TNF-α and Immune Response Mechanisms

Course Overview

• BIOL 359 is an immunology course covering basic and clinical immunology principles with applications to infection and global health
• Students will comprehend fundamental immunology principles in clinical and experimental contexts
• Emphasis is placed on host immune responses to pathogens and how these responses determine future immunity or susceptibility

Course Objectives

• To enable students to understand, comprehend, and appreciate the fundamental principles of immunology in both clinical and experimental settings

Introduction Topics

• Introduction covers definition, history, and immunology overview
• Immune system includes study of organs, tissues, cells, haematopoiesis, and differentiation of immune cells
• Types of Immunity features primary and secondary lymphoid organs and key immune cells that are innate and adaptive

Immunity Types

• Innate immunity non-specific and physiological barriers, the chemical/peptide immune system, target receptors/recognition, and the complement system
• Adaptive immunity exhibits acquired characteristics, passive/active aspects, and primary/secondary immune responses
• Recognition of targets and processing involves antigen recognition and processing.
• It is related to the Major Histocompatibility Complex (MHC) and antigen presentation

Immune Response

• B cell and T cell mediated immunity
• Structure and function
• Immunoglobulins and Antigens are antigens, haptens, and adjuvants. They also exhibit the structure/function of immunoglobulins, with antigen-antibody affinity, avidity, and cross-reactivity

Immune Dynamics

• Immunity to bacteria, parasites, viruses, and fungus
• Immune Evasion/Tolerance
• Immunodeficiencies, hypersensitivity, and autoimmunity are observed
• Transplant and immunology of cancer and the immunology of HIV are present

Immuno-techniques

• Immunodiagnostics, radial immune diffusion, and Ouchterlody double diffusion exist
• Agglutination reaction, agglutination titre, and incomplete agglutination
• Complement fixation and ELISA
• Immunocytochemistry

Immuno-vaccinology

• Vaccines-Types and application
• Polyclonal antibodies and monoclonal antibodies are present

Clinical Immunology

• Alloantigens-Immunohaematology includes blood groups, blood grouping, A, B, Rh antigens and antibodies, and Rh Bombay group

Learning Outcomes

• By the end of the course, students should be able to understand basic immunology concepts.
• The basic systems and cells involved in immune responses
• Explain how the immune system components work together to generate an effective immune response against a specific pathogen
• Determine what immunomodulatory strategies can be used to enhance immune responses or to suppress unwanted immune responses
• Explain the concept of immune response and abnormalities of the immune system
• Learn and explore the applications and impact of immunology

Attendance

• Lecture attendance is required
• If a student misses 3 or more lectures before the mid-semester, the are not eligible to complete the course

Evaluation

• Grades are decided by:
• Attendance and Participation in Lectures: 5%
• Assignment/presentation/Termpaper: 5%
• Mid-semester examination: 20%
• Final Examination: 70%
• The pass mark is 40%.
• A: 70-100%
• B: 60-69%
• C: 50-59%
• D: 40-49%
• F: 0-39%

Introduction to Background Immunology

• Immunology is described as physiological processes that provides the capacity to recognize materials as foreign to itself
• It is described to neutralize, eliminate, or metabolize them with or without injury to its own tissue(s)

Background of the Immune System

• Consists of cells, tissues, and soluble products for recognition, attacks, and destruction of harmful agents.
• "Immunitas," a Latin term, means "exempt."
• Immunity is the body's mechanisms against environmental agents that are foreign.
• Microorganisms/their products, foods, chemicals, drugs, pollen, or animal hair
• Allergens in house dust, cat litter, or pollen can induce a disease via an immune response.
• Autoimmune diseases include multiple sclerosis and diabetes.
• Most individuals do not suffer from autoimmune disease because they have developed tolerance towards their own (self) tissues.

Immune Response and Homeostasis

• A normal healthy person's body strives to maintain homeostasis: natural state of balance of all its organs, the nervous and circulatory systems
• The immune system responds to trauma, pathogens, or deregulation of body cells (cancer)

Timeline of Immunology History

• 430 BCE: The plague of Athens left survivors immune to the disease
• 1796: Edward Jenner demonstrates vaccination with cowpox to prevent smallpox
• 900 CE: Variolation was practiced by Chinese and Indians to generate immunity
• 1861-1865: Louis Pasteur develops the germ theory of disease involving microorganisms
• 1880-1908: Scientists like Pasteur and Ehrlich identified the roles of weakened bacteria, phagocytic cells, and antibodies in immunity
• 1940s-1990s: Discoveries include the ABO blood group system, T/B lymphocytes, major histocompatibility complex (MHC), Toll-like receptors and the eradication of smallpox worldwide plus the cause of AIDS identified
• 21st Century: includes achievements in cancer immunotherapy, mRNA vaccine technology, CRISPR, and cell therapies
• 1890-1900: Researchers discovered that toxicity diphtheria toxins could be neutralized by antibodies and that complement existed

Immunity Types

• Innate: Triggered by disruptions to non-infectious or infectious homeostasis
• Adaptive: composed of highly specialized, systemic cells, eliminates or prevents pathogen growth
• The principles of an immune response include:
• Discrimination of self vs. non-self
• Elimination of microbial agents through innate immune system
• Cues from the innate immune system inform the cells of the adaptive immune system

Basic Immune Concepts

• Adaptive immune system displays exquisitely specific recognition of foreign antigens
• Potent mechanisms mobilize for microbe elimination by such antigens
• The IS displays memory of previous responses with tolerance of self-antigens

Innate Immunity

• Innate immunity creates non-specific responses
• Includes physical, chemical, and cellular barriers and the inflammatory response
• Involves the complement system.
• Barrier defence, complement activation, and inflammation
• Pattern recognition, phagocytosis, and chemical distruction

Anatomic/Physical barriers

• Physical barriers can prevent pathogens from entering the body
• The skin and mucous membranes offer a physical barrier function with hair-like structures to trap pathogens.
• Destroy and flush enterable pathogens prior to establishment

Skin

• The skin is the primary barrier unless damaged.
• The skin is keratinized with a dry epithelium for bacterial growth protection
• Skin cells shed bacterial and pathogen attachments.
• Sweat and skin secretions have a low pH, contain toxic lipids and physically remove microbes

Exceptions to skin defense

• Human papillomavirus causes warts.
• Some parasites like Schistosoma mansoni and Strongyloides stercoralis
• Staphylococcus epidermidis is normal skin flora

Mucus membranes

• Layers of mucosal cells line body cavities open to the outside.
• The mucus layer covering the mucosal epithelium has a physical barrier component
• Epithelial cells and intraepithelial lymphocytes are tightly interlaced.
• Contains antimicrobial substances like lysozymes and lactoferrin
• Mucosal cells that rapidly divide and flush bacteria
• Local secretions that contain immunoglobulins and secretory IgA

Respiratory Tract

• Functions include; Nasal hair, nasal mucus secretions (phagocytes and antibacterial enzymes), irregular chamber design, and upper airway filters.
• Mucociliary epithelium transports pathogens from cavity, sinuses, bronchi, trachea, and coughing facilitate bacteria and pathogen removal

Aveoli in Lungs

• Include macrophages and tissue histiocytes with phagocytosis
• Defenses can be overwhelmed by large numbers of organisms or air pollutants

Gastrointestinal Tract

• Saliva contains lysozyme for antimicrobial activity
• Stomach acids and antibacterial activity are present
• Peristalsis and the normal loss of epithelial cells remove microorganisms.

Gut Defences

• Compromised GI defense predisposes patients to infections with antibiotics
• Normal flora inhibits pathogens and allows for overgrowth which can be prevented by antibacterial agents and cell mucus with antibodies including phagocytes
• The defecation contains up to 50% bacteria

Genitourinary Tract

• Sterile urine acidity and flushing maintain bladder and urethra hygiene,
• Secretory contain IgA.
• GU barriers consist primarily of the urethra's length.
• In females a healthy vagina consists of high acidity from epithelium to prevent microorganisms via lactic acid and Lactobacillus acidophilus present

Eyes

• Blinking mechanically removes microbes
• Tears move antimicrobial proteins and immunoglobulins that prevent infection

Outer and Inner Ear

• Tears bind to bacteria which can secrete cytokine
• Outer wax contains antibacterial components.
• Inner ear contains tissue Monocytes and macrophages

Physiological/Chemical Barriers

• Microbial antagonism uses colonization to outcompete binding and bacterial cell production. Specific bacteriocins kill other bacteria while normal gut flora produce metabolites inhibiting microorganisms
• The immune system contains a summary of all discussed physical barriers

Inflammatory Repsonse

• Inflammation is a series of events that removes or contain the offending agent and repair the damage tissues in response to an injury/infection.
• Heat, pain, swelling, and redness are key indicators
• It is immediate and nonspecific using cells, macrophages, neutrophils, dendritic cells, mast cells, natural killer (NK) cells, and molecules like chemokines, cytokines, complements, ROS

Major Events of Inflammation

• Vasodilation, permeability of capillaries, mobilization of peptides, neutrophils and mononuclear cells, and phagocytosis. It also works to localize infection, neutralize toxins and repair damage tissue.

Barrier Defense and Cellular Responses

Phagocytosis, use receptors to recognize foreign agents (PRRS, PAMPs and DAMPs), use chemotaxis, realse phagocytic and limit microbial spread.

Complement activation uses complement plasma proteins that mark pathogen destruction such as to trigger/tag/kill and destroy breakdown.

Chemokines

• Are signalling proteins that recruit immune cells to the site of infection/injury, suggest chemotaxis, and are very small between only 8kDA-12kDA
• There exist C, CC, CXC, CX3C versions that regulate cell interaction; Leukocytes travel along chemotactic gradients to injury sites and act through binding
• Leukocytes travel along gradients act by binding G-protein receptors such as CCR5&CXCR4, CCR7, CXCR3

Acute Phase Proteins (APPs)

• Group of proteins produced by the liver in response to tissue injury and stress.
• APP production is primarily regulated by some cytokines
• CRP, SAA are the major APPs that are involved in acute immune reactions

Function of Acute Phase Proteins

• Opsonization & Phagocytosis and CRP binding to pathogens, enhance microbial killing, ferritin limits bacteria by restricting their growth, and clotting with fibrinogen for tissue repair

Cytokines

• Large class of protein that mediate/regulate immunity
• Low weight proteins regulate immune systems. They require cell surface receptors that trigger cellular function changes with high receptor affinity. They can be regulated in a coordinate cellular level such as:
• Pieiotrophy function of the immune response
• Redundancy for mediate similar and adaptive immune systems Synergism- the combining effects for immune function

The Production of Fever

• There are 3 steps before production of a fever (pyrogen), where:
• Cytokines interleukins (1L-1), TNF_a and interleukin 6 (IL-6) travel to the hypothalamus to produce prostaglandin (PG) and induce vasoconstriction which then produce an increase of metabolism

Detection & Migration of Lymphocytes

• After producing a fever, the body has two primary components that assist lymphocytes: detection and migration. In detection, lymphocytes are received/sent, and in migration, the cells will move by extending to fight

Perforins and Granzymes

• Are proteins with cytotoxic activity that create holes in the pathogen membrane and diffuse more signal molecules
• Hepatins also increase capillary permeability and vasodilation of signal molecules

Histames

• A derivative is produced by histamine that is produced by the basophil and cell where the histime increases with permeability where is then regulate the proliferation response

Body Recognition System

• To help produce immunity or fight infections, cells that produce antibodies or destroy foreign bodies are created. The process of the proteins or foreign cells acting on the body is Opsonization

Opsonization

• A process where antigens on surface of microbes are used to be recognized via phagocytes
• Pathogens are recognized via pathogen-associated molecular parts during the immune repsonse

Bodies Defences

• To defend the body from pathogens, there are three main types:
• Cytoplasmic: The bodies sensors and subfamily will try to eliminate the pathogen
• Receptive: The toll of the sensor that recognize harmful pathogens
• Membrane: Transmembrane proteins trigger the synthesis

Explore the pivotal role of TNF-α in fever development during inflammation. Understand chemotaxis, perforins, and granzymes in immune cell function. Learn about Colony-Stimulating Factors (CSFs) and pyrogens like LPS in immune responses.