[PHY LEC - LE 2] 03 - WBC and Introduction to Immunology.pdf

PHYSIOLOGY LECTURE | TRANS 3 LE WBC and Introduction to Immunology ELINOR G. BARTOLOME, M.D., MS...

PHYSIOLOGY LECTURE | TRANS 3 LE WBC and Introduction to Immunology ELINOR G. BARTOLOME, M.D., MSc., MSPH | 10/02/23 | Version # 1 02 OUTLINE SOCS Suppressors Of Cytokine Signaling I. General Overview III. Adaptive Immunity ssRNA Single Stranded RNA A. Basic Definitions A. Features TAP Transporters associated with Antigen B. Roles of the Immune System B. Lymphoid Organs and Processing C. Features of the Immune Tissues TCR T - Cell Receptor Response C. B and T Lymphocytes TGF Transforming Growth Factor D. Levels of Defense D. Cell-mediated Immunity TLR Toll - Like Receptors E. Chronology of Immune E. Humoral Immunity TNF Tumor Necrosis Factor Response IV. “The Bad and the Ugly” WBC White blood cell F. Cells of the Immune System A. Immune Balance G.The Big Picture V. Review Questions LEARNING OBJECTIVES II. Innate Immunity VI. References ✔ Discuss the white blood cells (leukocytes) A. Recognition o Discuss the differentiation and maturation of the different B. Barrier Mechanisms WBCs C. Cells o Give the normal values of WBCs and their variations D. Molecules (Soluble o Give clinical significance of each WBC and situations Components) where abnormal levels of WBC occur E. Effector Mechanisms ✔ Discuss immunity o Distinguish innate immunity from specific acquired Must Lecturer Book Previous Youtube immunity ❗️ Know 💬 📖 📋 Trans 🔺 Video o Discuss innate immunity ▪ Describe how recognition is done by immune cells ▪ Distinguish the skin from mucosal barrier SUMMARY OF ABBREVIATIONS ▪ Distinguish the roles of the different components of ACTH Adrenocorticotropic Hormone innate immunity ADCC Antibody-Dependent Cell-mediated Cytotoxicity - Cells (granulocytes, APCs, NK cells) AICD Activation-Induced Cell Death - Complements AIDs Acquired Immunodeficiency Syndrome - Cytokines and INFs APC Antigen-presenting cell ▪ Distinguish the different leukocytes and explain their COVID Coronavirus Disease roles in: CpG Short Stranded Synthetic DNA - Phagocytosis C: Cytosine Triphosphate Deoxynucleotide - Inflammation G: Guanine Triphosphate Deoxynucleotide o Discuss phases of specific acquired immune response CRP C-Reactive Protein ▪ Explain the features of adaptive immune system to CSF Colony Stimulating Factor differentiate it from the innate immune system ▪ Identify the primary and secondary organs and CTL Cytotoxic T-cells describe their functions DAMPs Damage-associated molecular patterns ▪ Describe lymphocyte circulation dsRNA Double Stranded RNA ▪ Describe the development of B and T cells DTH Delayed-Type Hypersensitivity - Compare B and T cells ESR Erythrocyte Sedimentation Rate ▪ Discuss the cell mediated immune response FAB Antigen-binding Fragment - Describe antigen presentation Fc Crystalline Fragment - Explain the signals required for T cell activation GALT Gut-Associated Lymphoid Tissue and differentiation GCSF Granulocyte colony stimulating factor - Describe the roles of each type of T cell and each GIT Gastrointestinal Tract of the T helper cell subsets GM-SF Granulocyte-macrophage colony stimulating factor ▪ Discuss phases of the humoral immune response HSC Hematopoietic Stem Cell - Discuss ways of activating B cells - Discuss the cellular basis of antibody production HSPs Heat - Shock Proteins o Apply the concepts of immune response in the following ILC Innate Lymphoid Cell conditions: IFN Interferons ▪ Hypersensitivity reactions IL-1RA Interleukin-1 Receptor Antagonist ▪ Transplantation LPS Lipopolysaccharide ▪ Autoimmune disease MAC Membrane Attack Complex ▪ Immunodeficiency MALT Mucosa-Associated Lymphoid Tissue ▪ Chronic inflammation MHC Major Histocompatibility Complex NALT Nasal-Associated Lymphoid Tissue I. GENERAL OVERVIEW OF THE IMMUNE SYSTEM NET Neutrophil Extracellular Traps Primary functions: NK Cell Natural Killer Cell → Recognition and elimination → Development of immune cells PALS Periarteriolar Lymphoid Sheath PAMPs Pathogen-associated molecular patterns A. BASIC DEFINITIONS PRR Pattern Recognition Receptors Immunity RES Reticuloendothelial System → Our ability to protect ourselves from disease ROS Reactive Oxygen Species SALT Skin-Associated Lymphoid Tissue LE 2 TG 17, 18 | Chua, D., Chua C., Chua, J., Chua, W., TE | Collado, Condat, Cruz, C., AVPAA | Coronel, Dael, Daza PAGE 1 of 32 TRANS 1 *Clauss, Co, Collado, Condat, Constantino, Cruz, G Continuado, *Contreras, Crave, Crescini, Cristobal, Cruz, C., Cruz, G. PHYSIOLOGY | LE2 WBC and Introduction to Immunology | Elinor G. Bartolome, M.D., MSc, MSPH Immunology Barriers → Study of cells, organs, and molecules responsible for immunity, → Physical: skin and mucosal surfaces and how they respond and interact → Mechanical: flushing mechanisms (e.g. cilia, fluid flow) Immune system → Chemical: enzymes, antibodies, pH → Composed of cells and molecules responsible for immunity; Innate immune response includes their coordinated response to the introduction of → Rapid, nonspecific, no memory foreign substances → Cells and soluble factors that engage infectious agents that successfully penetrate the physical barriers B. ROLE OF THE IMMUNE SYSTEM Adaptive immune response Defense against infections → Slow, specific, memory → If we have deficient immunity, it results in increased → Divided into two responses: cell-mediated immunity and susceptibility to infections humoral immunity ▪ Exemplified by patients with HIV/AIDs ▪ Cell-mediated: B lymphocytes and T lymphocytes mediate Defense against tumors immune response → It has potential for immunotherapy for cancer patients ▪ Humoral: antibodies mediate immune response Control of tissue regeneration and scarring → Important for the repair of damaged tissues and organs E. CHRONOLOGY OF IMMUNE RESPONSE The immune system can injure cells and induce pathologic inflammation → Immune responses, especially when uncontrolled, can cause hypersensitivity reactions The immune system recognizes and responds to tissue grafts and newly introduced proteins → Immune response is actually a hindrance to tissue and organ transplantation C. FEATURES OF THE IMMUNE RESPONSE Recognition of Self vs. Non-self (distinguish foreign substances) → “Know thyself” - words originally inscribed in gold on the pronaos of the Temple of Apollo at Delphi Figure 2. Chronology of immune response [Asynchronous PPT] Elimination As soon as foreign bodies breach the barrier, immune cells are → “...in order to kill the enemy, our men must be roused to able to recognize them right away anger…” - Sun Tzu, The Art of War, circa 500 BCE Within 0-4 hours, innate immunity will be stimulated Memory If innate immunity cannot control the foreign bodies, adaptive → “Those who cannot remember the past are condemned to immunity will develop after >96 hours repeat it.” - George Santanyana, 1863-1952 Proportionality F. CELLS OF THE IMMUNE SYSTEM → Regulatory systems exist to ensure that the immune responses All cellular elements of the blood are derived from pluripotent are proportional to the level of threat D. LEVELS OF DEFENSE 💬 hematopoietic stem cells in the bone marrow 💬 “Leukocytes are WBCs are the immune cells” 5 million RBCs in one microliter of whole blood but only 7,000 leukocytes HEMATOPOIESIS Figure 3. Hematopoiesis [Asynchronous PPT] Pluripotent cells divide into two committed stem cells: → Myeloid progenitor → Lymphoid progenitor MYELOID PROGENITOR Figure 1. Levels of defense [Asynchronous PPT] Common myeloid progenitor gives rise to the myeloid lineage from which erythrocytes, megakaryocytes, and leukocytes arise PHYSIOLOGY LEC | LE2 PAGE 2 of 32 PHYSIOLOGY | LE2 WBC and Introduction to Immunology | Elinor G. Bartolome, M.D., MSc, MSPH → Leukocytes comprise of basophils, eosinophils, neutrophils, Pathogens may enter the body through mucosal surfaces or and monocytes through a breach in the skin ▪ Basophils, eosinophils, and neutrophils are termed → Threats can be bacteria, viruses, cancers, toxins, therapeutic granulocytes due to their cytoplasmic granules drugs, diagnostic procedures − Also termed polymorphonuclear leukocytes due to their Pathogens are detected by resident phagocytic cells (comprise irregularly shaped nuclei innate immunity) ▪ Monocytes in blood enter tissues where they differentiate → Cells release antimicrobial compounds, cytokines into phagocytic macrophages or dendritic cells → Help recruit other immune cells to the site (inflammation) − Immature dendritic cells are phagocytic cells that enter Free pathogen and other phagocytic cells that have engulfed the the tissues pathogen may go to the organs, specifically the lymph nodes o Mature after they have encountered a potential (secondary lymphoid structure) pathogen − Majority of dendritic cells are derived from the common myeloid progenitor cells 📖 → They intersect with lymphocytes from the blood Adaptive immunity is initiated in secondary lymphoid structures, where T helper cells, T cytotoxic cells, and B − Some dendritic cells arise from the common lymphoid cells with appropriate receptor specificity bind pathogen and progenitor cells are clonally selected ⇨ leads to rounds of proliferation and Mast cells also enter tissues where they complete their maturation differentiation B and T cells present in lymph nodes together with their products (e.g. antibodies) will migrate out of the lymph node and join the bloodstream → They travel to area where there is inflammation → Help destroy any remaining pathogens at the site Long-term memory B and T cells take up residence in various locations in the body II. INNATE IMMUNITY Figure 4. Types of nucleated WBCs[Google Images] Present at birth and persists throughout life Component cells are mobilized rapidly and acts quickly (around LYMPHOID PROGENITOR 7-10 days) for adaptive immunity to be generated A common lymphoid progenitor gives rise to the lymphoid lineage Paramedics at the site of an accident before patients are seen by of the innate lymphoid cells and the B and T lymphocytes specialists in the hospital Production of these cells is stimulated by interleukins and other cytokines such as stem cell factors, granulocyte colony stimulating A. RECOGNITION factor (GCSF), and granulocyte-macrophage colony stimulating Innate immunity recognizes: factor (GMCSF) made by endothelium and fibroblasts of bone → Pathogen-Associated Molecular Patterns (PAMPs) marrow and WBCs → Damage-Associated Molecular Patterns (DAMPs) CONCEPT CHECKPOINT 1. Identify which of the following cells are myeloid and which are PATHOGEN-ASSOCIATED MOLECULAR PATTERNS lymphoid: Molecular structures produced by microbial pathogens a. Dendritic cells - myeloid and lymphoid Often shared by classes of microbes b. Neutrophils - myeloid Essential for survival of microbes c. NK cells - lymphoid E.g. nucleic acids, proteins, cell wall lipids, carbohydrates d. Basophils - myeloid e. Macrophages - myeloid Table 1. Pathogen-Associated Molecular Patterns (PAMPs) f. T cells - lymphoid g. B cells - lymphoid PAMPs Microbe Type h. ILCs - lymphoid Nucleic acids ssRNA Virus 2. Using the same lists of cells, identify which cells belong to innate dsRNA Virus immunity and which cells belong to acquired immunity: CpG Virus, bacteria a. Innate immunity: dendritic cells, neutrophils, NK cells, basophils, Proteins Pilin Bacteria macrophages, ILCs Flagellin Bacteria b. Acquired immunity: T cells, B cells LPS Gram (-) bacteria G. THE BIG PICTURE Lipoteichoic acid Gram (+) bacteria Carbohydrates Mannan Fungi, bacteria Glucans Fungi DAMAGE-ASSOCIATED MOLECULAR PATTERNS Endogenous molecules that are produced by or released from damaged and dying cells Released by cell damage caused by infection Also through cell injury by chemical toxins, burns, trauma, or low blood supply Generally not released by cells dying from apoptosis Also known as Danger-Associated Molecular Patterns E.g. stress-induced proteins, crystals, nuclear proteins Table 2. Damage-Associated Molecular Patterns (DAMPs) DAMPs Stress-induced HSPs proteins Crystals Monosodium urate Nuclear proteins HMGB1 Figure 5. Collaboration between innate and adaptive immunity in resolving an Infection[Asynchronous PPT] PHYSIOLOGY LEC | LE2 PAGE 3 of 32 PHYSIOLOGY | LE2 WBC and Introduction to Immunology | Elinor G. Bartolome, M.D., MSc, MSPH PATTERN RECOGNITION RECEPTORS (PRR) − Produced by neutrophils and barrier-epithelial cells, skin Used by innate immunity to recognize PAMPs and DAMPs ▪ Both chemicals have direct toxicity to broad range of Most cell types express PRR microbes Phagocytes & dendritic cells express the widest variety and ▪ Cause activation of leukocytes to promote eradication of greatest amount of these receptors in keeping with their microbes fundamental roles → Killing of microbes and infected cells by intraepithelial Expressed on cell surfaces, in phagocytic vesicles and in the T-cells/T-lymphocytes cytosol of cells ▪ Mucosa associated lymphoid tissue (MALT) PRR binding to PAMPs and DAMPs − Initiates immune responses to specific antigens → Activate signal transduction pathways → Promote antimicrobial encountered along all mucosal surfaces and proinflammatory functions ▪ Intraepithelial T cells recognize and respond to a small May be extracellular, cytosolic, or endosomal (Figure 6) number of common microbial structures → Toll-like receptors (TLR) SKIN IMMUNE SYSTEM → Lectin-like receptors Surface of the skin Macrophages have a number of PRRs: mannose receptors, → With commensal organisms TLR-1, TLR-2 receptors, glucan receptors, scavenger receptors, Epidermis etc. (Figure 7) → Langerhan cells ▪ Type of dendritic cells ▪ Involved in development of T-helper mediated immunity against skin pathogens such as S. aureus and Candida ▪ Confers immunological tolerance to commensal organisms found on the skin surface → T cells Dermis ▪ Dermal dendritic cells − Initiate protective response against viruses involving helper and cytotoxic T cells ▪ NK cells ▪ Macrophage ▪ Mast cells ▪ Also has lymphatic drainage so the dermal immune cells can travel to the lymphatic vessels Figure 6. PAMPs and DAMPs diagram[Asynchronous PPT] MUCOSAL BARRIERS Found in the respiratory passages, gut/intestines, genitourinary tract Include mechanical and chemical barriers Also populated by commensal organisms → Commensal organisms compete effectively against many potential pathogens → When normal bacterial flora are disturbed by antibiotics, susceptibility to opportunistic infections such as Candida and Clostridium may increase Associated with specialized lymphoid tissues → Peyer’s Patches in the small intestine → Isolated lymphoid follicles Skin → Physical barrier, fatty acids, commensals Eyes Figure 7. PRR found on macrophages[Asynchronous PPT] → Lysozyme in tears and other secretions Respiratory tract B. BARRIER MECHANISMS → Mucus, cilia, removal of particles by rapid passage of air over Important to distinguish between skin and mucosal barriers turbinate bones, coughing, sneezing → Pathogens may enter through a breach in the skin or, Bronchi → Through mucosal surfaces of respiratory passages, → Mucus, cilia gastrointestinal tract, or genitourinary tract Gut EPITHELIAL BARRIERS → Acid, rapid pH change, commensals Surface area of all tissues exposed to the external environment Genitourinary tract → Physical barrier between microbes in external environment and → Flushing of urinary tract, low pH in vagina, commensals host tissue Other mechanical barriers → Includes skin and mucosal surfaces → Washing action of tears, saliva, urine 400 square meters in total Secreted body fluids → Skin is only about 2 square meters → Contain bactericidal component May be portals of entry for microbes → Acids in gastric juice Ways by which barriers work: → Spermin and zinc in sperm → Physical barrier → Lactoperoxidase in milk ▪ Tight junctions → Lysozyme in tears, nasal secretions, and saliva ▪ Keratin ▪ Mucus assisted by cilia and peristalsis → Killing of microbes by locally produced antimicrobial chemicals or agents ▪ Defensins − Produced by mucosal surfaces and granulocytes ▪ Cathelicidin PHYSIOLOGY LEC | LE2 PAGE 4 of 32 PHYSIOLOGY | LE2 WBC and Introduction to Immunology | Elinor G. Bartolome, M.D., MSc, MSPH Granules: C. CELLS → Lysozyme, collagenase, elastase, myeloperoxidase, and CELLS OF MYELOID LINEAGE microbicidal substances (defensins, cathelicidin) Neutrophil extracellular trap (NET) formation → Formed when neutrophils are activated → Followed by granule lysis → DNA and granule contents then released to form the NET → Immobilize and eventually kill extracellular microbes → Occurs 1-2 hours after neutrophil activation Figure 9. Klebsiella trapped in NET[Asynchronous PPT] EOSINOPHILS 1-3% of total leukocytes Pink-staining cytoplasmic granules Can also be phagocytic Have Fc receptors, TLR, receptors for IL-5 and IL-3 5-12 days lifespan BASOPHILS