Immune System: Pattern Recognition and Innate Defense

Innate Immunity

• Innate immunity is the non-specific, immediate immune defense system.
• It has two main lines of defense
• The first line includes physical barriers such as skin and mucous membranes and chemical barriers, e.g., secretions and reflexes.
• The second line involves inflammatory response, phagocytosis, fever, complement system, interferons, and natural killer cells.

Barrier Defenses

• Skin: A semi-watertight barrier made up of the epidermis and dermis.

• The epidermis comprises multiple layers of tightly packed dead cells containing keratin, which makes the skin tough, flexible, and semi-waterproof.

• The epidermis continuously sheds, removing microbes.

• Normal flora microbes inhibit growth of other microbes.

• Skin synthesizes proteins (e.g., psoriasin) with antimicrobial activity against E. coli.

• Skin pH (salty and acidic) inhibits bacterial growth.

• Sebum (oily secretions) contains chemicals that are toxic to bacteria.

• Hair follicles and sweat glands produce lysozyme and toxic lipids to kill bacteria.

• Skin-associated lymphoid tissue (SALT) is beneath the skin surface, containing cells for killing microbes and starting adaptive immune responses.

• Mucous Membranes: Formed by an epithelium and a connective tissue layer.

• Line body cavities opening to the outside environment.

• Constantly sloughing cells to remove microbes.

• Resident normal flora inhibits potentially harmful microbes.

• Stomach mucosa secretes HCl and protein-digesting enzymes to kill pathogens.

• Mucus helps defend against intrusions through a mucociliary escalator mechanism.

• Goblet cells in the lower respiratory tract produce mucus which traps microorganisms.

• Ciliated cells move the mucus to be swallowed or expectorated.

• Mucus coats the stomach wall to protect it from the acidic digestive fluids.

• Lacrimal Apparatus: A group of organs producing and draining tears.

• Tears are produced in the lacrimal glands and flush any foreign particles into the nasal cavity.

• Tears contain lysozyme (enzyme destroying bacterial cell walls), lipocalin (inhibit pathogens by binding iron), and IgA (antibody preventing microbial attachment and neutralizing toxins).

• Saliva: Produced by salivary glands.

• Functions in cleansing teeth and mouth mucous membranes.

• Prepares food for digestion.

• Washes microbes down the esophagus and into the stomach.

• Contains lysozyme, IgA, and histatin (antifungal peptide with wound repair role).

• Epiglottis: Tissue flap at the back of the throat.

• Prevents food, liquids, and saliva from entering the lower respiratory tract.

• Urine and Vaginal Secretions:

• Urine's acidity inhibits microbial growth in the urinary tract.

• Urine's flushing action keeps microbes from attaching to tissues.

• Urine contains lysozyme.

• Vaginal secretions and lactic acid help make the vagina acidic, inhibiting potentially pathogenic bacteria.

• However, low-pH conditions allow fungal organisms to grow; yeast infections are common in women.

• Transferrins: Blood proteins that bind iron, preventing microbes from using it for growth and metabolism.

Molecules of Innate Immunity

• PRRs: Pattern recognition receptors identify non-self foreign substances.

• PRRs differentiate between self and non-self.

• PRRs are mainly expressed by antigen-presenting cells (APCs) and also found in other immune and non-immune cells.

• The PRRs are divided into Toll-like receptors (TLRs), nucleotide oligomerization receptors (NLRs), C-type lectin receptors (CLRs), and RIG-1-like receptors (RLRs).

• Receptors are present at the cell surface to recognize extracellular pathogens, within the cytoplasm for intracellular invaders, and within the cytoplasm.

• PRRs recognize overall molecular patterns of the pathogen.

• These patterns are generally absent from the host organism.

• PAMPs: Pathogen-associated molecular patterns are the unique microbial patterns not shared with host organisms.

• PAMPs include combinations of sugars, proteins, lipid-bearing molecules, and nucleic acid motifs.

• These molecular patterns exist in groups of related microbes.

• These structures are relatively invariant, so don't evolve rapidly.

• TLRs: Specific TLRs bind to non-self molecules (ligands) including lipoproteins, bacterial lipoproteins, double-stranded RNA, lipopolysaccharides (LPS), flagellar proteins, lipotechoic acid, single-stranded RNA, bacterial DNA, for recognition.

Cytokines

• Cytokines are low-molecular-weight proteins secreted by cells of both innate and adaptive immune systems.
• Function in diverse ways regulating immune responses.
• Enable communication within the immune system and with host tissues to exchange information.
• Act non-specifically, affecting any cells with appropriate receptors in a physiological state.
• Action is dependent on concentration.
• Major cytokine families include hematopoietin family includes growth hormones and interleukins (ILs) and tumor necrosis factor (TNF) family.
• Various roles include inflammation promotion, inducing fever, decrease iron concentration, stimulating acute-phase proteins & histamine, stimulating B & T cell proliferation & differentiation, and bone marrow synthesis.
• Cytokines action can be autocrine (affecting the cell that produced the cytokine).
• Paracrine (affecting neighboring cells).
• Endocrine (affecting distant cells).
• Cytokines can display pleiotropy (have different effects on different cells), redundancy (two or more cytokines with similar function), synergism (combined effect>additive effect), and antagonism (one cytokine inhibits another cytokine).
• Cytokines can initiate a cascade induction, where the action of one cytokine leads to production of other cytokines.

Cells of the Innate Immune System

• Leukocytes (white blood cells) lack hemoglobin and contain a nucleus.

• They are classified as granulocytes (neutrophils, eosinophils, basophils) or agranulocytes (monocytes, lymphocytes).

• Granulocytes have granules in their cytoplasm, while agranulocytes lack them.

• Neutrophils: The first defenders during bacterial invasion.

• Increase in the number during acute bacterial infections.

• Phagocytes that sense infection sites, migrate, destroy infectious organisms via phagocytosis, and attach to blood vessel walls, preventing antigen spread.

• Produce toxic substances damaging host cells.

• Eosinophils: Associated with allergic conditions (e.g., asthma, hay fever) internal parasitic infestations (e.g., worms).

• Less active phagocytes compared to Neutrophils.

• Attach to and secrete substances to kill worms.

• Modulate inflammatory response.

• Basophils: Least numerous, poorly understood leukocytes.

• Not phagocytic, but synthesize and store histamine.

• Involved in allergic reactions and inflammation, amplifying immune response.

• Monocytes/Macrophages: Largest leukocytes, professional phagocytes.

• Monocyte numbers increase during infection.

• Monocytes are called to infection sites by chemotactic factors.

• Migrate into tissues, differentiating into macrophages and producing granules within themselves).

• Recognize, engulf, and destroy bacteria, fungi, protozoa, tumor and virus-infected cells, apoptotic cells.

• Function in wound healing, tissue repair, and bone remodeling.

• Process antigens to be recognized by T cells, and secrete cytokines playing various roles in the immune system.

• Dendritic Cells: Participate in both innate via phagocytosis and adaptive immune responses via presenting antigens.

• Have long extensions resembling nerve fiber dendrites.

• Located in skin and mucosal tissues with pathogen entry routes (oral, respiratory, genital mucosae).

• Help trigger adaptive immune responses, migrating to lymph nodes upon activation.

• Mast Cells: Abundant granules synthesize and storing histamine and heparin.

• Associated with allergic reactions and parasitic infections.

• Commonly found in tissues exposed to the external environment (e.g., mucous membranes).

• Rapidly and selectively produce mediators working as host defense, recruiting effector cells responding to infection.

• Influence adaptive immune response.

Mechanisms of Innate Immunity

• Inflammation: The initial, rapid, localized response to tissue damage/injury, infection, antigen challenge, or physical/chemical trauma.

• Components include destroying infectious agents and removing debris

• Localizing infectious agents preventing spread and

• Repairing and replacing damaged tissue.

• Inflammation induced by releasing chemicals like histamine and kinins from damaged mast cells and leukocytes.

• Sequence of events includes vasodilation of blood vessels, increasing permeability to leukocytes, plasma & antibodies (in tissue spaces). - Inducing chemotaxis to attract more leukocytes adhering to endothelial cells and entering tissue spaces.

• Possible systemic activation e.g. fever to affect leukocyte proliferation.

• Cardinal signs of inflammation, e.g., redness, swelling, heat.

• Phagocytosis: Process of solid substance ingestion like cells (e.g., bacteria, necrotic tissue) by phagocytes for transport and breakdown within lysosomal enzymes.

• Chemokines released by traumatized tissues attract phagocytes to damaged sites (chemotaxis).

• Phagocytes engulf microbes, destroying them within phagolysosomes.

• Phagocytes release chemokines further amplifying the defensive response.

• Neutrophils and macrophages are the most active phagocytes with engulfing capacity.

• Fever: A beneficial response induced by cytokines (e.g., interleukin 1) acting as endogenous pyrogens.

• Elevated body temperatures often triggered by invading organisms reaching the blood stream, and exogenous pyrogens from pathogens (e.g., bacterial toxins).

• Elevated body temperatures reset hypothalamus to induce the release of prostaglandins and thus induce body temperature elevation.

• Benefits include inactivating bacterial toxins, lowering plasma iron concentration, and increasing host defence speed, phagocytosis rate & inflammatory activities promoting immune cell production.

• Complement System: Comprises soluble proteins (glycoproteins) often existing in inactive forms which activate in two ways.

• Activation via the alternative pathway (innate): directly binding to foreign invaders and

• Activation via the classical pathway (adaptive): binding to antibodies that attach to foreign invaders.

• Complement fixation mediates opsonization and causes inflammation & membrane attack complexes resulting in cell lysis.

• Interferons: Proteins produced by virus-infected host cells released to neighboring uninfected cells inducing antiviral protein synthesis and degrading viral mRNA.

• Interferons stop viral replication & inhibit protein synthesis.

• Interferons are not virus-specific and are a response to any virus infection.

• Other roles include enhancing phagocytic activity of macrophages, stimulating antibody production, boosting killer cell power and slowing cell division/suppressing tumor growth.

• Natural Killer (NK) Cells: Participate in innate immunity through direct target cell killing and production of cytokines.

• NK cells destroy cells infected by virus or tumor cells.

• Release of perforin (forms pores in target membranes for subsequent granzyme to induce apoptosis or cell lysis).