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Chapter 15. Immunology

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1. Overview of the Animal Immune System

2. Innate Immunity

3. Adaptive Immunity: Antigen, Lymphocytes, MHC

4. Overview of Immune Response

5. Adaptive Immunity: T Lymphocytes

6. Adaptive Immunity: B Lymphocytes

7. T Cells vs. B Cells

8. Immune System Disorders

a. Microcytotoxicity Experiment

1. Overview of the Animal Immune System

⑴ Innate Immunity (Nonspecific Immunity): Present in all animals

① Recognizes common characteristics shared by specific groups of pathogens using a small number of receptors

② Rapid response occurs

○ Order of action by white blood cells: NK cells → neutrophils → monocytes → T lymphocytes

○ Interferon and immunoglobulin act faster than NK cells

③ Types: Barrier defense, internal defense

○ Barrier defense (1^st line): Skin, mucous membranes, secretions, normal flora

○ Internal defense (2^nd line): Phagocytes, natural killer cells, antimicrobial proteins, inflammatory response, complement system

⑵ Adaptive Immunity (Acquired Immunity, Specific Immunity): Present only in vertebrates

① Recognizes very specific characteristics of specific pathogens using a wide diversity of receptors

② Slower response occurs

③ Immunological memory: Since the adaptive response is slow, memory cells are generated after the primary immune response to enhance the magnitude and speed of the response

○ Primary immune response: First exposure to a specific antigen

○ Secondary immune response: Second exposure to a specific antigen

④ Types : Cellular immunity, humoral immunity

○ Cellular immunity : Cytotoxic T lymphocytes respond to foreign molecules infecting host cells

○ Humoral immunity : Antibodies respond to foreign molecules in body fluids

⑶ Active Immunity and Passive Immunity

① Active immunity = Acquired immunity

○ Immunity formed naturally by infection or artificially by vaccination

○ Vaccine: A type of antigen administered to activate the immune function against infectious diseases

○ Examples: Bacterial toxins, attenuated bacteria, microbial components, nonpathogenic microbes, etc.

② Passive immunity

○ Immunity formed by transferring antibodies or cells from an immunized individual to a non-immunized individual

○ Example 1. IgG transferred to the fetus through the placenta

○ Example 2. IgA transferred to newborns through breast milk

○ Example 3. Administration of anti-D antibodies to prevent Rh incompatibility

⑷ Cytokines: Chemical substances that regulate immune responses

① Interleukins (IL)

○ IL-1

○ Secreted by macrophages to activate Th1 cells

○ Also known as prostaglandin (PG)

○ IL-1β: Pro-inflammatory chemokine

○ IL-2

○ Secreted by Th1 cells along with IFN-γ and TNF-β to activate cytotoxic T cells (Tc)

○ CD4⁺ T lymphocyte marker

○ Regulates white blood cells

○ IL-3

○ Stimulates the proliferation of bone marrow stem cells and progenitor cells

○ IL-4

○ Differentiates Th0 cells into Th2 cells (involved in humoral immunity)

○ Activates reciprocal secretion between Th2 and B lymphocytes

○ Additionally promotes IgE antibody production

○ Activates Tc cells

○ Used as an inflammatory marker

○ IL-5

○ Secreted by Th2 cells along with IL-4 to activate B lymphocytes

○ Activates Tc cells

○ Also acts as a chemoattractant for eosinophils

○ IL-6

○ Secreted by Th2 cells along with IL-4 to activate B lymphocytes

○ Activates T lymphocytes

○ Macrophage marker

○ Pro-inflammatory cytokine

○ Anti-IL6R: Tocilizumab (Actemra)

○ IL-8

○ Pro-inflammatory chemokine

○ Attracts neutrophils

○ Does not exist in mice or rats

○ IL-10

○ Secreted by Th2 cells along with IL-4 to activate B lymphocytes

○ Anti-inflammatory marker/chemokine

○ Plays an important role in regulating Treg cells along with TGF-β1

○ IL-12

○ Differentiates Th0 cells into Th1 cells along with IFN-γ

○ Involved in cellular immunity (Th1)

○ Dendritic cell marker, macrophage marker

○ IL-17A

○ Involved in the differentiation of M1 macrophages

○ IL-23

○ Plays a significant role in Th17 differentiation

② Tumor Necrosis Factor (TNF)

○ TNF-α

○ Increases vascular permeability and induces inflammation

○ NK cell marker

○ Pro-inflammatory cytokine

○ Inflammatory response marker

○ Anti-TNF-α antibodies: Adalimumab (Humira), etanercept, infliximab, golimumab, certolizumab

○ TNF-β

③ Interferons (IFNs)

○ IFN-α: Secreted by plasmacytoid dendritic cells (pDCs), macrophages, white blood cells, etc., to activate T lymphocytes and natural killer cells

○ IFN-β-1a: Cytokine used to treat multiple sclerosis

○ IFN-γ: Activates macrophages. CD8⁺ T cell marker

④ Clusters of Differentiation (CD)

○ CD3 : Refers to CD3D, CD3E, CD3G, etc.

○ CD11c : Marker for dendritic cells

○ CD80 : Marker for macrophages, dendritic cells

○ CD86 : Marker for macrophages, dendritic cells

⑤ GM-CSF: Promotes the proliferation and differentiation of neutrophils, eosinophils, monocytes, and macrophages

⑥ C-reactive Protein (CRP)

○ Acute-phase protein derived from the liver

○ Increased secretion of CRP by IL-6 produced by macrophages and T lymphocytes

○ Better prognosis with lower levels of CRP

⑦ Myeloperoxidase (MPO)

○ Performs defensive action against pathogens

⑧ Other Cytokines

2. Innate Immunity

⑴ Defense barriers: External defense

① Skin, exoskeleton of insects, internal epithelium: Primary innate defense barriers

○ Pathogens escape with the skin

○ Skin: Inhibits microbial growth with low pH, secretion of chemicals that delay bacterial growth

② Normal flora (normal microbiota)

○ Contributes to innate defense by competing for habitat and nutrients with pathogens

○ Secretes substances toxic to pathogens

○ Examples: Dominant flora of the intestine, such as E. coli

③ Mucus

○ Mucus traps pathogens

○ Lysosomes: Substances toxic to pathogens found in tears, nasal mucus, saliva, etc.

○ Secretions from sweat glands and oil glands have acidic pH

○ Expulsion of mucus (sneezing, coughing): Captures foreign molecules in the air → Expelled through respiratory tract by ciliary movement

④ Digestive System: Stomach (hydrochloric acid, protein-digesting enzymes), small intestine (dense population of bacteria, secretion of enzymes), large intestine (removal along with feces)

⑵ Cellular Innate Defense

① Pathogens that penetrate into the body are eliminated by phagocytes with phagocytic activity

② Types of phagocytes

○ Acidophils : Secretion of histamine, promotion of T lymphocyte differentiation

○ Basophils : Killing of parasites coated with antibodies

○ Neutrophils : Killing of pathogens coated with antibodies

○ Macrophages : Removal of aged cells, digestion of foreign molecules, stimulation of white blood cell production, activation of T lymphocytes

○ Dendritic cells: Act after the function of phagocytes, present antigens in lymph nodes, provide antigens to T lymphocytes

③ Types of Macrophages

○ Classification 1. Based on function

○ 1-1. M1 Macrophages (M1, classically activated macrophages)

○ Inflammatory cells: Involved in cell death, anti-tumor activity

○ Elongation factor: Ratio of length to width is close to 1

○ Cytokines that induce M1 type: TLR, TNF-α, IFN-γ, CSF2, LPS, STAT1, IRF5, IL-17A

○ Cytokines secreted by M1 type: IL-6, IL-8, IL-23p40, TNF-α, IL-1β, IL-12p70, IL-12p40, IFN-γ

○ Genetic markers of M1 type: HLA-DR, CD11c, CD86, iNOS, pSTAT1, IL-12, MHC-II, CD80, 27E10, CCL2, S100A8, S100A9

○ 1-2. M2 Macrophages (M2, alternatively activated macrophages)

○ Anti-inflammatory cells: Involved in cell repair, pro-tumor activity

○ Elongation factor: Ratio of length to width is large

○ Cytokines that induce M2 type: IL-4, IL-10, IL-13, TGF-β, PGE2, STAT3, STAT6, IRF4

○ Cytokine secreted by M2 type: IL-10

○ Genetic markers of M2 type: CD68, CD163, CD204, CD206, VEGF, cMAF, ARG1, YM1, CCL20, CCL22, IDO1

○ Majority of tumor-associated macrophages (TAM) are M2 macrophages

○ Classification 2. Based on tissue

○ Kupffer Cells

○ Macrophages present in the liver sinusoids

○ Related to the intrinsic immune system, RES (reticuloendothelial system)

○ Kupffer cells are the only macrophages located in blood vessels

○ Splenocytes: Located in the spleen

○ BMDM (bone marrow-derived macrophage): Located in the bone

○ Dust Cells: Located in the lungs

○ microglial cell: Located in the brain

○ TAM (tumor-associated macrophage)

④ Recognition and elimination process of pathogens by phagocytes

○ Types of TLRs (Toll-like receptors)

○ TLR-1: Recognizes multiple triacyl lipopeptide

○ TLR-2: Recognizes lipoteichoic acid and activates innate immunity

○ TLR-3: Recognizes dsRNA present in viruses

○ TLR-4: Recognizes LPS (lipopolysaccharide) present in gram-negative bacteria

○ TLR-5: Recognizes flagellin, a component of bacterial flagella

○ TLR-6: Recognizes multiple diacyl lipopeptide

○ TLR-7: Recognizes single-stranded RNA

○ TLR-8: Recognizes small synthetic compounds and single-stranded RNA

○ TLR-9: Recognizes unmethylated CpG DNA sequences and oligodeoxynucleotide DNA

○ 1^st. Phagocytes engulf foreign molecules bound to TLRs (toll-like receptors) (phagocytic action of phagocytes)

○ 2^nd. When TLRs bind to antigens, cytokines associated with inflammation are secreted

○ 3^rd. Phagosomes containing pathogens merge with lysosomes

○ 4^th. Foreign molecules within phagosomes are eliminated by toxic gases from lysosomes (such as nitric oxide) and pathogen-degrading enzymes (such as lysozyme)

○ 5^th. Residual pathogens are expelled through extracellular excretion

⑤ Natural killer cell (NK cell)

○ Recognizes and eliminates cells that do not express MHC class I molecules

○ Eliminates cells with low levels of MHC class I expression, such as infected cells and cancer cells

○ Cancer cells with high levels of MHC class I expression are destroyed by cytotoxic T cells

○ Cytotoxic ability: CTL > NK cell

○ ADCC (antibody-dependent cell-mediated cytotoxicity) is associated with antibodies, perforin, and granzymes

○ Interferon α and β activate NK cells and induce the secretion of interferon γ

⑶ Internal defense system: Hemocytes (insect immune cells)

① Activation of phagocytes, synthesis and secretion of antimicrobial peptides (targeting molds and bacterial pathogens)

② Possession of phenoloxidase enzymes → Formation of melanin polymers → Inhibition of parasite transmission to other parts

③ Selective immune responses occur depending on the type of pathogens

○ Example: Fruit fly infected with red bread mold → Binding of mold cell wall components with insect recognition proteins → Activation of Toll receptors → Induction and secretion of specific anti-fungal peptides

○ LPS (lipopolysaccharide) present only in gram-negative bacteria also serves as a target for Toll receptors

⑷ Antimicrobial protein molecules

① Complement proteins: A group of about 20 antimicrobial proteins present in the blood of vertebrates. Produced in the liver

○ Mechanism: Three types, but all form MAC (membrane attack complex) similarly

○ Type 1: Classical pathway

○ Type 2: Lectin-mannose pathway

○ Type 3: Alternative pathway

○ Function 1: Neutralization → Prevents antigens from penetrating host cells. Neutralizes the attack of antigens

○ Function 2: Opsonization → Facilitates phagocytosis by the binding of exposed antibody Fc regions to Fc receptors on phagocytes

○ Involves IgG

○ Mediates antibody-dependent cell-mediated cytotoxicity (ADCC) resulting in cell death

○ The more hydrophobic the antigen surface, the more opsonin adsorption occurs → Filtered out by the reticuloendothelial system (RES)

○ Opsonization is similar to aggregation

○ Function 3: Induction of phagocytes → Enhances phagocytic activity, increases capillary permeability, causes vascular dilation

○ Function 4: Induces degranulation of basophils, eosinophils, and mast cells (e.g., histamine)

○ Function 5: Complement system → Activation of complement by IgG and IgM, leading to the formation of MAC and membrane attack complex (C_5b-C₉)

○ Also known as complement-dependent cytotoxicity (CDC)

○ Complement system activation is carried out by C_1q, C_1r, C_1s, etc.

○ 5-1. Perforin

○ Molecule that forms pores in the target cell membrane

○ Cancer cells can repair perforin-induced membrane pores using ESCRT complexes

○ 5-2. Granzymes → A type of proteolytic enzyme that enters target cells via endocytosis and induces apoptosis, resulting in fragmentation of the nucleus and cytoplasm

○ Function 6: Activation of antibodies

○ Function 7: Activation of complement proteins by IgG and IgM

② Interferons: Innate antiviral proteins

○ Interferon α: Produced in leukocytes, activates natural killer cells

○ Interferon β: Produced in fibroblasts, activates macrophages and natural killer cells

○ IFN-β-1a: A cytokine used to treat multiple sclerosis

○ Interferon α, β

○ 1^st. Cell gets infected by a virus

○ 2^nd. Cell secretes interferons to surrounding cells

○ 3^rd. Interferons act as signals to induce the production of antiviral proteins in surrounding cells, inhibiting viral replication

○ Interferon γ: Produced in lymphocytes, activates cytotoxic T cells and macrophages

○ Activation of macrophages → Secretion of defensins and increased phagocytic activity of phagocytes → Elimination of foreign molecules

○ CD8⁺ T cell marker

③ Kinins: Powerful peptides that cause vasodilation

⑸ Inflammatory response

① Sequence of reactions

○ 1^st. Tissue (usually epithelial tissue) damage

○ 2^nd. Histamine secretion from mast cells, pyrogen secretion from activated macrophages

○ 3^rd. Actions of histamine: Expansion of capillaries, increased vascular permeability, increased blood flow to the injured area (increased influx of complement proteins), smooth muscle relaxation

○ 4^th. Prostaglandins: Inflammatory response (fever generation), mucus formation, headache, blood clotting, smooth muscle contraction (e.g., uterine contraction in females)

○ Prostaglandins are produced in almost all cells

○ Acts as a local regulator due to its unstable molecular structure

○ Cyclooxygenase → Activation of arachidonic acid → Activation of prostaglandins

○ Aspirin: Inhibits cyclooxygenase

○ Suppresses prostaglandin production

○ Aspirin’s primary actions: Antipyretic, analgesic, prevention of heart attacks, antithrombotic

○ Aspirin’s side effects: Gastric ulcers (related to mucus formation), cases of bleeding during surgery leading to death, gastrointestinal bleeding, cerebral hemorrhage

○ 5^th. Recruitment of more phagocytes, removal of foreign molecules by eosinophils and macrophages

○ 6^th. Accumulation of pus (white blood cells, bacterial corpses) (phagocytes may engulf pus as well)

○ 7^th. Reduction of inflammatory symptoms (fever, redness, swelling)

○ Promotion of T cell activation

○ Promotion of intracellular chemical reactions

○ Decreased plasma iron concentration inhibiting bacterial growth through the reticuloendothelial system (RES)

○ 8^th. Wound healing

② Systemic inflammatory response

○ Endocarditis, appendicitis: Secretion of substances that increase production of neutrophils in the bone marrow from damaged cells and infectious microorganisms

○ Fever generation: Bacterial toxins → PG secretion by activated macrophages → Setting point increase in the hypothalamus → Delayed bacterial growth and enhanced cellular metabolism

○ Septicemia: Severe fever, hypotensive state (due to vasodilation) → Death

3. Adaptive immunity: Antigens, Lymphocytes, MHC

⑴ Antigen: Foreign molecules recognized specifically by lymphocytes and induce immune responses.

① Epitope (Antigenic determinant): Fragments of antigens that induce immune responses.

○ Multiple epitopes can exist on a single antigen.

○ The binding site of the antibody that binds to the antigen is called a paratope.

○ Multiple types of antibodies (polyclonal antibodies) can be generated against a specific antigen ↔ Monoclonal antibodies.

② Conditions

○ Size: Immune responses rarely occur for molecules below 1,000 Da.

○ Antigen specificity: Lymphocytes do not recognize molecules that are similar to self-molecules through a selection process.

○ Suitability for antigen degradation and presentation (e.g., D-amino acids).

③ Classification 1

○ Internal antigens: Virus, cancer cells related to MHC class I.

○ External antigens: Bacteria, parasites related to MHC class II.

④ Classification 2

○ Protein antigens: T-cell dependent (related to MHC class I). Secondary immune response possible. Possess antigenicity and immunogenicity.

○ Non-protein antigens: T-cell independent. React only with antibodies. Possess antigenicity only.

⑤ Adjuvants vs. Immunopotentiators

○ Adjuvants:

○ Organic substances that provide antigenicity (humoral immunity) by binding to endogenous proteins.

○ Induce humoral immunity but not cellular immunity.

○ Examples: Penicillin, aspirin, dinitrophenol.

○ Immunopotentiators : Can induce both humoral and cellular immunity.

⑵ Lymphocyte Generation: “(Stem cells in the thymic pouch) → (Fetal liver)” → Hematopoietic stem cells in the bone marrow → Lymphoid progenitor cells → Various lymphocytes.

① Note: “ “ represents the process that occurs during development.

② Natural Killer (NK) cells: Attack and lyse infected cells or cancer cells.

○ NK cells have stronger cytotoxicity against cancer cells.

③ B cells: Differentiate into plasma cells and memory cells.

○ Plasma cells: Secrete antibodies.

④ Cytotoxic T lymphocytes (Tc, T cytotoxic lymphocytes): Cytotoxic to infected cells.

⑤ T helper lymphocytes (Th, T helper lymphocytes): Assist in the activation of other lymphocytes.

⑥ T regulatory lymphocytes (Treg, T regulatory lymphocytes): Regulate the activity of other lymphocytes.

⑶ Lymphoid Organs: Red blood cells and albumin do not enter lymphoid organs.

① Primary Lymphoid Organs: Sites where lymphocytes attach to receptors.

○ Thymus: T lymphocytes are generated in the bone marrow, then migrate to the thymus for maturation.

○ The origin of T lymphocytes is the initial of the thymus.

○ Bone marrow: Production of lymphocytes. B lymphocytes are generated and matured in the bone marrow.

○ The origin of B lymphocytes is the initial of bone marrow.

○ Fetal liver.

② Secondary Lymphoid Organs: Sites where lymphocytes encounter antigens, cell storage, foreign material filtration, and inflammatory reactions during infection.

○ Spleen

○ Adenoid

○ Appendix

○ Other lymphatic vessels, lymph nodes: React to antigens in tissues.

③ Structure of Lymph Nodes:

○ Afferent lymphatic vessels, efferent lymphatic vessels, medulla, cortex.

○ T cells are mainly located in the medulla of lymph nodes.

○ Activated B cells differentiate into plasma cells in the cortex.

④ Spleen: The largest lymph node.

○ Features:

○ Stores and purifies blood.

○ Contains high concentrations of lymphocytes and antibodies.

○ Gathering place for mature lymphocytes

○ Responds to systemic infections.

○ Divided into multiple compartments by trabeculae.

○ Two types of pulp: inner white pulp and relatively outer red pulp.

○ The marginal zone is located at the boundary between white pulp and red pulp.

○ Red pulp (RP):

○ Macrophages (degradation of old red blood cells), red blood cells, a few lymphocytes.

○ Appears red due to the presence of red blood cells.

○ Appears pink in H&E staining (due to a decrease in the number of nuclei).

○ White pulp (WP):

○ Abundant B cells, T cells, etc.

○ Periarteriolar lymphoid sheath (PALS): Mainly contains T lymphocytes and surrounds the arteries.

○ Appears purple in H&E staining (due to an increase in the number of nuclei).

○ Process:

○ Antigen and lymphocytes enter through the splenic artery.

○ Move to the marginal zone.

○ Antigen is phagocytosed by macrophages in the marginal zone.

○ Move to PALS and present to T cells.

○ Activation of Th cells.

○ Move to the center with B cells to form primary follicles.

○ B cells mature in the germinal center and differentiate into secondary follicles.

○ Marginal zone (MZ): Contains lymphocytes and macrophages.

⑷ Major Histocompatibility Complex (MHC)

① Glycoproteins present on the cell membrane that can attach random peptides to the end and perform antigen presentation.

○ Note: Lipids and carbohydrates cannot be presented on MHC.

② MHC class I

○ Presented by all cells except red blood cells.

○ Peptides derived from degraded cellular proteins are transported to the cell membrane and presented to Tc cells.

○ Normal state: Self-peptides are presented.

○ Infection state: Non-self peptides (antigens) are also presented → Recognition of infected cells (antigen recognition).

○ Cases of presenting non-self peptides: Cancer cells, viruses.

③ MHC class II

○ Presented by antigen-presenting cells that have antigen presentation capability.

○ APC(antigen presenting cell): B cells, macrophages, dendritic cells

○ B cells: Present specific antigens with BCR on MHC class II. Activated by Th2.

○ Macrophages, monocytes: Engulf antigens and present them on MHC class II. Can present various types of antigens. Activate Th1.

○ Dendritic cells: Increase mobility when recognizing bacteria-specific molecules and migrate to lymph nodes. Antigen presentation during negative selection of T lymphocytes. Activate Th and Tc cells.

○ Thymic epithelial cell

○ HLA class II also exists in activated T cells, immature hematoblasts, certain epithelial cells, and some cancer cells.

○ Provides antigens derived from lysosomal degradation to Th cells.

○ When presenting non-self peptides: bacteria, parasites

④ MHC class III

○ Some proteins in the complement system that act with antigen-antibody complexes to lyse foreign cells.

⑤ MHC polymorphism

○ Human MHC genes: Human leukocyte antigen (HLA) group, located on chromosome 6, co-dominantly expressed.

○ Also known as human leukocyte antigen (HLA).

○ MHC class I: HLA-A, HLA-B, HLA-C

○ MHC class II: HLA-DR, HLA-DP, HLA-DQ

○ Mouse MHC genes: H-2 group

○ MHC class I: H-2-K, H-2-D, H-2-L

○ MHC class II: H-2-IA, H-2-IE

○ Since there are hundreds of alleles at each MHC locus, except for identical twins, MHC combinations cannot match.

○ T lymphocyte proliferation experiment according to MHC restriction

○ Mature erythrocytes do not have HLA antigens.

○ Reasons why MHC does not need to be considered during blood transfusion

⑸ Mechanism of antigen presentation by MHC class I

① 1^st. Intracellular antigens (e.g., viruses, cancer cells) are proteolytically cleaved by proteasomes.

○ Cleaved into 9 to 15 amino acid fragments.

② 2^nd. MHC class I molecules are generated in the endoplasmic reticulum.

③ 3^rd. Antigens pass through the transporter associated with antigen processing (TAP) and move from the cytosol to the endoplasmic reticulum.

④ 4^th. Peptide-MHC binding occurs in the endoplasmic reticulum.

⑤ 5^th. Antigen is presented on the cell membrane with MHC class I expression.

⑥ 6^th. Recognized by CD8⁺ T cells.

⑹ Mechanism of antigen presentation by MHC class II

① 1^st. Antigen-presenting cells engulf external antigens (e.g., bacteria, parasites).

○ Macrophages: Phagocytosis

○ B cells: Receptor-mediated endocytosis

② 2^nd. External antigens are proteolytically cleaved in endosomes.

○ Cleaved into 12 to 15 amino acid fragments.

③ 3^rd. MHC class II molecules are generated in the endoplasmic reticulum.

④ 4^th. Antigen peptide vesicles and MHC class II vesicles merge to form endolysosomes (a type of lysosome).

⑤ 5^th. Endosome Vesicles undergo peptide-MHC binding.

⑥ 6^th. Antigen presentation occurs on the cell membrane with MHC class II.

⑦ 7^th. Recognized by CD4⁺ T cells.

⑺ Cross-presentation: The phenomenon where epitopes that should go to MHC class II end up going to MHC class I.

4. Overview of Immune Response

⑴ 1^st. Primary antigen exposure.

⑵ 2^nd. Dendritic cells capture the antigen and present it via MHC class II, activating Th1.

⑶ 3^rd. B lymphocytes capture the antigen and present it via MHC class II, activating Th2.

⑷ 4^th. Macrophages capture the antigen and present it via MHC class II, activating Tc cells.

⑸ 5^th. Th1 cells further activate Tc cells, leading to recognition of the antigen by MHC class I and elimination of infected cells.

⑹ 6^th. Th2 cells reactivate B lymphocytes.

⑺ 7^th. Activated B lymphocytes produce antibodies.

⑻ 8^th. Secondary antigen exposure.

⑼ 9^th. Rapid progression due to memory cells.

① Tc cells undergo cellular immune response whenever they receive activation signals from activated memory Th1 cells, macrophages, or MHC class I antigen-presenting infected cells.

○ In ⑵ to ⑻, it is not described, but Tc cells can also receive activation signals from MHC class I antigen-presenting infected cells.

② For B lymphocytes, memory B lymphocytes differentiate into plasma cells as soon as they bind to the antigen (no separate signal needed).

5. Adaptive immunity: T lymphocytes (T cells)

⑴ TCR (T cell receptor): The receptor on T lymphocytes that exists on the T cell membrane, recognizing antigen peptides bound to MHC.

① Structure: I-shaped.

② Quaternary structure: Alpha chain and beta chain linked by disulfide bonds.

③ Antigen-binding site: One, recognizing the primary structure of the antigen.

○ Recognizes the amino acid sequence of the protein antigen bound to MHC.

○ Due to recognizing the primary structure, TCR is resistant to heat and pH.

④ TCR needs to cooperate with CD proteins for antigen recognition.

⑤ “TCR + CD3 + CD247”: Signaling complex in operation.

⑥ “TCR + CD3 + CD247” + CD8: Auxiliary protein group that recognizes MHC class I.

⑦ “TCR + CD3 + CD247” + CD4: Auxiliary protein group that recognizes MHC class II.

⑵ 1^st. Generation: T cell precursors are generated in the bone marrow, or in the case of fetuses, in the liver.

① CD4^-, CD8^-, TCR^-

⑶ 2^nd. T cell precursors migrate to the thymic cortex.

⑷ 3^rd. Differentiation: T cell precursors in the thymic cortex differentiate into immature naive T cells and immature γδ T cells.

① 3^rd - 1^st. RAG gene expression: Occurs only once.

○ RAG genes are genes expressed only in T cells and B cells.

○ RAG (recombination activation gene): Recombination enzyme that recognizes recombination signal sequences (RSS).

② 3^rd - 2^nd. 1^st differentiation: T cell precursors (CD4^-, CD8^-, TCR^-) → immature naive T cell precursor + immature γδ T cell.

○ Immature naive T cell precursor: CD4^-, CD8^-, TCR αβ^-

○ Immature γδ T cell: CD4^-, CD8^-, TCR γδ⁺

③ 3^rd - 3^rd. Immature naive T cell precursor → Immature naive T cell (CD4⁺, CD8⁺, TCR αβ low) (bipotent)

④ 3^rd - 4^th. 2^nd differentiation.

○ 3^rd - 4^th - 1^st. Immature naive T cell: CD4⁺, CD8⁺, TCR αβ low → CD4⁺, CD8⁺, TCR αβ.

○ 3^rd - 4^th - 2^nd. Immature γδ T cell: Further differentiation.

⑸ 4^th. 1^st clonal deletion: Positive selection, occurs in the thymic cortex.

① 4^th - 1^st. Clones that fail to bind to self peptides presented by thymic epithelial cells undergo apoptosis.

○ Evaluates the ability to bind to MHC regardless of strong self-recognition.

○ MHC types: There are various types of MHC, and antigens presented on non-self MHC of different types cannot be recognized.

○ Organ transplant rejection is related to MHC type and Th cells.

② 4^th - 2^nd. T cell precursors bound to MHC class II differentiate into Th cells (e.g., degeneration decision of CD4).

○ Immature naive Th cell: CD4⁺, CD8⁺, TCR αβ.

③ 4^th - 3^rd. T cell precursors bound to MHC class I differentiate into Tc cells (e.g., degeneration decision of CD8).

○ Immature naive Tc cell: CD4⁺, CD8⁺, TCR αβ.

④ The ratio of immature naive Th cells to immature naive Tc cells is approximately 2:1.

⑹ 5^th. Mature naive Th and mature naive Tc, which have undergone positive selection, migrate to the thymic medulla.

⑺ 6^th. 2^nd clonal deletion: Negative selection, occurs in the thymic medulla.

① 6^th - 1^st. If macrophages strongly recognize self peptides presented by MHC class II, they induce cell apoptosis.

② Differentiation between self and non-self: Both immature naive Th and immature naive Tc that have undergone negative selection only respond to non-self.

③ Failure of negative selection leads to autoimmune diseases.

⑻ 7^th. Maturation: Final maturation occurs in the thymic medulla.

① 7^th - 1^st. Immature naive Th cell → Mature naive Th cell.

○ Immature naive Th cell: CD4⁺, CD8⁺, TCR αβ.

○ Mature naive Th cell: CD4⁺, CD8^-, TCR αβ.

② 7^th - 2^nd. Immature naive Tc cell → Mature naive Tc cell.

○ Immature naive Tc cell: CD4⁺, CD8⁺, TCR αβ.

○ Mature naive Tc cell: CD4^-, CD8⁺, TCR αβ.

③ 7^th - 3^rd. Immature γδ cell → Mature γδ cell.

○ The selection mechanism of γδ cells is not specifically elucidated.

④ Tip: Since energy is wasted if maturation is achieved and clonal deletion occurs, maturation is the final step.

⑼ 8^th. Mature T cells migrate to lymph nodes.

① Mature naive Th cells migrate to lymph nodes in a Th0 state.

⑽ Helper T lymphocyte (helper T cell).

① Naive Th cells are activated by antigen-presenting cells in lymph nodes.

② Helper T cells: Approximately 5 types, cytokine secretion that determines the type of naive Th cells depending on the type of antigen engulfed by antigen-presenting cells.

○ Helper T cell 0 (Th0).

○ Differentiation into Th1 by IL-12 or IFN-γ: Secretion of IL-2, interferon γ, associated with cellular immunity.

○ Differentiation into Th2 by IL-4: Secretion of IL-4, associated with humoral immunity.

○ Helper T cell 1 (Th1): CD4⁺ / CD25^-.

○ T-bet is essential for Th1 differentiation.

○ Secretion of IL-2, IL-10, IFN-γ, TNF-β.

○ Step 1: Acting on macrophages: Th1 recognizes antigen presentation by macrophages.

○ Step 2: Interaction: Macrophages activate Th1 with IL-1, Th1 self-activates with IL-2, IFN-γ, and activates macrophages.

○ Step 3: Activated macrophages generate reactive oxygen species to eliminate bacteria.

○ Acting on Tc: Th1 recognizes antigen presentation by Tc → Activation of naive Tc with IL-2, interferon γ.

○ Helper T cell 2 (Th2): CD4⁺ / CD25^-.

○ Secretion of IL-4, IL-5, IL-6, IL-13.

○ Step 1: Acting on B cells: Th1 recognizes antigen presentation by mature naive B cells.

○ Step 2: Activating B cells into plasma cells with IL-4, B cells also activate Th2 with IL-4.

○ Suppressor T lymphocytes (T regulatory lymphocytes): CD4⁺ / CD25⁺.

○ Function 1: Inhibition of excessive immune response.

○ Function 2: Inhibition of autoreactive lymphocytes that have not been eliminated during lymphocyte development, abnormal cases can lead to autoimmune diseases.

○ Secretion of inhibitory cytokines, deactivation of all effector cells when the antigen is cleared.

○ Cytokines secreted by helper T lymphocytes also contribute to acquired immunity.

○ Example: Differentiation into monocytes.

○ Example: Promotion of eosinophil activation.

③ When Th recognizes the antigen presented by antigen-presenting cells, it secretes cytokines that act on itself, initiating cell division (clonal selection).

○ Mostly: Participate directly in immune responses as effector cells.

○ Some: Upon re-exposure to the same antigen, elicit a rapid and strong response as memory cells.

○ Memory cells induced from a single helper T lymphocyte have the same TCR.

④ Memory cells can be activated with a small amount of cytokines, so effector cells and B lymphocytes can activate Th memory cells.

⑾ Cytotoxic T lymphocytes (CTL, cytotoxic T lymphocyte, killer T cell).

① Naive Tc is activated by antigen-presenting cells and Th1 in lymph nodes → Cellular immunity.

② 1^st. Cytokines (e.g., IL-2) released by Th1 finally activate Tc.

○ 1^st - 1^st: Naive Tc binds to the antigen presented on MHC class I of professional APCs (mainly macrophages) with TCR.

○ 1^st - 2^nd: CD28 on the Tc cell surface binds to CD80 (B7-1) or CD86 (B7-2) on the cell membrane surface of APCs in addition to antigen binding.

○ 1^st - 3^rd: Cytokines released by Th1, in collaboration with CD80 or CD86, activate naive Tc.

○ Cytokines: Interferon γ, IL-2, tumor necrosis factor β (TNF-β).

○ Infected APCs also present antigens on MHC class I, but without the above mechanisms, activated Tc eliminates them.

③ 2^nd. Activated Tc undergoes cell division, mostly becoming effector cells, and some become memory cells (clonal selection).

④ 3^rd. Effector cells recognize that they are external antigens from MHC class I (antigen recognition).

⑤ 4^th. Tc induces cell death by binding to its target, causing cell lysis (perforin/granzyme).

○ Fas: Cell membrane receptor, induction of cell death when FasL (Fas ligand) binds to Fas.

○ Problem type: Both the Fas mechanism and the cell death mechanism must be inhibited to suppress Tc function.

⑥ 5^th. Upon re-exposure to the same antigen, long-lived memory cells elicit a rapid and strong response.

○ Memory cells induced from a cytotoxic T lymphocyte have the same TCR.

⑿ Regulatory T lymphocyte (Treg)

① Expression of CD4 and CD25

② Reduction in antibody production in the presence of Treg

③ It can be considered as a protective mechanism against the production of severe autoimmune antibodies

⒀ T lymphocyte proliferation experiment according to MHC restriction

① Process

○ 1^st. Radiation of recipient mice to eliminate all lymphocytes and bone marrow cells

○ 2^nd. Bone marrow transplantation to recipient mice followed by antigen injection after 3 months

○ 3^rd. Immunization of recipient mice with antigens

○ 4^th. Co-culture of T lymphocytes isolated from recipient mice and stromal cells isolated from a third party mouse

○ 5^th. Observation of T lymphocyte proliferation in the culture medium containing the antigen

② Interpretation

○ In the case of a × b bone marrow transplantation, both a type MHC-expressing T lymphocytes and b type MHC-expressing T lymphocytes exist.

○ In the case of a type bone marrow transplantation, a type MHC-expressing T lymphocytes exist.

○ Only a type MHC is expressed in the thymic epithelial cells of a type recipient mice.

○ Positive selection: Only T lymphocytes expressing a type MHC are preserved in the case of a type recipient mice.

○ Maturation: a type T lymphocytes mature when they encounter stromal cells expressing a type MHC.

○ Normal mice expressing a type MHC express a type epithelial cells and a type stromal cells.

○ Normal mice expressing a × b type MHC express both a type and b type epithelial cells and both a type and b type stromal cells.

○ In the case of recognizing a new MHC type, it is treated as an external antigen and subjected to immune attack.

6. Adaptive Immunity: B lymphocyte (B cell)

⑴ B cell receptor (BCR): Receptor on B lymphocytes

⑵ Antibody: BCR in a detached form

① Structure: Y-shaped, 150 kDa, 10 nm

② Composition: Two heavy chains (H chain) + two light chains (L chain)

③ Quaternary structure: Disulfide bonding between chains and within chains

④ Heat resistance: Antibodies are generally stable even at high temperatures (56 ℃), unlike complement.

⑤ N-terminus and C-terminus

○ N-terminus: Variable region or Fab (fragment of antigen binding)

○ C-terminus: Constant region or Fc (fragment of crystallization). It crystallizes when placed in cold areas with small amino acid differences.

○ The part of the variable region that binds to the antigen is called the complementarity determining region (CDR).

○ One antibody is connected by disulfide bonding to two Fabs and one Fc.

○ The C-terminus can bind to phagocytes.

⑥ Antigen binding site: The variable (V) region is the key to antibody diversity, with two antigen binding sites that recognize the tertiary structure of the antigen.

○ BCR recognizes the tertiary structure of the antigen, so it is sensitive to heat and pH.

○ Antigen-antibody binding affinity: Weak binding through non-covalent interactions.

⑦ Biological functional region: Region (C region) associated with immune functions (complement activation, phagocytosis, etc.)

⑧ Classification of antibody types based on the type of constant (C) region in the heavy chain.

⑨ Enzymatic digestion of antibodies

○ Pepsin digestion: One F(ab’)₂

○ Mercaptoethanol reduction: Two H chains + two L chains

○ Papain digestion: Two Fabs + one Fc. Each Fab and Fc are about 50 kDa.

⑩ History

○ Discovered by Behring through experiments with diphtheria vaccination in mice in 1890.

○ When serum is electrophoresed, it appears on the (-) side compared to albumin, α-globulin, and β-globulin, so it was called γ-globulin.

○ Also known as immunoglobulin, meaning immune globulin, because it represents the immunological action.

⑶ 1^st. Generation: Pro-B cells are generated in the bone marrow.

① 1^st - 1^st. Hematopoietic stem cells → Lymphoid cells

② 1^st - 2^nd. Lymphoid cells → pro-B cells: Partial recombination of H chain genes.

⑷ 2^nd. Genetic recombination (Somatic recombination)

① Antibody diversity : Human genes (30,000) cannot account for antibody diversity.

② Genetic recombination : Process of obtaining new DNA by cutting and joining segments in the variable region of antibody genes.

③ 2^nd - 1^st. RAG gene : Protein produced for genetic recombination.

○ RAG (recombination activation gene) : Recombination signal sequence (RSS) recognizing recombination enzyme.

④ 2^nd - 2^nd. Class-switch recombination : Genetic recombination occurs first in the chain. Combination of V, D, J, C segments.

○ 2^nd - 2^nd - 1^st. D-J-Cμ-Cδ-Cε-Cγ-Cα DNA → V-D-J-Cμ-Cδ-Cε-Cγ-Cα DNA

○ 2^nd - 2^nd - 2^nd. Transcription : V-D-J-Cμ-Cδ-Cε-Cγ-Cα DNA → V-D-J-Cμ-Cδ-Cε-Cγ-Cα mRNA

○ 2^nd - 2^nd - 3^rd. Alternative splicing : V-D-J-Cμ-Cδ-Cε-Cγ-Cα mRNA → V-D-J-C mRNA

○ Alternative splicing is not random, so in the example in the figure below, there are n × 30 × 6 possibilities.

⑤ 2^nd - 3^rd. Junctional gene recombination : Combination of V, J, C segments.

○ 2^nd - 3^rd - 1^st. Transcription : V-J-C1-···-Cn DNA → V-J-C1-···-Cn mRNA

○ 2^nd - 3^rd - 2^nd. Alternative splicing : V-J-C1-···-Cn mRNA → V-J-C mRNA

○ There are n × 6 possibilities in the example in the figure below.

○ The light chain can have κ or λ, but cannot have both types together.

⑥ 2^nd - 4^th. DNA addition occurs during the recombination process.

○ Heavy chain : Addition of P segment and N segment DNA.

○ Light chain : Addition of P segment DNA only.

⑦ 2^nd - 5^th. Inactivation of RAG genes after one round of genetic recombination.

⑸ 3^rd. pro-B-cell → pre-B-cell : Completion of rearrangement of H chain genes.

① After completing gene rearrangement in pro-B-cell, immature BCR is expressed on the surface.

⑹ 4^th. pre-B-cell → immature naive B cell : Rearrangement of L chain genes.

① Instead of the incomplete BCR in the pre-B-cell, IgM is expressed, becoming an immature naive B cell.

⑺ 5^th. immature naive B cell → mature naive B cell.

① 5^th - 1^st. Alternative splicing : Alternative splicing to include Cδ instead of Cμ in the mature mRNA.

② 5^th - 2^nd. IgD is expressed next to the existing IgM.

⑻ 6^th. Negative selection = Clonal deletion.

① Mature naive B cells that recognize self-peptides in the bone marrow are eliminated.

② Clonal elimination: Elimination of the clone.

③ Clonal anergy: Inactivation of the receptors of the clone.

⑼ 7^th. Mature naive B cells after negative selection leave the bone marrow and migrate to the spleen and lymph nodes.

① B-1 subtype with low BCR remains in the bone marrow, while B-2 subtype with high BCR moves to the spleen.

② Marginal B-cell: A differentiated form of B-2 subtype that remains in the spleen.

③ Follicular B-cell: A differentiated form of B-2 subtype that leaves the spleen and migrates to the lymph nodes.

④ Tip: Memorize lymph node migration after negative selection!

⑽ 8^th. Clonal expansion of 1^st clone: mature naive B cell → Plasma cell + Memory cell.

① Mechanism 1: Activation dependent on antigen-contacting T lymphocytes.

○ Ⅰ - 8^th - 1^st. IgD of mature naive B cells recognizes the antigen → Phagocytosis by receptor-mediated endocytosis.

○ Ⅰ - 8^th - 2^nd. Exogenous antigen is processed by lysosomes, converted into 1^st structure.

○ Ⅰ - 8^th - 3^rd. MHC class II molecules are generated in the rough endoplasmic reticulum.

○ Ⅰ - 8^th - 4^th. Antigen peptide vesicles and MHC class II vesicles merge, and antigen peptides bind to MHC class II.

○ Ⅰ - 8^th - 5^th. Antigen presentation.

○ Ⅰ - 8^th - 6^th. When mature Th2 cells recognize the exogenous antigen, they secrete the cytokine IL-4.

○ Ⅰ - 8^th - 7^th. Clonal selection: IL-4 activates mature naive B cells, leading to rapid cell division.

○ Ⅰ - 9^th. Most mature naive B cells become plasma cells, while some become memory cells.

② Mechanism 2: Activation dependent on antigen-contacting T lymphocytes.

○ Ⅱ - 8^th - 1^st. IL-4 secreted by mature Th2 cells in Mechanism Ⅰ activates mature naive B cells.

○ Ⅱ - 8^th - 2^nd. Activated mature naive B cells’ IgD binds to the exogenous antigen.

○ Ⅱ - 8^th - 3^rd. Clonal selection: Activated mature naive B cells undergo rapid cell division.

○ Ⅱ - 9^th. Most mature naive B cells become plasma cells, while some become memory cells.

③ Mechanism 3: Activation independent of T lymphocytes.

○ Ⅲ - 8^th - 1^st. IgM of mature naive B cells binds to the exogenous antigen.

○ Example 1: Foreign polysaccharides.

○ Example 2: Unmethylated CpG DNA: PAMP (pathogen-associated molecular pattern). Increased in microorganisms, decreased in vertebrates.

○ Example 3: Nanoparticles: Accelerated blood clearance (ABC) is observed in BALB/c nu/nu mice (T cell deficient), but not in BALB/c SCID (T cell and B cell deficient).

○ Ⅲ - 8^th - 2^nd. IgM secretion: IgM is the first antibody secreted in the primary immune response and does not participate in the secondary immune response.

○ Mature naive B cells mainly produce membrane-bound IgM → Secreted IgM production.

○ Membrane-bound IgM mRNA: S region is removed, and M1M2 is predominantly translated with hydrophobic amino acids appearing in the center, forming a transmembrane region.

○ Secreted IgM mRNA: The first AAUAAA sequence is recognized and cleaved, and the hydrophilic S region is translated.

○ Secreted IgM mRNA is shorter and becomes the secreted form as it lacks the transmembrane region or cytoplasmic region.

○ Characteristics:

○ Rapid, within a day: Takes several days for T lymphocyte-dependent activation.

○ No formation of memory cells.

○ Antibodies generated have lower affinity and diversity compared to T lymphocyte-dependent activation.

⑾ 9^th - 1^st. Class switch recombination: 2^nd genetic recombination.

① 9^th - 1^st - 1^st. Somatic recombination: Defects occur in the constant region of B cell antibodies.

○ Specifically, during class switching, Cμ and Cδ regions are deleted through genetic recombination.

○ Genetic deletion shortens the transmembrane region or cytoplasmic region, resulting in antibody secretion.

② 9^th - 1^st - 2^nd. IgM on the cell membrane of the original B cell changes to IgG, IgA, or IgE depending on the location.

○ IFNγ promotes the production of IgG, while TGFβ promotes the production of IgA.

③ 9^th - 1^st - 3^rd. B cells function as plasma cells. Antibodies are more specific as they are highly specialized, increasing antigen-antibody affinity.

○ The antigen-binding site is constant.

④ 9^th - 1^st - 4^th. Plasma cells perish within a few days.

⑤ AICDA gene is involved in class switch recombination.

⑿ 9^th - 2^nd. Somatic hypermutation.

① 9^th - 2^nd - 1^st. Point mutations occur in the variable regions of the chain and junctional DNA in some cells of mature naive B cells.

② Increased affinity of antigen-antibody binding, functioning as memory cells.

③ Memory cells survive for several years to decades.

⒀ 10^th. Secondary immune response: When the same antigen is encountered for the second time.

① 10^th - 1^st. Rapid cell division occurs in memory B cells upon binding of their BCR to the antigen.

② 10^th - 2^nd. Memory B cells differentiate into plasma cells and secrete antibodies.

③ 10^th - 3^rd. Antibody secretion is greater, with higher affinity and specificity compared to the primary immune response.

○ Participation in the 3rd and 4th immune responses leads to enhanced antibody-antigen affinity due to accumulation of somatic mutations.

⒁ Effector cells and memory cells

① Effector cells (plasma cells): Secretory type

○ Perform humoral immunity by secreting antibodies.

○ Secrete a type of soluble BCR antibody, with a small amount of BCR on the cell membrane.

○ Secreted antibodies are specific to the same antigen that induced the immune response.

○ Express a large number of rough endoplasmic reticulum (RER) to produce a large amount of antibodies.

② Memory cells: Surface-bound type

⒂ Types of antibodies

① IgM: μ-heavy chain, surface-bound type

○ Each monomer in a pentamer is linked by a J chain.

○ Before the primary immune response: Expressed as a monomeric antigen receptor on B cell membrane.

○ During the primary immune response: Secreted as a pentamer by plasma cells, binds to large antigens (subsequently decreases in bloo» d concentration).

○ The first antibody to be produced and released in the primary immune response.

○ Highly effective in complement activation, cell lysis, agglutination, and neutralization reactions.

○ ABO blood group antibodies.

② IgD: δ-heavy chain, surface-bound type

○ Monomeric form.

○ Present on the surface of naive B cells that have not been exposed to antigens.

○ Acts as an antigen receptor during the proliferation and differentiation process (clonal selection) of B cells stimulated by antigens.

③ IgG: γ-heavy chain, secretory type

○ Monomeric form.

○ Abundant in plasma (approximately 80% of circulating antibodies).

○ Most abundant antibody in the 1st and 2nd immune responses due to its relatively long lifespan compared to other secretory antibodies.

○ Placental immunity: The only antibody that can pass through the placenta, providing passive immunity to the fetus.

○ Enhances antigen neutralization, agglutination, complement activation, and macrophage activation.

○ Subdivided into IgG1, IgG2, IgG3, and IgG4.

④ IgA: α-heavy chain, secretory type

○ Dimeric form, with each monomer connected by a J chain.

○ Mainly secreted antibodies.

○ Found in mucous membranes of saliva, tears, respiratory and digestive tracts, and breast milk.

○ Found as monomers in plasma.

○ Found as dimers (or tetramers) in secretions such as saliva, tears, milk, and bronchial secretions.

○ Protects mucosal surfaces through antigen agglutination and neutralization.

○ Provides passive immunity through breast milk.

○ Subdivided into IgA1 and IgA2.

⑤ IgE: ε-heavy chain, secretory type

○ Monomeric form.

○ Secreted by effector cells in the skin, gastrointestinal tract, and respiratory tract.

○ Present in very low concentrations in serum.

○ Involved in allergic reactions and immune response to parasites.

○ Mediates antibody-mediated hypersensitivity reactions (immediate hypersensitivity), such as hay fever, asthma, rash, and anaphylactic shock.

⑥ Summary

⒃ Mechanisms of antigen elimination by antibodies

① Opsonization: Antibodies bind to antigens, enhancing the phagocytic activity of phagocytes (neutrophils and macrophages).

○ IgG is most commonly involved in opsonization.

○ Antibody-dependent cellular cytotoxicity (ADCC).

○ Opsonized antigens are recognized by Tc cells and NK cells.

○ Antigens bound by IgG antibodies are more easily killed by macrophages, monocytes, and NK cells.

○ Involves FcγRII, FcγRIII, and other receptors.

○ Antibody-dependent cellular phagocytosis (ADCP).

○ Complement-dependent cytotoxicity (CDC).

② Neutralization: Antibodies bind to antigens, preventing their penetration into host cells and neutralizing their harmful effects.

③ Agglutination and precipitation reactions

○ Agglutination: Antibodies bind to antigens, causing clumping and making them targets for phagocytosis.

○ Precipitation: Antibodies bind to antigens, making them heavier and causing them to settle.

④ Complement system activation and formation of membrane attack complex (MAC)

○ Also known as complement-dependent cytotoxicity (CDC).

○ 1^st. Antibodies bind to antigens on the surface of foreign cells, activating the complement system.

○ Both Fab, which binds to antigens, and Fc, which binds to the complement system, are required for complement activation.

○ 2^nd. Upon complement system activation, membrane attack complexes are formed and create pores in the cell membrane of foreign cells.

○ 3^rd. Water and ions enter the cell through the pores, causing cell swelling and leakage of cellular contents, ultimately leading to cell death.

⒄ Polyclonal antibodies and monoclonal antibodies

① Polyclonal antibodies

○ A collection of B lymphocytes that produce various types of antibodies.

○ It means that individual B lymphocytes produce different antibodies, not that one B lymphocyte produces multiple antibodies.

② Monoclonal antibodies

○ A collection of B lymphocytes that produce a single type of antibody.

○ 1^st. Spleen cells (SC) are extracted: Contains B lymphocytes.

○ 2^nd. Hybridoma generation: Fusion of immortal myeloma cells (MC) with spleen cells.

○ 3^rd. Hybridomas proliferate and become hybridoma cells: As the number of hybridomas increases, a large amount of a single type of antibody is produced.

○ 4^th. Cultivate in HAT (hypoxanthine-aminopterin-thymidine) medium to extract viable cells.

○ Survival requires the presence of HGPRT (hypoxanthine-guanine phosphoribosyl transferase), an enzyme secreted by SC.

○ 5^th. Expected results:

○ Case 1: SC, SC-SC: Die naturally in culture.

○ Case 2: MC, MC-MC: Die in selective HAT medium.

○ Case 3: Heterokaryotic hybrid (SC-MC): Survive in HAT culture medium.

○ 3-1: Non-producer.

○ 3-2: Non-specific antibody producer.

○ 3-3: Specific antibody producer.

⒅ Antibody drugs

① Feature 1: Antibody drugs have a long half-life in the bloodstream, so they can be prescribed occasionally.

② Feature 2: Antibodies themselves are large, so generally only a portion is used as a drug.

○ Fab (50 kDa)

○ F(ab’)₂ (100 kDa)

○ Monospecific Fab₂ (100 kDa)

○ Bispecific Fab₂ (100 kDa)

○ Trispecific Fab₂ (150 kDa)

○ Monovalent IgG (75 kDa)

○ scFv (25 kDa)

○ Bispecific diabody (50 kDa)

○ Trispecific triabody (75 kDa)

○ scFv-Fc (100 kDa)

○ Minibody (75-80 kDa)

○ IgNAR (175 kDa)

○ V-NAR (15 kDa)

○ HcIgG (75 kDa)

○ VhH (15 kDa)

○ VH

○ scFv-CH

○ scFab

○ scFv-zipper

○ Comparison: IgG (150 kDa)

③ Naming convention: Prefix + antibody target + antibody source + suffix (e.g., -mab)

④ Antibody target

○ Bone: -o(s)-

○ Cardiovascular: -c(l)-

○ Immuno-modulating: -l(i)-

○ Interleukin: -k(l)-

○ Tumor: -t(u)-

○ Virus: -v(l)-

⑤ Antibody source

○ Humanization: Antibody drugs should be humanized to avoid inducing an immune response in the human body.

○ Types of humanization: “mab” stands for monoclonal antibody.

○ Fully human (100% human): -u-, -su-

○ Murine (0% human): -o-. Can act as an antigen in humans.

○ Rat (0% human): -a-

○ Chimeric (65% human): -xi-

○ Humanized (>90% human): -zu-

○ Humanization methods:

○ Phage display

○ Transgenic mouse

⑥ Major antibody donors: abcam, cell signaling, Thermo Fisher Scientific, Santa Cruz Biotechnology, Creative Biolabs.

7. T Cells vs. B Cells

⑴ Naive T cells have a relatively smooth surface, but naive B cells have a rough surface (due to higher BCR expression).

⑵ Mechanisms of antigen receptor diversity:

① Genes involved in antibody production: 20,000 genes

② Through DNA rearrangement in B cells and T cells, millions to billions of antigen receptors and antibodies can be generated.

8. Immune System Disorders

⑴ Infectious diseases:

① Viral diseases, etc.

② Vaccines: Formation of memory cells in B cells.

⑵ Autoimmune diseases:

① Rh blood type: Forms protein antigen memory cells and generates IgG antibodies.

② In the case of Rh (+), it has the D antigen and does not produce anti-D antibodies.

③ In the case of Rh (-) mothers, initially they do not have the D antigen or anti-D antibodies.

○ If the first child is Rh (+), during delivery, when fetal blood mixes with the mother’s blood through a small wound, the mother produces antibodies against the Rh antigen.

○ If the second child is also Rh (+), the mother’s IgG crosses the placenta and causes hemolysis of the fetus’s red blood cells.

○ Administering anti-D antibodies around 7 months and after childbirth can prevent the formation of memory cells.

○ Antibodies against the D antigen, such as RhoGAM, can perform the immune response in place of the mother.

④ ABO blood type: Involves carbohydrate antigens.

○ Since they are carbohydrates, they do not form memory cells, and only IgM antibodies are produced.

○ IgM cannot pass through the placenta, so it does not harm a fetus with a different blood type even if the mother is pregnant with such a fetus.

○ Anti-A antibodies and anti-B antibodies are antibodies produced when infected with bacteria that lack respective A and B antigens and have similar characteristics to self.

⑶ Immune rejection

① Transplant immunology

○ Specificity and memory of allograft rejection reactions

○ Assuming a rejection reaction occurred when tissue A was first transplanted into B.

○ If tissue A is transplanted into B for the second time, the rejection reaction occurs faster than the first transplantation.

○ When tissue C is transplanted into B, B recognizes C differently and exhibits primary immune response → A and C are perceived diffe» rently.

○ CD4 T cells play an important role in transplant rejection reactions.

○ The success rate of allogeneic transplantation depends on antigen similarity (tissue compatibility), with MHC genes being the most closely related.

② Organ transplantation

○ Phenomenon where Th cells and Tc cells of the recipient attack the transplanted organ.

○ Recognition of organs with different MHC types as antigens.

○ Bone, tendons, ligaments, cartilage, veins, skin, and cornea are relatively less susceptible to immune rejection.

○ Success rate of sibling organ transplantation = Probability of having the same 6^th chromosome = 25% ≫ Success rate of parent-child organ transplantation.

○ Generally, immunosuppressive agents such as cyclosporine are administered to the recipient before organ transplantation.

○ Even if MHC types are the same, if the sexes are different, a specific protein of SRY (e.g., smyc) acts as an antigen, leading to immune rejection.

○ Microcytotoxicity test

③ Bone marrow transplantation

○ Phenomenon where Th cells and Tc cells in the transplant graft react against the recipient’s organs.

○ Most patients experience graft-versus-host reaction, and 30-50% of them have severe symptoms.

○ As a treatment for graft-versus-host reaction, bone marrow is pretreated by radiation to remove lymphocytes before transplantation.

④ Immunological privilege

○ Prevention of immune cell influx and removal of immune cells through close adhesion.

○ Examples: eyeball, testis, brain.

⑷ Immune hypersensitivity reactions

① Type I hypersensitivity

○ IgE-mediated

○ Involvement of mast cells, peripheral blood basophils (PBB), etc.

○ Symptoms: allergic rhinitis to anaphylaxis

② 1-1. Allergy: Acute hypersensitivity reaction, similar to parasitic immunity.

○ 1^st: Initial exposure to allergens → IgE production and binding of Fc region to mast cells, basophils, and eosi»> nophils.

○ Allergen: Substance that triggers allergies, such as food, pollen, insect venom, etc.

○ 2^nd: Secondary exposure to the same allergen → IgE attached to mast cells, basophils, and eosinophils recognize and bind to the allergen.

○ 3^rd: Cross-linking of allergen-bound IgE molecules.

○ Allergic reaction requires a sufficient amount of IgE to be cross-linked.

○ Anti-IgE receptor antibodies can also trigger allergic reactions because both antigen-binding sites send signals to the IgE receptor simultaneously.

○ 4^th: Mast cell degranulation induced → Excessive release of histamine, serotonin, leukotrienes, etc., from mast cells.

○ Histamine: Smooth muscle contraction in bronchioles, relaxation of vascular smooth muscles (increased vascular permeability).

○ Allergic reactions are inhibited in hypocalcemia since calcium ion influx is required for mast cell degranulation.

○ 5^th: Allergic symptoms (e.g., flushing, asthma, inflammatory response) appear.

○ Treatment: Epinephrine - allergy treatment, increases lowered blood pressure and relaxes airways.

③ 1-2. Delayed hypersensitivity: Reaction that occurs several hours after contact with an antigen.

○ 1^st: Antigen invasion.

○ Examples: Mycobacterium tuberculosis infecting the lungs.

○ 2^nd: Mutual activation of macrophages and Th1 cells - a prolonged reaction.

○ 3^rd: Activation of Tc cells by Th1.

○ 4^th: Hyperactivity of Tc cells.

○ Treatment: Corticosteroids.

④ 1-3. Antibody-mediated hypersensitivity: Anaphylactic shock.

○ Involvement of IgE as a representative.

○ 1^st: Organic substances (e.g., penicillin, aspirin) that provide antigenicity enter the bloodstream.

○ 2^nd: Increased antibodies against the organic substances.

○ 3^rd: Systemic allergic reaction upon secondary exposure to the substances in the bloodstream.

○ 4^th: Increased vascular permeability and smooth muscle relaxation throughout the body → Accelerated leakage of blood into tissues, resulting in decreased blood pressure.

○ 5^th: Acute shock reaction.

○ 6^th: Compensation mechanism for smooth muscle relaxation leads to contraction of other smooth muscles → Contraction of airway smooth muscles → Respiratory distress.

○ Example: Penicillin.

○ Penicillin has a β-lactam ring.

○ The β-lactam ring is non-immunogenic as a non-protein, but it forms a hapten by conjugating with host proteins.

○ Haptens can trigger allergic reactions.

⑤ Type II hypersensitivity: Non-IgE-mediated.

⑥ 2-1. Complement activation-related pseudoallergy (CARPA)

○ Mechanism: Immune complex → Activation of complement → Precipitation on the basement membrane. IgE is not involved.

○ 77% of hypersensitivity reactions

○ Example: RCM (radiocontrast media), liposomes, micelles, Cremophor EL (CrEL) in Taxol

⑦ Comparison of type I hypersensitivity and type II hypersensitivity

⑸ Autoimmune disease: Immune response occurs against self-antigens due to the failure of clonal deletion.

① Systemic erythematous lupus

○ Possess antibodies against DNA and nuclear proteins, induce inflammatory response, and have B cells that produce excessive antibodies.

② Rheumatoid arthritis

○ Onset: Reduced activity of CTLA4 (a protein that inhibits the reaction of T cells with self-antigens) allows self-recognizing T cells to enter the joints and cause inflammation.

③ Multiple sclerosis

○ Onset: T cells attack myelin surrounding nerve fibers (autoimmune demyelinating disease).

○ Symptoms: Fatigue, facial and limb paralysis, sexual dysfunction, impaired balance, dizziness, depression, etc.

④ Myasthenia gravis

○ Onset: Antibodies are generated against acetylcholine receptors in skeletal muscles, leading to muscle weakness.

⑤ Type 1 diabetes (insulin-dependent diabetes)

○ T cells attack beta cells of the islets of Langerhans.

⑥ Hashimoto’s thyroiditis

○ T cells attack thyroid cells.

⑦ Guillain-Barré syndrome

○ Stiffness starting from the extremities.

⑧ Systemic lupus erythematosus

⑨ Experimental autoimmune encephalomyelitis (EAE)

○ The most well-studied animal model of autoimmune disease.

○ Induction of diseases such as multiple sclerosis is possible with T cells alone.

⑩ Agammaglobulinemia

⑹ Immunodeficiency disorders

① Congenital immunodeficiency disorders

○ Genetic or developmental abnormalities in the immune system.

○ Example: Severe combined immunodeficiency (SCID) → Congenital lymphocyte impairment → Treatment: Gene insertion into the bone marrow.

② Acquired immunodeficiency disorders

○ Occur during life due to exposure to chemicals or physiological substances.

○ Example: Hodgkin’s disease (lymphatic system damage cancer), AIDS (acquired immune deficiency syndrome)

③ Immunodeficient mice

○ SCID mice: rag gene-deficient mice

○ Nude mice: thymus-deficient mice

⑺ Immune evasion

① Antigenic variation: Changes in epitope expression.

○ Example 1: Trypanosomes causing sleeping sickness randomly change surface proteins.

○ Example 2: Influenza viruses, RNA viruses (high mutation rate)

○ HIV reverse transcriptase is prone to errors.

② Latency

○ A phenomenon where viruses reside in an inactive state without stimulating the host’s immune defense system.

○ Virus DNA exists independently in the nucleus or inserted into the host genome.

○ Activation conditions: Conditions where the host’s survival is difficult and conditions favorable for virus transmission.

○ Example: Herpes simplex virus (DNA virus)

○ Type 1 (oral virus): primarily infects lips, face, and eyes.

○ Type 2 (genital virus): primarily infects the external genitalia and perianal area.

○ Latency in sensory neurons: Sensory neurons have low expression of MHC class I, making antigen presentation inefficient.

③ AIDS (acquired immune deficiency syndrome): Immune attack by HIV virus

○ Cause: Immunodeficiency caused by HIV

○ Altered antigen presentation due to MHC class I mutation in HIV-infected T4 cells.

○ Altered antigen presentation due to MHC class II mutation in HIV-infected antigen-presenting cells.

○ Failure of antigen recognition due to abnormalities in the receptors of HIV-infected helper T cells → Loss of proper function of helper T lymphocytes → Opportunistic infections occur.

○ Onset:

○ Transmission occurs only through contact with bodily fluids such as semen, blood, vaginal fluids, and rarely breast milk.

○ Early stage: HIV primarily infects antigen-presenting cells, helper T cells, and macrophages present in the blood and tissues. Inflammatory symptoms similar to flu.

○ Late stage: Virus is transmitted to major lymph nodes by antigen-presenting cells, helper T cells, and macrophages.

○ Progression:

○ Stage 1: Infection: Virus levels reach a peak but are suppressed by the immune system. Influenza-like symptoms. High levels of helper T cells, increasing antibodies, a pulse graph of virus.

○ Stage 2: Asymptomatic: The virus is almost absent in the blood, and the person appears healthy.

○ Stage 3: AIDS: Increased virus levels and decreased CD4⁺ T cell levels. Opportunistic infections occur.

○ Decreased helper T cells, decreased antibodies, increased virus.

○ 1^st: Lymph node swelling

○ 2^nd: Infections by bacteria and fungi on the skin and oral cavity

○ 3^rd: Kaposi’s sarcoma

○ 4^th: Tuberculosis

○ 5^th: Pneumonia

○ 6^th: Lymphoma

○ 7^th: Cytomegalovirus infection

○ Treatment: AZT (azidothymidine)

○ Contains an azide functional group (-N3) at the 3’ end.

○ Once AZT participates in the reverse transcription process, further chain extension becomes impossible, blocking the reverse transcription process.

○ Theoretically, can treat all RNA viruses that use the reverse transcription process.

○ AZT acts as a competitive inhibitor.

○ AZT targets RNA-dependent DNA polymerase, so it does not cause significant problems in normal cells.

○ Treatment: Crixivan (one of the HIV protease inhibitors used as an AIDS treatment)

○ HIV vaccines have been under development since 1987, but no approved vaccines are available yet.

Input: 2015.07.23 11:23

Updated: 2019.05.10 21:58