Innate Immunity: Mechanisms and Overview

Innate Immunity Objectives

• The objectives are to describe the two major systems of immunity and their roles
• The objectives are to discuss the relationship between microbial structure and innate immune mechanisms
• The objectives are to identify features of the innate immune system that affect acute versus chronic inflammation
• The objectives are to explain how activating innate immunity influences disease symptoms

Overview of the Immune System

• The immune system is a collection of organs, tissues, cells, and cell products
• It differentiates self from non-self
• It rids the body of non-self substances

Types of Immunity

• Innate immunity is the 1st and 2nd line of defense, present at birth, immediate, non-specific, and lasts from incubation until infection ends
• Adaptive immunity is the 3rd line of defense, involves lymphocytes, is highly specific, slower to respond, and maintained long after infection ends

Innate Immune System Overview

• External barriers include skin, mucous membranes, respiratory system, eyes, and normal microbiota
• Internal and protective cells and chemicals include defensins, lysozyme, white blood cells, phagocytes, opsonization, oxygen-dependent killing, interferons, NK cells, Toll-like receptors, complement, inflammation, and fever

First Line of Defense

• The first line of defense includes structures, chemicals, and processes
• These work to prevent pathogens from entering the body
• Skin and mucous membranes of the respiratory, digestive, urinary, and reproductive systems are included

The Skin

• The skin is composed of two major layers: the epidermis and the dermis
• The epidermis has multiple layers packed with keratinocytes, and sheds dead skin cells
• Few pathogens can penetrate the epidermis
• Skin-associated lymphoid tissue (SALT) contains Langerhans cells that phagocytize pathogens
• Dermis collagen fibers help the skin resist abrasions
• Chemicals in skin defend against pathogens.
• Perspiration secreted by sweat glands contains salt, antimicrobial peptides like defensins, and lysozyme
• Sebum secreted by sebaceous (oil) glands keeps skin pliable and lowers pH to 4-6

Mucous Membranes

• Mucous membranes line all body cavities that are open to the environment
• the epithelium is the thin outer covering of the mucous membranes with living epithelial cells
• These are tightly packed to prevent entry of pathogens and continually shed to remove microorganisms
• Cells alive and involved in diffusion of nutrients and oxygen and elimination of waste
• Mucus from squamous epithelial cells traps microbes and has lysozyme and lactoperoxidase
• A deeper connective layer provides mechanical and nutritive support for the epithelium

Lymphoid Tissue

• Mucosa-associated lymphoid tissue (MALT) is scattered along mucosal linings, and populated with macrophages, B and T cells
• Gut-associated lymphoid tissue (GALT) includes tonsils, adenoids, and Peyer's patches in intestines
• M cells (“microfold”) are specialized intestinal cells, that sample luminal microbes and are engulfed by macrophages

Respiratory System

• Mucous membranes are present in the trachea
• Goblet cells secrete sticky mucus that traps bacteria and pathogens
• Ciliated columnar cells cilia propel mucus and trapped particles from lungs
• Membranes produce lysozyme and defensins
• Larger organisms get trapped by hairs and cilia in the nasal cavity
• Sneezing clears organisms from the respiratory tract
• Alveolar macrophages phagocytize cells in lungs

Lacrimal Apparatus

• Produces and drains tears
• Blinking spreads tears and washes surface of eye
• Gram-positive bacteria are destroyed by lysozyme in tears
• Lysozyme is an antimicrobial enzyme present in body secretions and secreted by immune cells
• Beta-1,4 glycosidic bonds are broken by lysozyme between NAG and NAM in the bacterial cell wall

Normal Microbiota

• Microbial antagonism is when normal microbiota compete with potential pathogens
• Pathogens are prevented from competing by normal microbiota
• They consume nutrients
• They create an unfavorable environment
• They stimulate the body's second line of defense
• They promote overall health by providing vitamins like Biotin, Pantothenic Acid, Folic acid, and Precursors to Vit K

Chemical Barriers to Infection

• Antimicrobial peptides (Defensins): present in skin, mucous membranes, neutrophils.
• Destroys cytoplasmic membranes of range of microbes
• Many organs secrete antimicrobial chemicals

Second Line of Defense

• Operates when pathogens penetrate the skin or mucous membranes
• Composed of cells, antimicrobial chemicals, contained/originate in blood

Components of Blood

• Blood is produced by hematopoiesis from blood stem cells in the bone marrow
• Red blood cells (erythrocytes) carry oxygen and carbon dioxide
• White blood cells (leukocytes) defend body against invaders
• Platelets involved in blood clotting and inflammation
• Plasma is mostly water containing electrolytes, dissolved gases, nutrients, and proteins
• Serum is plasma with clotting factors removed
• It includes iron-binding compounds, complement proteins, and antibodies

White Blood Cells (WBCs)

• Polymorphonuclear Leukocytes (PMNs) granulocytes contain large granules that stain
• Multi-lobed, contain enzyme-rich lysosome organelles
• Basophils stain blue with basic dye methylene blue, are involved in allergic reactions, and release inflammatory chemicals (vasoactive)
• Eosinophils stain red/orange with acidic dye eosin
• They phagocytize parasitic pathogens
• They are capable of extravasation
• They involve parasitic worm defense
• Neutrophils stain lilac, phagocytize pathogens, are capable of extravasation
• Mast cells separate lineage of PMNs and contain granules rich in histamine and heparin
• They reside in connective tissues and mucosa, and play a role in inflammation/wound healing
• IgE antibodies are bound on the surface of the mast cells
• Agranulocytes cytoplasm appears uniform under a light microscope
• Types include lymphocytes B cells – Antibody mediated response & T cells – Cell mediated response
• Monocytes/Macrophages Leave the blood and mature into macrophages, performing Phagocytosis
• Monocytes are agranulocytes, single nucleus, involved in phagocytosis
• Migrate out of blood Microphages into tissues

Mononuclear Phagocyte System

• Monocytes, macrophages, and dendritic cells
• MPS are specialized endothelial cells lining the sinusoids (capillaries) of the liver (Kupffer cells), spleen, and bone marrow
• Macrophages are involved in first contact, direct killing by phagocytosis, part of MPS, antigen presenting cell (APC)
• Dendritic cells involved in first contact, direct killing by phagocytosis, part of MPS, antigen presenting cell (APC)
• Located in spleen, lymph nodes, and dermal layer
• Different from macrophages as they take up small soluble antigens from surrounding area

Lymphoid Organs

• Lymphoid stem cells include lymphocytes and natural killer cells
• Primary lymphoid organs develop immature lymphocytes into B and T cells
• Secondary lymphoid organs encounter antigens and trap organisms

Phagocytosis

• A type of immune cell that surrounds and kills microorganisms, ingests foreign material, and removes dead cells
• Monocytes, Macrophages, Dendritic cells, Neutrophils, Eosinophils
• Stages of Phagocytosis: Chemotaxis, Adherence, Ingestion, Formation of a Phagosome, Fusion with Lysosome, Formation of Phagolysosome, Killing in Phagolysosome, Egestion of debris
• Antigen Presenting Cells (APCs) involved in Adaptive Immune Response
• Phagocytes recognize foreign cells and particles
• Glycoproteins are bound for self-recognition on all human cell membranes
• There is CD47 protein on the surface of cells, macrophages don't eat these
• Foreign cells lack CD47 glycoproteins and are recognized as foreign
• Some cancer cells have CD47, thus avoiding immune detection

Immune process

• Opsonization uses opsonins to tag pathogens for elimination
• Without opsonin, cell walls of pathogen and of phagocyte would repel each other
• Impeding factors from pathogens are bacterial capsules, which are too slippery for pseudopods to grab
• Some pathogens live within the toxic phagolysosome
• Some pathogens escape phagosome before fusion with lysosome
• Some pathogens prevent fusion of lysosome
• Some pathogens cause cell death (apoptosis) of phagocyte

Non Phagocytic killings

• Eosinophils attack parasitic helminths with toxins and are elevated due to parasitic infection
• The mitochondrial DNA and proteins form structure that kills bacteria
• Neutrophils produce chemicals that kill nearby invaders such as Nitric oxide and Superoxide radicals
• Neutrophils generate fibers (NETs), that bind to, and kill bacteria

Interferons

• Cytokines produced by Eukaryotic cells in response to intracellular viral or bacterial infection, responsible for many symptoms
• Type 1 functions for viral infections
• Type II enhance activity of phagocytes and natural killer (NK) cells
• Virus infects cell, with viral replication triggering transcription and translation of Type I interferons
• Interferon binds to uninfected cells leading to inactive antiviral proteins
• If cell becomes infected dsRNA activates, degrading mRNA and stopping viral protein synthesis and replication

Natural Killer (NK) Cells

• Class of lymphoid cells
• Normal host cells have Major Histocompatibility Complex Class I (MHC I) molecule that identifies as self
• NK cells recognize the cells that have lost expression of MHC I molecules
• Secrete perforin and granzymes onto surface of virally infected cells and tumors
• Can also kill by ADCC
• NK cells contain antibody-binding Fc receptors and cell surface viral proteins of infected cells
• Binds to the infected cell (adaptive immunity), NK cellkills innate immunity with perforins and granzymes
• Toll-Like Receptors, NOD Proteins, and MAMPs: Pattern Recognition Receptors (PRRs)
• Toll-like receptors (TLR) on cell membrane
• NOD-like receptors (NLR) in cytoplasm
• PRRs (TLRs, NLRs) bind various microbe-associated molecular patterns (MAMPs)

Pattern Detection

• Directs host cells to make cytokines (chemical signals) to attract phagocytic white blood cells (WBC)
• Initiates defensive responses
• Toll-Like Receptors, NOD Proteins, and MAMPs are components that elicit immune responses (do not memorize chart)
• Complement System enhances the ability of antibodies and phagocytic cells
• Three pathways include Classical, Alternative, Lectin
• Cascade of proteins produce a Membrane Attack Complex (MAC), causing cytoplasmic leakage and lysis
• Fragments attract phagocytes with bacterium opsonized by C3b protein and 4 things are activated
• C3a causes antitoxins in neutrophils and C5-C9 creates pores in cell membranes
• C3A, C3B causes inflammation

Inflammation

• Nonspecific response to tissue damage from various causes and phagocytic movement
• Characterized by heat, edema, redness, pain, loss of function
• Types are Acute and Chronic
• Develops, benefits including Increased permeability of blood vessels, tissue repair

Inflammatory Mediators

• Vasoactive increasing blood volume and permeability, also Leukotrienes
• Cytokines chemical signals with receptors on selectins with Interleukin 1 and TNF-a
• Acute inflammation is short lived Dilation of blood vessels,migration of phagocytes,tissue repair

Vasodilation Effect

• Vessels mediators with stimulate dilation of vessels
• Stimulates dilation
• Factor increase
• Vasoactive cause
• Increase vessel permeability

Diapedesis

• Leucocytes move into surround tissue due to tissue damage
• Causes signal molecules,selectins,and Integrins
• Integrins bind adhesion molecules
• The capillaries release enzymes
• Allows exitis and trigger prostaglandinas
• Chronic inflimation:Persistent process leading to tissue damage
• Caused aggregation of lymphocites
• In turn caused by pathogens like tuberculosis bacteria, ending is apoptosis to prevent damage
• Is only a week, removed with phagocytosis
• Wound Lymphatic system, wound healing,
• Is at heat of 38C
• And Normal is 37C