The Human Immune System & MHC

• The human immune system initiates responses involving antigen presentation, distinguishing between self and non-self antigens, and dealing with cellular, non-cellular pathogens and allergens.

Distinguishing Self

• The immune system recognizes its own cells through the major histocompatibility complex (MHC).
• MHC is a tight cluster of genes on human chromosome 6.
• The MHC genes encode protein molecules/antigens attached to the surface of cells.
• MHC antigens distinguish its own cells from foreign material.
• Class I MHC antigens are on most human cells.
• Class II MHC antigens are restricted to macrophages and B-lymphocytes.

The Role of MHC Receptors

• There are two types of MHC receptors: Class I and Class II.
• Both MHC receptor types display antigenic peptides on the cell surface so antigens can be processed by T-cells.
• T-cells only recognize antigen if shown by MHC receptors.
• MHC receptors without foreign antigenic peptides signal a healthy cell, and are ignored by T-cells.
• MHC receptors bound to foreign antigenic peptides attract T-cells, causing an immune response.
• Different MHC receptors display antigenic peptides from different sources.
• Class I MHC receptors display the antigenic peptides of intracellular parasites (i.e. viruses).
• Class II MHC receptors display antigenic peptides originating from outside the cell (i.e. ingested microbes).

Types of Antigens

• Non-self antigens are foreign materials inducing an immune response, including pathogens like bacteria, viruses, and fungi.
• The body recognizes non-self antigens as foreign and attacks.
• Self-antigens occur when the self-tolerance system fails, causing the body to attack its own cells and tissues, resulting in autoimmune disorders.
• Allergens are antigens that cause allergic reactions, where the immune system overreacts to harmless substances.

Tissue Rejection

• The MHC is responsible for tissue graft and organ transplant rejections.
• Foreign MHC molecules are antigenic, thereby causing an immune system response.
• T cells directly lyse foreign cells during tissue graft and organ rejection.
• Macrophages are activated by T cells and engulf foreign cells.
• Antibodies are released to identify and attack the foreign cell.
• The complement system injures blood vessels near the the graft or transplant.
• MHC matching between organ donors and recipients is important.

Types of Pathogens

• Pathogens include bacteria, fungi, worms, protozoa, viruses and prions.
• Pathogens can be cellular or non-cellular.
• Cellular pathogens have a cellular structure and are living organisms.
• Non-cellular pathogens do not have a cellular structure and are non-living.

Cellular Pathogens

• Cellular pathogens have a cellular structure and are living organisms.
• Bacteria are unicellular prokaryotes infecting much of the body, and producing toxins/enzymes to affect cell function, or cause cell death.
• Bacteria reproduces asexually via binary fission.
• Neisseria meningitidis bacteria causes meningitis, and Clostridium tetani causes tetanus.
• Fungi are eukaryotic organisms containing yeasts/molds with branching filaments called hyphae.
• Fungi reproduces both sexually and asexually via spore formation.
• Fungi causes Thrush, Trichophyton spp causes athlete's foot (Tinea pedis), and Ringworm also know as Tinea.
• Worms are multicellular invertebrate parasites with egg, larval and adult stages.
• Worms reproduces sexually via a complex lifecycle.
• Parasite infections (e.g. tapeworm) can cause malnutrition, and roundworm infection (Ascaris).
• Protozoa are single-celled eukaryotes that are either free-living or parasitic.
• Protozoa reproduces both sexually and asexually.
• Protozoa contains several mechanisms of action – for example, some can inhibit nucleic acid synthesis, protein synthesis, and various stages of cellular respiration.
• Plasmodium protozoa causes malaria.

Non-Cellular Pathogens

• Non-cellular pathogens do not have a cellular structure and are non-living.
• Viruses consist of genetic material (DNA or RNA) inside a protein coat (capsid), and sometimes a lipid envelope.
• Viruses cannot independently reproduce, but hijacks a host's cell machinery to replicate.
• Viruses can cause disease by lysis during replication, cancer through gene expression changes, and immune system over-stimulation
• Viruses reproduce by inserting genetic material into a host cell to use the host's machinery.
• Rhinovirus, influenza, Ebola, and SARS-CoV-2 cause the common cold, the flu, Ebola, and COVID-19, respectively.
• Prions are abnormally folded proteins inducing misfolding of normal proteins nearby, found only in mammals and only affect neural structures.
• Prions do not reproduce but induce misfolding in nearby proteins, 'spreading' throughout tissue.
• Prions causes Creutzfeldt-Jakob disease and Bovine spongiform encephalopathy (mad cow disease).

First Line of Defense

• The first line of defense is a component of the innate immune system.
• The first line of defense provides physical, chemical, and microbiological barriers to prevent pathogenic invasion.

First Line of Defense: Barriers in Plants

• Plants have physical and chemical barriers as first line defenses.
• Physical Barriers in Plants prevent or impede pathogens entry.
• Examples include thick bark, waxes on cuticles of leaves, formation of galls to prevent infection spread, thorns and trichomes to deter insects/grazers, closing of stomata to prevent pathogen invasion during carbon dioxide uptake
• Chemical Barriers in Plants act to inhibit the growth or development of pathogens and/or act to destroy pathogens.
• Examples include chitinases, phenols, defensins, saponins, oxalic acid, and glucanases.
• Chitinases are enzymes present in a number of different plants with antifungal properties.
• Phenols are secreted by wounded plants to repel or kill invading microorganisms.
• Defensins are small peptides that are toxic to microbes and fungi
• Saponins disrupt cell membranes of various fungi.
• Oxalic acid can harm insects or animals that damage the plant
• Glucanases defend plants against fungi.

First Line of Defense: Barriers in Animals

• Animals utilize physical, chemical, and microbiological barriers as first lines of defense.
• Physical Barriers in Animals prevent or impede pathogens entry.
• Examples include intact skin between external/internal environments (e.g. integumentary, respiratory, gastrointestinal, and genitourinary tracts), and mucous secretions/hairs/cilia in the respiratory tract, which traps and sweep out pathogens..
• Chemical Barriers in Animals destroys or that act to inhibit the growth or development of pathogens.
• Examples include lysozyme enzymes, acidic sweat, stomach acid, antibacterial compounds in ear wax, antibacterial proteins in semen, and low vaginal pH.
• Microbiological Barriers prevent the growth of microorganisms by utilizing non-pathogenic bacteria (normal flora).
• Examples include presence of bacteria on skin, the lower gastrointestinal tract, and the vagina.

The Second Line of Defense of the Innate Immune System includes

• Macrophages
• Neutrophils
• Dendritic Cells
• Eosinophils
• Natural Killer Cells
• Mast Cells
• Complement Proteins
• Interferons

Phagocytes

• Phagocytes consume and destroy foreign material by engulfing it via endocytosis.
• Lysosomes containing antimicrobial enzymes (lysozymes) fuse with engulfed vesicles, destroying their contents.
• Neutrophils, macrophages, and dendritic cells are examples of phagocytes.
• Phagocytes release cytokines, which promote cell signaling to protect against pathogens and guide immune cells to sites of infection.
• Macrophages and dendritic cells can also express MHC Class II, use antigens to interact with the adaptive immune system, and are Antigen-Presenting Cells (APCs).

Natural Killer (NK) Cells

• Natural killer cells targets abnormal and virally infected cells.
• These cells contain killer inhibitory, and killer activation receptors.
• Killer inhibitory receptors examine the surface of cells for MHC Class I Markers.
• Killer activation receptors bind to molecules on cells undergoing cellular stress, and are associated with infection or cancer.
• The presence of MHC Class I markers can be altered due to different diseases.
• During a viral infection, cells can either suppress or destroy MHC Class I markers.
• Gene expression of MHC Class I markers may be affected/absent in infected and cancer cells.
• Apoptosis (cell death) is initiated only in infected and abnormal cells lacking sufficient levels of MHC Class I markers,

Mast Cells release Histamine

• Mast cells reside in connective tissues throughout the body.
• Upon detection of injury/stimulation by antigens or allergens, mast cells activate and degranulate, releasing histamine

Eosinophils contain Chemical Mediators

• Eosinophils are large granulated cells containing toxic chemical mediators such as DNases, RNases, and proteases.
• They target pathogens too large to be phagocytosed by degranulation on contact, releasing chemical mediators from their granules

Interferons protect against Virus

• When a cell is infected, a cytokine (interferon) is released.
• Interferons interacts with receptors on neighboring cells, causing changes which reduce susceptibility to viral infection, preventing them spreading between cells

Complement System promote Pathogen Destruction

• In the blood, a variety of complement proteins work together.
• Reacting to certain pathogens, these proteins begin a series of reactions called the complement cascade, and promote pathogen destruction.

Fever

• Fever is a temporary increase in body temperature.
• Fever represents an innate response to potential infection, as many pathogens can not survive fever temperatures.
• Fevers also help activate other immune components.
• Prolonged fevers are detrimental.

Inflammatory Response 3 main aspects

• Initiation
• Vasodilation
• Migration
• Inflammation increases blood flow to injured areas.
• Increased blood flow brings greater numbers of immune cells and components aiding in clearing debris and fighting pathogens.
• Inflammation triggers common symptoms as well, including:
• Swelling
• Pain
• Heat
• Redness
• Inflammatory responses act to eliminate an injury's effects, clear out damage/destroyed cells, defend against pathogens, and initiate repair for pathogens or injury.
• Complex, non-specific process occurs independently of what pathogen or injury has occurred.

Inflammation: the Process

• Initiation: macrophages activate and release cytokines at the tissue that is injured. Mast cells degranulate as well, releasing histamine.
• Vasodilation histamine released from mast cells travels to nearby blood vessels and binds to specific receptors, causing vasodilation, and increases permeability.
• Migration: Due to vasodilation and blood vessel leakiness a variety of immune responses are activated at the injured tissue.

Key Concepts of Adaptive Immunity

• The third line of defense is a specific resistance.
• The third line of defense targets pathogens.
• Specialized cells of the immune system are called Lymphocytes.
• B-Cells produce unique antibodies.
• T-Cells targets pathogens.

The Humoral and Cell-Mediated Immune Systems

• Humoral immune system is associated with B cells that produce antibodies to respond to antigens outside of cells
• Cell-mediated immune system associated with T cells recognize infected cells.
• B cells and T cells work together as a defence .

B-Cells defend against Bacteria

• B-cells (B-lymphocytes) originate/mature in bone marrow (long bones).
• B-Cells protect against bacteria, viruses, and bacterial toxins outside of cells.
• Mature B-Cells contain 100,000 antigenic receptors.

T-Cells respond to Antigens from a Foreign Source

• T-Cells originate from stem cells and mature within the thymus organ.
• Cellular immunity (T-Cells) fight protozoa, fungi or tumour cells.

Humoral Immunity and Clonal Selection

The humoral response begins when a specific B-Cell binds to its complementary foreign protein antigen.

• B-Cell clonal selection and differentiation results in production of plasma cells and memory cells, controlled with helper T cells.
• Plasma cells produce antibodies.
• Memory cells produce antibodies against existing pathogens that enter the body again.

B-Cell Differentiation

• B-Cells differentiate into plasma and memory cells.
• Plasma cells secrete antibodies against specific antigens, with a short lifespan of days, producing ~2000 antibody molecules per second.
• Memory cells are long lived in lymph nodes providing future immunity.

Clonal Selection and Expansion

• Antigen presentation is followed by clonal expansion and differentiation, leading to selected B-lymphocytes developing into plasma cells and B memory cells.

T-Cell Activation

• T cells are activated by antigenic fragments that are processed and presented bound to MHC molecules by antigen-presenting cells.
• Macrophages and dendritic cells are an antigen-presenting cells (APCs).

Cell Mediated Immunity

• Cytotoxic T cells and specific MHC I markers attach.
• Releasing Perforin to signalling molecule for Apoptosis.

Antigens and Antibodies work with the Immune Response

• Antibodies / antigens play key roles.
• Antigens are foreign substances and cause the creation of antibodies.
• Examples include toxins, microbes, pollen cells and cells from other people.

Lymphatic System

• Lymphatic system is important to the immune processes.
• Lymph fluid transports through the body.
• Lymph vessels transport lymph to the circulatory system.
• Lymphatic system protects against infection or cancer.

The Lymphatic System

The Lymphatic System contains primary and secondary lymphoid tissues Primary lymphoid tissue involves mature lymphocytes Secondary lymphoid tissue involves APCs that recognize antigens

Lymphoid Tissue contains lymphocytes

• Bone marrow/ thymus.
• APCs recognize antigens to have a adaptive immune response.
• APCs go to a lymph node to activate a immune response.

Tissue Fluid

• Fluid leaks from capillaries.
• Nutrients and oxygen gets to the cells.
• Tissue fluid is similar to plasma .
• Blood volume is regulated in body.
• Fluid gets to the brain.
• fluid into vessels.

Lymph Nodes filter against foreign antigens

• Lymph Nodes are the storage site for lymphocytes ( T Cells, B Cells) .
• Trapping fibres to destroy particles.