collect interstitial fluid (lymph) from tissues.
• Contain valves to ensure one-way flow toward the heart.
• Lymph capillaries → collecting vessels → lymphatic trunks → ducts.

2. Lymph:

• Clear fluid derived from blood plasma.
• Contains lymphocytes, proteins, and waste products.

3. Lymphoid Organs:

• Primary: Bone marrow, thymus.
• Secondary: Lymph nodes, spleen, tonsils, MALT.

4. Lymphatic Ducts:

• Thoracic duct: Drains most of the body.
• Right lymphatic duct: Drains upper right side.

Functions:

• Fluid balance: Returns excess interstitial fluid to blood circulation.
• Immune surveillance: Transports antigens and lymphocytes to lymph nodes.
• Fat absorption: Lacteals in intestines absorb dietary fats (chyle).
• Filtration: Lymph nodes filter pathogens and debris.
• Site of immune response: Lymphocytes encounter antigens and get activated.

Significance: It acts as the transport and surveillance network connecting immune cells with antigens throughout the body.

Lymph nodes are small, bean-shaped secondary lymphoid organs distributed along lymphatic vessels. They filter lymph and serve as sites for immune activation.

Structure (three regions):

1. Cortex (outer region):

• Contains B lymphocytes organized into primary and secondary follicles.
• Secondary follicles have germinal centers where B cells proliferate.

2. Paracortex (middle region):

• Rich in T lymphocytes.
• Contains dendritic cells presenting antigens.
• Has high endothelial venules (HEVs) for lymphocyte entry.

3. Medulla (inner region):

• Contains medullary cords (plasma cells, macrophages) and medullary sinuses.

Other features:

• Afferent lymphatic vessels bring lymph in.
• Efferent lymphatic vessel carries filtered lymph out (at hilum).
• Surrounded by a fibrous capsule with trabeculae.

Functions:

• Filtration of lymph — removes microbes, debris, and cancer cells.
• Antigen presentation — dendritic cells present antigens to T cells.
• Site of lymphocyte activation and proliferation.
• Antibody production by plasma cells.
• Immune surveillance — trap and destroy pathogens.

Clinical Note: Swollen lymph nodes (lymphadenopathy) indicate active infection.

The spleen is the largest secondary lymphoid organ, located in the upper left abdomen. It filters blood (unlike lymph nodes which filter lymph).

Structure:
The spleen consists of two functionally distinct regions:

1. Red Pulp:

• Composed of splenic sinusoids and splenic cords (of Billroth).
• Contains many macrophages and RBCs.
• Site of destruction of old/damaged RBCs and blood filtration.
• Acts as a blood reservoir.

2. White Pulp:

• Composed of lymphoid tissue around central arterioles.
• PALS (Periarteriolar Lymphoid Sheath): T-cell rich region.
• Lymphoid follicles: B-cell rich region with germinal centers.
• Marginal zone: Separates red and white pulp; contains macrophages and B cells.

Functions:

• Filtration of blood — removes old RBCs, platelets, and pathogens.
• Immune response — activation of B and T cells against blood-borne antigens.
• Antibody production by plasma cells.
• Removal of encapsulated bacteria (e.g., pneumococci).
• Hematopoiesis in fetus and reserve capacity in adults.
• Storage of platelets and RBCs.

Clinical Note: Splenectomy increases susceptibility to encapsulated bacterial infections.

MALT (Mucosa-Associated Lymphoid Tissue) refers to lymphoid tissue found in the mucosal linings of the body, guarding surfaces exposed to the external environment.

Significance: Mucosal surfaces (respiratory, digestive, urogenital tracts) are major entry points for pathogens; MALT provides localized immune protection.

Types of MALT:

1. GALT (Gut-Associated Lymphoid Tissue):

• Found in the gastrointestinal tract.
• Includes Peyer's patches (in small intestine), appendix, and isolated lymphoid follicles.

2. BALT (Bronchus-Associated Lymphoid Tissue):

• Found in the respiratory tract.
• Protects against inhaled pathogens.

3. NALT (Nasopharynx-Associated Lymphoid Tissue):

• Includes tonsils and adenoids.

4. Other: Tissue in urogenital tract, salivary glands, mammary glands.

Structural Features:

• Contains M cells that sample antigens from the lumen.
• Rich in IgA-secreting plasma cells.
• Contains B cells, T cells, and dendritic cells.

Functions:

• First-line defense at mucosal surfaces.
• Production of secretory IgA (sIgA) — prevents pathogen attachment.
• Antigen sampling and immune surveillance.
• Induction of oral tolerance to food antigens.

Summary: MALT provides critical protection at the largest surface area exposed to antigens in the body.

Lymphoid organs are classified based on their role in lymphocyte development and function.

Primary Lymphoid Organs:

• Bone marrow: Site of hematopoiesis and B-cell maturation.
• Thymus: Site of T-cell maturation and selection.
• Lymphocytes acquire antigen receptors and self-tolerance here.

Secondary Lymphoid Organs:

• Lymph nodes: Filter lymph, activate lymphocytes.
• Spleen: Filter blood, respond to blood-borne antigens.
• MALT/Tonsils: Mucosal immunity.
• Provide environment where mature lymphocytes encounter antigens and mount immune responses.

Summary: Primary organs 'educate' lymphocytes; secondary organs are the 'battlegrounds' of immune responses.

The humoral immune response (antibody-mediated immunity) is the branch of adaptive immunity mediated by antibodies produced by B lymphocytes. It targets extracellular pathogens (bacteria, toxins, viruses in body fluids).

Steps of the Humoral Response:

1. Antigen Recognition:

• B cells recognize a specific antigen through their B-cell receptor (BCR).

2. Antigen Processing and Presentation:

• B cell internalizes the antigen and presents it via MHC-II to a Helper T cell (CD4+).

3. B-cell Activation:

• Helper T cell releases cytokines (IL-4, IL-5, IL-6) providing the second signal.
• B cell becomes fully activated.

4. Clonal Expansion and Differentiation:

• Activated B cells proliferate and differentiate into:
  • Plasma cells — secrete large amounts of antibodies.
  • Memory B cells — provide long-term immunity.

5. Antibody Action:
Antibodies eliminate pathogens through:

• Neutralization — block toxins/viruses.
• Opsonization — coat pathogens for phagocytosis.
• Complement activation — trigger the complement cascade.
• Agglutination — clump pathogens together.
• ADCC — mark cells for NK-cell killing.

Primary vs Secondary Response:

• Primary: Slow, low antibody levels, mainly IgM.
• Secondary: Rapid, high antibody levels, mainly IgG (due to memory cells).

Summary: Humoral immunity provides antibody-based protection against extracellular threats with lasting memory.

The humoral response differs significantly between the first and subsequent exposures to the same antigen.

Primary Response:

• Naïve B cells first encounter the antigen.
• Slow because clonal expansion and differentiation take time.
• IgM appears first, followed by IgG.

Secondary Response:

• Memory B cells rapidly respond.
• Faster, stronger, and predominantly high-affinity IgG.
• Basis of vaccination and long-term immunity.

Graphical Representation:

• Antibody titer vs. time shows a small early peak (primary) and a much larger, faster peak (secondary).

Summary: The secondary response is faster, stronger, and more efficient due to immunological memory.

T lymphocytes mature in the thymus and are central to cell-mediated immunity. They are classified into functional subsets based on surface markers and roles.

1. Helper T Cells (CD4+, T_H):

• Recognize antigens presented on MHC-II.
• Central coordinators of the immune response.
• Subtypes:
  • T_H1: Activate macrophages and cytotoxic T cells (cell-mediated immunity); secrete IFN-γ.
  • T_H2: Help B cells produce antibodies (humoral immunity); secrete IL-4, IL-5.
  • T_H17: Defend against fungi and bacteria; secrete IL-17.

2. Cytotoxic T Cells (CD8+, T_C / CTL):

• Recognize antigens presented on MHC-I.
• Directly kill infected, tumor, or transplanted cells.
• Use perforin and granzymes to induce apoptosis.

3. Regulatory T Cells (Treg, CD4+CD25+):

• Suppress immune responses to maintain tolerance.
• Prevent autoimmunity and excessive inflammation.
• Express transcription factor FOXP3.

4. Memory T Cells:

• Long-lived cells that provide rapid response upon re-exposure.

Summary: Helper T cells coordinate immunity, cytotoxic T cells kill infected cells, and regulatory T cells maintain balance — together enabling effective cell-mediated defense.

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs), acting as the crucial link between innate and adaptive immunity.

Origin: Derived from both myeloid and lymphoid progenitors in the bone marrow.

Structure:

• Characterized by long, branching cytoplasmic projections (dendrites) that increase surface area for antigen capture.

Types:

• Conventional/Myeloid DCs: Main antigen presenters.
• Plasmacytoid DCs: Produce large amounts of type-I interferons (antiviral).
• Langerhans cells: DCs of the skin.
• Follicular DCs: Present antigens to B cells in lymph nodes.

Functions:

1. Antigen Capture:

• Capture antigens at sites of infection via phagocytosis, endocytosis, and pinocytosis.

2. Antigen Processing:

• Process antigens and load fragments onto MHC-I and MHC-II molecules.

3. Migration:

• Migrate from peripheral tissues to secondary lymphoid organs (lymph nodes).

4. Antigen Presentation:

• Present antigens to naïve T cells, providing the primary activation signal.
• Only APC capable of activating naïve T cells.

5. Co-stimulation:

• Express co-stimulatory molecules (B7/CD80/CD86) that provide the second signal.

Significance: Dendritic cells initiate the adaptive immune response by activating naïve T cells, making them essential 'sentinels' of the immune system.

Phagocytosis is the process by which specialized cells (phagocytes) engulf and destroy pathogens, dead cells, and foreign particles. It is a key mechanism of innate immunity.

Major Phagocytes:

• Neutrophils, Macrophages, Monocytes, and Dendritic cells.

Stages of Phagocytosis:

1. Chemotaxis:

• Phagocytes are attracted to the site of infection by chemical signals (chemoattractants) such as bacterial products, complement fragments (C5a), and cytokines.

2. Adherence (Attachment):

• Phagocyte binds to the pathogen surface.
• Enhanced by opsonization (coating with antibodies or complement C3b).

3. Ingestion (Engulfment):

• The phagocyte extends pseudopodia around the pathogen.
• Pathogen is enclosed in a vesicle called a phagosome.

4. Phagosome-Lysosome Fusion:

• The phagosome fuses with a lysosome to form a phagolysosome.

5. Digestion (Killing):
Pathogen is destroyed by:

• Oxygen-dependent mechanisms: Reactive oxygen species (ROS), respiratory burst, nitric oxide.
• Oxygen-independent mechanisms: Lysozymes, defensins, hydrolytic enzymes, low pH.

6. Elimination (Exocytosis):

• Digested debris is expelled from the cell.

Significance: Phagocytosis eliminates pathogens directly and enables antigen presentation, linking innate and adaptive immunity.

The cells of the immune system all originate from hematopoietic stem cells and are classified based on lineage and function.

A. Lymphoid Lineage (from Common Lymphoid Progenitor):

1. B Lymphocytes:

• Mediate humoral immunity.
• Differentiate into plasma cells (antibody secretion) and memory B cells.

2. T Lymphocytes:

• Mediate cell-mediated immunity.
• Include Helper T (CD4+), Cytotoxic T (CD8+), and Regulatory T cells.

3. NK Cells:

• Innate cells that kill virus-infected and tumor cells.

B. Myeloid Lineage (from Common Myeloid Progenitor):

1. Granulocytes:

• Neutrophils: Phagocytosis of bacteria (first responders).
• Eosinophils: Anti-parasitic defense, allergy.
• Basophils: Release histamine; allergic/inflammatory response.

2. Monocytes/Macrophages:

• Phagocytosis, antigen presentation, cytokine secretion.

3. Dendritic Cells:

• Professional APCs; activate naïve T cells.

4. Mast Cells:

• Tissue-resident; release histamine in allergy and inflammation.

5. Megakaryocytes → Platelets:

• Aid in clotting and inflammation.

Summary Table:

Significance: These cells work together, coordinating innate and adaptive responses to protect the body.