Immunology

Chapter 1-3

immune system

an integrated network of organs, cells, tissues, and molecules that protect, defend, and maintain host integrity

Normal processes for the immune system

• Protection: Protects the host against pathogenic infections, tumor cells, cancer growth, and harmful environmental factors.

• Defense: Mediates defense through inflammation, phagocytosis, and the rejection of foreign tissue transplants.

• Maintenance: Promotes tissue repair, clearance of foreign substances, and the destruction and removal of damaged or necrotic host cells.

Innate Immunity (Natural / Naïve):

• Timing: Present at birth and available immediately prior to infection with no time lag.

• Specificity: Limited specificity; relies on germline-encoded invariant receptors to recognize shared, conserved microbial structures (PAMPs).

• Memory & Intensity: Lacks immunological memory; repetitive exposures generate the exact same intensity of response every time.

Adaptive Immunity (Specific / Acquired):

• Timing: Develops over time following exposure to a specific foreign trigger; requires days to weeks to activate.

• Specificity: High/extreme specificity; discriminates fine structural details of unique protein antigens.

• Memory & Intensity: Generates long-lasting immunological memory; secondary exposures trigger exponentially faster and more powerful responses.

Components of the first line of defense

• Physical & Epithelial Barriers

• Mechanical & Microbiological Barriers

• Chemical Barriers

• Intraepithelial Cells

Physical & Epithelial Barriers (1st line of defense)

The outer skin covered in a protective keratin layer (stratified squamous epithelium), as well as mucosal epithelial linings throughout the gastrointestinal, respiratory, and genitourinary tracts.

Mechanical & Microbiological Barriers (1st line of defense)

Epithelial cells joined by tight junctions, cilia-driven mucociliary flow, peristalsis in the gut, epithelial sloughing, and competitive exclusion by normal microbiota.

Chemical Barriers (1st line of defense)

Antimicrobial peptides (defensins and cathelicidins), low pH in gastric secretions, enzymes (lysozyme) in tears and saliva, and pulmonary surfactant proteins.

Intraepithelial Cells (1st line of defense)

Resident intraepithelial lymphocytes, dendritic cells, macrophages, and neutrophils stationed within epithelial layers to ingest invaders.

Active Immunity

Induced by exposure to an active infection or vaccination.

• It takes time to develop but produces long-lasting protection and immunological memory.

Passive Immunity

Acquired via the direct transfer of pre-formed antibodies or cells from an immune individual (e.g., maternal antibody transfer, antibody infusions, antitoxins).

• It provides immediate protection but is short-lived and leaves no immunological memory

Adaptive Immunity Properties

• Diversity

• Specificity

• Immunologic Tolerance (Nonreactivity to Self)

• Immunologic Memory

Diversity

The system maintains a vast repertoire capable of recognizing millions of distinct antigen types. Every individual lymphocyte expresses a unique receptor type; when triggered, matching clones expand into millions of identical cells.

Specificity

Selective recognition occurs through non-covalent 3D binding between an antigen and an antibody binding cleft (B cells) or a TCR interacting with a peptide bound in an MHC cleft (T cells). A slight change in 3D shape completely alters recognition.

Immunologic Tolerance

The immune system learns to eliminate or tolerate self-antigens and harmless substances. Breakdown of tolerance leads to autoimmune diseases (e.g., Rheumatoid Arthritis, Type I Diabetes, Lupus) or allergies.

Immunologic Memory

Following initial exposure, lymphocytes produce long-lived memory clones. Second encounters trigger a magnified, faster, and more effective secondary response.

Clonal selection theory

• Pre-existing Diversity: Prior to antigen encounter, precursor lymphocytes undergo genetic rearrangement in primary lymphoid organs to produce clones with distinct, unique antigen receptors.

• Selection & Expansion: When a specific foreign antigen enters the body, it binds to the matching pre-existing lymphocyte clone (which exists at a frequency of 1 in 1,000 to 10,000 cells).

• Proliferation: Antigen binding selects that specific clone and triggers its proliferation and differentiation into millions of identical effector cells recognizing that exact antigen.

Primary Immune Response:

• Triggered by the initial encounter with a foreign antigen.

• Driven by naïve lymphocytes; takes 10–14+ days to develop fully.

• Produces lower cell numbers and lower antibody titers (predominantly IgM, with low IgG).

• Generates memory cell clones.

Secondary Immune Response:

• Triggered by subsequent encounters with the same antigen.

• Engages pre-existing memory cells; acts rapidly within 2–3 days.

• Yields higher cell numbers and significantly elevated antibody titers (predominantly IgG and IgA) with higher binding affinity.

Why do we vaccinate?

• Objective: Vaccination safely introduces an antigen to induce active immunity and generate long-lasting immunological memory without causing clinical disease.

• Global Impact: Worldwide vaccination programs have eradicated smallpox and dramatically reduced major infectious diseases, including polio, measles, mumps, and whooping cough (pertussis).

All blood cells of both innate and adaptive immunity originate where?

in the red bone marrow from a single cell type:

-the pluripotent hematopoietic stem cell

Lineage Divergence: Stem cells differentiate into two main lineages:

• Myeloid Lineage

• Lymphoid Origin

Myeloid Lineage

Gives rise to erythrocytes, megakaryocytes/platelets, granulocytes (neutrophils, eosinophils, basophils),

Lymphoid Lineage

Gives rise to B lymphocytes, T lymphocytes, Natural Killer (NK) cells, and innate lymphoid cells (ILCs).

Neutrophils Fxn

• Most abundant WBC in blood

• primary cell in acute inflammation

• rapidly phagocytoses and kills microbes

Monocytes / Macrophages Fxn

• Monocytes circulate in blood and enter tissues to differentiate into long-lived macrophages.

• Functions include phagocytosis, cytokine production, tissue repair, and antigen presentation

Dendritic Cells Fxn

• Sentinel cells in tissues;

• capture and process antigens, then migrate to secondary lymphoid organs to prime naïve T cells

B Lymphocytes Fxn

• Mediators of humoral immunity;

• recognize extracellular antigens via surface antibodies and differentiate into antibody-secreting plasma cells

Helper T Cells (CD4+) Fxn

• Secrete cytokines to activate B cells, macrophages, and induce inflammation

Cytotoxic T Cells (CD8+) Fxm

Mediators of cell-mediated immunity; directly kill virus-infected cells, damaged host cells, and tumor cells

Regulatory T Cells Fxn

• Suppress other lymphocytes to regulate responses and maintain self-tolerance

Mast Cells fxn

Resident in tissues; release histamine and lipid mediators to defend against parasites and venoms; mediate allergic symptoms

Natural Killer (NK) Cells Fxn

Innate lymphoid cells that recognize and kill virus-infected or abnormal cells and secrete IFN-y.

Primary Lymphoid Organs

Sites where lymphocytes undergo genetic rearrangement and maturation

• Bone Marrow and Thymus

Bone Marrow

Origin of all leukocytes; primary site where B lymphocytes mature.

Thymus

Precursor T cells travel from the bone marrow to the Thymus to mature into naïve T cells

Tissue Differentiation

Circulating monocytes exit blood vessels into tissues to differentiate into specialized mature macrophages (e.g., Langerhans cells, Kupffer cells, Alveolar macrophages).

Naïve Lymphocyte Trafficking

Mature naïve B and T cells continuously exit primary organs into the blood and migrate into secondary peripheral lymphoid organs (lymph nodes, spleen, GALT, MALT, SALT) to sample for foreign antigens.

Antigen Presenting Cell (APC) Migration

Sentinel dendritic cells in barrier tissues capture antigens, undergo maturation, express the chemokine receptor CCR7, and migrate through lymphatic vessels to draining lymph nodes.

Migration of cells to the secondary lymph tissues functional purpose

Secondary lymphoid tissues concentrate lymphocytes and APCs within a small anatomical region, enabling efficient cell-to-cell communication, chemical signal exchange, and rapid clonal selection

Lymph Node Architecture

• Encapsulated, bean-shaped organs distributed throughout the body that collect and filter tissue lymph fluid.

• B Cell Zone (Follicles): Located in the outer cortex/periphery; contains germinal centers where selected B cells rapidly divide.

• T Cell Zone (Paracortex): Located in the parafollicular cortex surrounding follicles; rich in T cells and dendritic cells presenting antigens.

Spleen Architecture:

• Highly vascularized major secondary lymphoid organ located in the upper left abdomen that filters and samples blood-borne antigens.

• White Pulp: Comprises the Periarteriolar Lymphoid Sheaths (PALS) rich in T cells, surrounded by B cell follicles.

• Red Pulp: Filters blood, removing old or damaged erythrocytes and platelets.

Recirculation

The continuous, systemic cycling of naïve lymphocytes between the blood and secondary lymphoid organs. Naïve T cells pass through lymph nodes at least once a day; if unactivated by an antigen, they re-enter circulation via efferent lymphatics to repeat the cycle.

Migration (Homing):

The targeted movement of activated effector lymphocytes out of the blood and directly into specific peripheral tissue sites of infection or inflammation, guided by chemokine gradients and endothelial adhesion molecules.

Pathogen-Associated Molecular Patterns (PAMPs):

Shared, highly conserved molecular structures essential for the survival, structure, or infectivity of microbes that cannot easily be mutated.

Examples include lipopolysaccharide (LPS / endotoxin) on Gram-negative bacteria, peptidoglycan and lipoteichoic acid on Gram-positive bacteria, bacterial lipopeptides, flagellin, double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), and unmethylated CpG DNA.

Damage-Associated Molecular Patterns (DAMPs):

• Molecules released from host cells that are damaged, stressed, or undergoing necrotic cell death. 

  • Examples include HMGB1 (high mobility group box protein 1), extracellular ATP, uric acid / urate crystals, cholesterol crystals, and cytosolic self-DNA.

Epithelial system barrier

• Physical

• Mechanical

• Chemical

Physical Barriers

• Stratified squamous epithelium of the skin covered in a protective keratin layer;

• mucosal epithelial linings throughout the gastrointestinal, respiratory, and genitourinary tracts.

• Cells are joined by tight junctions to block entry. Includes specialized intraepithelial lymphocytes (predominantly yS-T cell-related) stationed directly within epithelial layers.

Mechanical Barriers

• Cilia-driven mucociliary flow in the respiratory tract,

• peristalsis in the gut,

• epithelial cell sloughing,

• fluid washing (tears, saliva),

• competitive exclusion by normal microbiota.

Chemical Barriers

• Antimicrobial peptides (defensins and cathelicidins) that disrupt microbial cell membranes;

• enzymes such as lysozyme in tears and saliva; l

• ow pH in gastric juice;

• pulmonary surfactant proteins.

Characteristics of DCs

• Tissue-resident sentinel cells with long, fingerlike projections.

• Originate from hematopoietic stem cells and act as the principal Antigen Presenting Cell (APC) to bridge innate and adaptive Immunity.

Types of DCs:

• Conventional (Classic) DCs

• Plasmacytoid DCs

Conventional (Classic) DCs:

Reside in epithelia (e.g., Langerhans cells in skin) and lymphoid organs; specialize in capturing and presenting protein antigens to T cells.

Plasmacytoid DCs

• Resemble plasma cells; present in blood and tissues; primary producers of Type I IFNs IFN-a/B upon sensing viral nucleic acids.

Dendritic Cell Actions

• Sense PAMPs/DAMPs via TLRs and cytosolic PRRs, triggering phagocytosis or macropinocytosis;

• secrete pro-inflammatory cytokines (TNF, IL-1) to initiate inflammation;

• downregulate tissue adhesion molecules and express CCR7 to migrate along a CCL19/CCL21 chemokine gradient into draining lymph nodes;

• upregulate Class I MHC, Class II MHC, and costimulators (B7-1/CD80, B7-2/CD86) to prime naïve T cells.

NK Cell Characteristics

Invariant lymphoid cells residing in blood and secondary lymphoid organs that lack antigen-specific T cell receptors (TCRs) or surface antibodies.

NK cell actions

• Recognize and kill virus-infected, damaged, or tumor cells by releasing cytotoxic granules (perforin and granzymes) directly into target cells to induce apoptosis.

• Secretes IFN-y to activate macrophages.

• Mediates Antibody-Dependent Cellular Cytotoxicity (ADCC) via surface CD16 binding the Fc region of IgG antibodies.

Activating Signaling (ITAMs):

Activating receptors (NKG2D, CD16) bind stress ligands on infected or tumor cells. Signaling triggers phosphorylation of Immunoreceptor Tyrosine-based Activation Motifs (ITAMs), which recruit tyrosine kinases to induce granule exocytosis and IFN-y production.

Inhibitory Signaling (ITIMs):

Inhibitory receptors (KIR, CD94/NKG2) bind self Class I MHC molecules present on all healthy nucleated host cells. Engagement activates Immunoreceptor Tyrosine-based Inhibitory Motifs (ITIMs), which recruit tyrosine phosphatases that remove phosphate groups from ITAMs, blocking NK activation and protecting normal host cells.

TLR Structure & Location

Transmembrane pattern recognition receptors composed of an extracellular/lumenal leucine-rich repeat (pathogen-recognizing) domain and a cytosolic Toll-IL-1 Receptor (TIR) domain. Located on the plasma membrane (for extracellular microbes) or in endosomal membranes (for internalized microbial nucleic acids).

Signaling & Gene Activation of TLR

Ligand binding causes receptor dimerization and engagement of cytosolic adaptors such as MyD88 or TRIF.

TLR activates what pathway?

• Activates the NF-kB pathway to drive transcription of pro-inflammatory cytokines (TNF, IL-1, IL-6), endothelial adhesion molecules (E-selectin), and costimulators.Activates Interferon Regulatory Factors (IRFs) (IRF3/IRF7) to stimulate transcription of Type I IFNs IFN-a/B for antiviral defense.

NK-kb actions

Activated in response to diverse stimuli (TLRs, cytokine receptors, TNF receptor superfamily, TCR, BCR) via the TAK1 signaling integrator. Activation requires the phosphorylation and degradation of the inhibitory protein IkBa by the IkB kinase (IKK) complex.

• Actions Across Immune Cells:

  • Innate Phagocytes & Macrophages: Drives M1 macrophage polarization, promoting expression of pro-inflammatory cytokines (TNF-a, IL-1, IL-6, IL-12) and chemokines. Regulates inflammasome activation

  • Vascular Endothelial Cells: Induces expression of pro-inflammatory cytokines, chemokines, and endothelial adhesion molecules (E-selectin, ICAM-1) to promote leukocyte recruitment.

  • T Lymphocytes: Promotes differentiation and effector functions of Th1 (via IL-12 regulation) and Th17 cells; regulates Treg cell function to maintain self-tolerance.

  • Pathology & Systemic Balance: Deregulated NF-kB activation contributes to autoinflammatory diseases, inflammatory bone loss (osteoclast differentiation), and autoimmune autoantibody production. Systemic therapeutic inhibition must be balanced, as complete blockade causes severe adverse side effects due to NF-kB's role in baseline cell survival and normal immunity.

Toll-Like Receptors (TLRs)

• Cell membrane (for extracellular signals) or endosomal membrane (for internalized nucleic acids)

• Action: Dimerize and signal via MyD88 or TRIF to activate NF-κB (driving acute inflammation, cytokines, and endothelial adhesion molecules) or IRFs (inducing Type I Interferons)

Nod-Like Receptors (NLRs)

• Location: Cytosol

• Action: Detect cytosolic PAMPs and DAMPs to trigger inflammation and host defense genes

• Specific Types & Recognized Ligands:

  • NOD1: Senses peptidoglycan dipeptides in the cytosol; activates NF-κB

  • NOD2: Senses peptidoglycan dipeptides in the cytosol; activates NF-κB5. Highly expressed in Paneth cells of the small intestine to stimulate defensin production

Inflammasomes

• Location: Cytosol. 

• Multiprotein complexes consisting of a sensor (like an NLR protein), an adaptor, and inactive Caspase-1.

• Action: Cleaves pro-IL-1β into active IL-1β and IL-18 to drive acute inflammation. Cleaves gasdermin D to form membrane channels, causing ion influx, cell swelling, and pyroptosis (inflammatory cell death)

• Specific Type:

  • NLRP3 Inflammasome: Senses cytosolic PAMPs/DAMPs, extracellular ATP, uric acid crystals, cholesterol crystals, reduced K efflux, and reactive oxygen species (ROS)

RIG-Like Receptors (RLRs)

• Location: Cytosol

• .Action: Signal through MAVS (mitochondrial antiviral signaling protein) to activate IRF3/IRF7, driving transcription of Type I IFNs (IFN-a\B) to establish an antiviral state

• Specific Types & Recognized Ligands:RIG-I & MDA-5: Recognize cytosolic viral double-stranded RNA (dsRNA) and RNA with a 5' triphosphate.

Cytosolic DNA Sensors (CDS)

• Location: Cytosol and Endoplasmic Reticulum (ER)

• Action: Detect cytosolic double-stranded DNA (dsDNA) from intracellular viruses, bacteria, or damaged self-DNA

• Specific Pathway:cGAS / STING Pathway: Cytosolic dsDNA binds cGAS (cGMP-AMP synthase), generating cGAMP, which binds STING on the ER. STING recruits TBK1 to phosphorylate IRF3, activating Type I IFN production and inducing autophagy to destroy intracellular pathogens.

Complement activation

• Alternative Pathway

• Lectin Pathway

• Classical Pathway

Alternative Pathway

• Innate

First to be activated. Initiated when C3 undergoes spontaneous low-level hydrolysis or direct interaction with microbial surface molecules; C3b binds factor B (FB) and factor D (FD) to form the C3bBb convertase.

Lectin Pathway

• Innate

Second to be activated. Triggered when plasma Mannose-Binding Lectin (MBL) or ficolins bind terminal mannose/carbohydrate residues on pathogens. MASPs cleave C4 and C2 to form the C4b2b convertase.

Classical Pathway

• Adaptive/Humoral

• Last to be activated. Triggered when antibodies (IgM or IgG) or C-reactive protein (CRP) bind specific antigens on a microbial surface. C1 (C1q, C1r, C1s) binds the complex and cleaves C4 and C2 to form the C4b2b convertase.

Convergence of Complement activation

Both C3 convertases (C3bBb and C4b2b) cleave C3 into C3a and C3b. C3b attaches to the pathogen and recruits additional factors to form C5 convertase, which cleaves C5 into C5a and C5b.

Opsonization & Phagocytosis

• C3b covalently binds microbial surfaces, acting as an opsonin that binds complement receptors (CR1) on phagocytes to dramatically enhance phagocytic uptake.

Goal of three pathways of complement

• Opsonization & Phagocytosis

• Inflammation

• Cell Lysis

Inflammation

• Cleavage fragments C3a and C5a (anaphylatoxins) stimulate local inflammation. They act as chemoattractants for neutrophils and monocytes, activate endothelial cells, and trigger mast cell degranulation.

Cell Lysis

• C5b initiates assembly of terminal complement components to construct the Membrane Attack Complex (MAC), forming a transmembrane pore that causes osmotic lysis of foreign cells.

MAC complex

• Composition: Assembled from terminal complement proteins C5b, C6, C7, C8, and multiple polymerized C9 molecules (C5b-C9).

• Assembly Process:

  • Cleavage of C5 yields C5b, which binds C6 and C7.

  • The hydrophobic C5b67 complex inserts into the target cell's lipid bilayer.

  • C8 binds C5b67 and anchors deeper into the membrane.

  • multiple C9 molecules (10–16) polymerize around C5b678 to form a hollow, membrane-spanning channel.

• Function: Disrupts cell membrane permeability, causing unregulated influx of water and ions that leads to osmotic swelling and cell lysis (most effective against Gram-negative bacteria).

TNF (Tumor Necrosis Factor):

• Produced by macrophages, T cells, mast cells.

• Activates endothelial cells (adhesion molecules),

• activates neutrophils,

• induces fever (hypothalamus),

• stimulates liver acute-phase proteins

• causes cachexia; excess levels cause septic shock (hypotension, intravascular coagulation)

IL-1

Produced by macrophages, DCs, endothelial cells. Activates endothelial cells, induces fever, stimulates liver acute-phase reactants, and drives Th17 differentiation

IL-6

Produced by macrophages, endothelial cells, T cells. Triggers liver synthesis of acute-phase reactants (CRP, fibrinogen) and promotes B cell proliferation

IL-12

Produced by DCs and macrophages. Stimulates NK cells and T cells to produce IFN-y and enhances their cytotoxic activity; drives Th1 differentiation

IFN-y

Secreted by NK cells and T lymphocytes. Mediates classical activation of macrophages (M1) to increase microbicidal killing

Type I IFNs (IFN-a, IFN-b):

Secreted by virus-infected cells and plasmacytoid DCs. Establish an antiviral state in host cells (blocks protein synthesis, degrades viral RNA), upregulate Class I MHC, and activate NK cells

IL-10

Produced by macrophages, DCs, and Tregs. Anti-inflammatory cytokine that inhibits cytokine/chemokine production by macrophages and downregulates costimulators and MHC II

IL-15 & IL-18:

IL-15 drives NK and T cell proliferation; IL-18 stimulates IFN-y synthesis

Chemokines

Secreted by macrophages, DCs, and endothelial cells. Increase leukocyte integrin affinity and direct leukocyte chemotaxis to infection sites

Neutrophil killing Characteristics

• Polymorphonuclear leukocytes (PMNs) are the most abundant WBCs in blood and the primary cell in acute inflammation; short-lived (hours to 1–2 days)

Natural Killing Mechanisms

• Phagocytosis: Ingests microbes into phagosomes, which fuse with granules/lysosomes

• Respiratory / Oxidative Burst: Phagocyte oxidase assembly converts O2 into superoxide radicals and toxic Reactive Oxygen Species (ROS)

• Degranulation: Releases lysosomal enzymes (elastase, myeloperoxidase) into phagolysosomes and the extracellular environment

• Neutrophil Extracellular Traps (NETs): Upon cell death, neutrophils extrude nuclear chromatin networks embedded with granule enzymes to physically trap and kill extracellular bacteria.

Ingesting and killing by phagocytes

• Chemotaxis: Phagocytes (neutrophils, monocytes/macrophages, DCs) migrate toward the infection guided by chemokines, C5a, C3a, and bacterial formyl peptides.

• Recognition & Attachment: Surface receptors bind PAMPs directly (e.g., mannose receptors) or recognize opsonized microbes coated with C3b (via complement receptors) or IgG (via Fc receptors).

• Engulfment: Pseudopods extend around the microbe, fusing to enclose it inside a phagosome.

• Phagolysosome Fusion: The phagosome fuses with lysosomes to form a phagolysosome.

• Microbial Destruction:

  • ROS: Phagocyte oxidase generates toxic reactive oxygen species.

  • Nitric Oxide (NO): In macrophages, inducible nitric oxide synthase (iNOS) converts arginine into toxic nitric oxide.

  • Enzymatic Degradation: Lysosomal proteases, defensins, low pH, and iron-binding compounds degrade microbial components.

• Recycling & Waste Removal: Debris is exocytosed, and peptide fragments are loaded onto MHC molecules for antigen presentation.

Anti-inflammatory Cytokines

• Production of IL-10 (suppresses macrophage expression of TNF, IL-12, MHC II, and costimulators) and TGF-B.

Cytokine Antagonists

Secretion of IL-1 receptor antagonist (IL-1ra) directly blocks IL-1 signaling

Recruitment and migration of phagocytes

• Endothelial Activation: Macrophages/DCs detect microbes and release TNF and IL-1, activating endothelial cells of local postcapillary venules.

• Selectin-Mediated Rolling (Weak Adhesion): Endothelial cells express E-selectin and P-selectin. Circulating neutrophils/monocytes bind selectins via surface carbohydrates, slowing down and rolling along the vessel wall.

• Chemokine Activation: Chemokines displayed on endothelial proteoglycans bind leukocyte chemokine receptors, triggering a conformational change in leukocyte integrins from a low-affinity to a high-affinity state.

• Integrin-Mediated Firm Adhesion (Stopping): High-affinity leukocyte integrins (LFA-1, Mac-1) bind endothelial ligands (ICAM-1), stopping leukocyte rolling and flattening the cell.

• Transmigration (Diapedesis): Leukocytes squeeze between endothelial cell junctions into the extravascular tissue.

• Chemotaxis: Leukocytes crawl through tissue along a chemical concentration gradient of chemokines, C5a, C3a, and bacterial formyl peptides to reach the exact site of infection

T cell recognition requires

• MHC Restriction: T cell receptors (TCRs) do not recognize cell-free, soluble, or native 3D folded proteins. They recognize only linear peptide fragments held inside the peptide-binding cleft of a Major Histocompatibility Complex (MHC) molecule on an Antigen Presenting Cell (APC).

• Coreceptor Specificity: CD4+ T cells recognize peptides displayed on MHC Class II molecules, whereas CD8+ T cells recognize peptides displayed on MHC Class I molecules

How are antigens captured by APC

• Portals of Entry & Sampling: Antigens enter through epithelial barriers (skin, GI tract, respiratory, genitourinary) and are captured by resident sentinel cells (dendritic cells, macrophages) using Pattern Recognition Receptors (PRRs) via phagocytosis, pinocytosis, or receptor-mediated endocytosis.

• Delivery Routes: Antigens reach secondary lymphoid tissues through two primary routes:

  • Cellular Transport: Activated dendritic cells ingest foreign proteins in tissues and physically migrate through lymphatic vessels into draining lymph nodes.

  • Fluid Transport: Soluble, cell-free antigens drain passively via lymphatic fluid into lymph nodes or travel through the bloodstream to be filtered by resident APCs in the spleen.

Dendritic activation and migration

• Activation: Tissue-resident dendritic cells (e.g., Langerhans cells) capture antigens and sense microbial PAMPs/DAMPs via PRRs, as well as pro-inflammatory cytokines (TNF, IL-1).

• Loss of Adhesion & Receptor Expression: Activated DCs lose their physical adhesiveness to epithelial tissues and express the chemokine receptor CCR7.

• Migration: CCR7 senses a chemical concentration gradient of chemokines (CCL19/CCL21) produced by lymphatic endothelial and stromal cells in lymph nodes. This directs mature DCs through afferent lymphatic vessels into the T-cell rich paracortex of the draining lymph node.

• Maturation: As they travel, DCs mature from capturing cells into presenting cells by dramatically upregulating Class I and Class II MHC molecules and costimulatory surface molecules (B7-1/CD80, B7-2/CD86).

Antigen presenting cell characteristics

What are MHC complex molecules

• Definition: Membrane-bound surface proteins (termed Human Leukocyte Antigens [HLA] in humans) that act as the primary display mechanism for peptide fragments to T cells.

• Role: They serve as cell surface "self" markers unique to every individual and are the principal molecular targets determined during tissue graft and organ transplant matching

Polymorphism

• Population Diversity: MHC genes are the most polymorphic genes in humans, containing thousands of different alleles across the population (e.g., HLA-A, HLA-B, HLA-C for Class I; HLA-DP, HLA-DQ, HLA-DR for Class II)

• Location & Purpose: Genetic variations are concentrated in the floor pockets of the peptide-binding cleft a1\a2 in Class I, a1\b1 in Class II). This structural variation alters which peptides fit into the cleft, ensuring that the human population as a whole can bind and respond to diverse microbial peptides. Genes are expressed codominantly

Peptide binding in the MHC complex

• Mechanics: The peptide-binding cleft holds one peptide at a time.

• Residues:

  • Anchor Residues: 1–2 specific amino acids of the peptide extend downward into pockets on the cleft floor to physically hold the peptide in place.

  • Projection Residues: Amino acids projecting upward out of the cleft contact the variable loops of the T Cell Receptor.

• Broad Specificity: A single MHC molecule can present many distinct peptides, provided they possess matching anchor amino acids.

• Length Constraints: Class I clefts hold 8–11 amino acids; Class II clefts hold 10–30 amino acids.