Innate Nonspecific Host Immunity

Innate Nonspecific Host Immunity

Chickenpox and Inflammation

• Chickenpox (Varicella) is caused by the varicella-zoster virus.
• The rash associated with chickenpox is partly due to inflammation, which is the body's immune response.
• Inflammation is a response mechanism of innate immunity that helps the body fight off a wide range of infections.

Case Study: Angela

• Angela, a 25-year-old female, experiences shortness of breath and airway constriction.
• She has no history of asthma or allergies, but her father died of similar respiratory issues.
• Possible causes: constriction and swelling of the airway, swelling of body tissues.

The Big Picture of Immunity

• Innate Immunity:
  • Response is the same whether or not the pathogen has been previously encountered.
  • External barriers (skin, mucous membranes) and internal defenses (phagocytic cells, NK cells, defensive proteins, inflammatory response).
  • 1st and 2nd line of defense.
• Acquired Immunity:
  • Found only in vertebrates; previous exposure enhances immune response.
  • Involves antibodies and lymphocytes.
  • 3rd line of defense.

Overview of Nonspecific Innate Immune Defenses

• Physical Defenses
  • Physical barriers: Skin/exoskeleton, Secretions, Mucous membranes
  • Mechanical defenses: Includes mechanisms to physically remove pathogens.
  • Microbiome: Normal flora that competes with pathogens.
• Chemical Defenses
  • Chemicals and enzymes in body fluids
  • Antimicrobial peptides
  • Plasma protein mediators
  • Cytokines
  • Inflammation-eliciting mediators
• Cellular Defenses
  • Granulocytes (e.g., neutrophils, eosinophils, basophils)
  • Agranulocytes (e.g., lymphocytes, monocytes).

The Concept of Immunity

• Host Toll-like receptors (TLRs) attach to Pathogen-associated molecular patterns (PAMPs).
• Examples of PAMPs: LPS, flagellin, peptidoglycan, DNA of bacteria, DNA/RNA of viruses, components of fungi & parasites.
• TLRs induce cytokines that regulate the intensity and duration of immune responses

Physical Defenses: Cell Junctions

• Tight Junctions: Rivet cells together, preventing material exchange between them.
• Desmosomes: Intermediate fibers tie cells together, allowing small materials to pass.
• Gap Junctions: Channels between cells that permit communication via signals.

The Skin Barrier

• Human skin has three layers: epidermis, dermis, and hypodermis.
• The epidermis consists of tightly packed cells with keratin.
• Dead skin cells on the surface are continually shed, removing microbes.

Physical Factors: Skin

• Epidermis: Tightly packed cells with keratin, a protective protein.
• Chemicals: Oils, sebum, salt, lysozyme.

Rose Gardener’s Disease

• Rose gardener’s disease occurs when the fungus Sporothrix schenkii breaches the skin through small cuts.

Physical Factors: Mucous Membranes

• Mucus prevents drying out and traps microbes.
• It also prevents biofilm formation and communication.
• Ciliary escalator: Microbes trapped in mucus are transported away from the lungs.

Mucous Membranes - Ciliary Escalator

• Ciliated epithelial cells from the human trachea push mucus away from the lungs.
• The mucus moves up to the esophagus where it can be removed by swallowing.

Goblet Cells

• Goblet cells produce and secrete mucus in the intestinal epithelium.

Flushing Out Microbes

• Tears flush microbes away from the surface of the eye via the lacrimal apparatus.
• Urine washes microbes out of the urinary tract.
• Saliva washes microbes off the teeth and contains lysozyme.
• Vaginal secretions flow out.

Lacrimal Apparatus

• Lacrimal glands, lacrimal canal, nasolacrimal duct, nose

Chemical Defenses

• Fungistatic fatty acid in sebum
• Low pH (3–5) of skin
• Lysozyme in perspiration, tears, saliva, and urine
• Low pH (1.2–3.0) of gastric juice
• Low pH (3–5) of vaginal secretions

Sebaceous Glands

• Sebaceous glands secrete sebum, which lubricates and protect the skin from microbes.
• Sebum is a food source for resident microbes that produce oleic acid.

Normal Microbiota and Innate Immunity

• Microbial antagonism/competitive exclusion: Normal microbiota compete with pathogens or alter the environment.
• Commensal microbiota: One organism benefits and the other is unharmed; may be opportunistic pathogens.

Characteristics of Selected Antimicrobial Peptides (AMPs)

Some Acute-phase Proteins and Their Functions

• C-reactive protein: Coats bacteria (opsonization), preparing them for ingestion by phagocytes
• Serum amyloid A, Ferritin, Transferrin: Bind and sequester iron, inhibiting the growth of pathogens.
• Fibrinogen: Involved in formation of blood clots that trap bacterial pathogens.
• Mannose-binding lectin: Activates complement cascade.

The Complement System

• Serum proteins activated in a cascade manner
• Activated by:
  • Antigen-antibody reaction
  • Proteins C3, B, D, P, and a pathogen.
• $C3b$ causes opsonization
• $C3a + C5a$ cause inflammation
• $C5b + C6 + C7 + C8 + C9$ cause cell lysis

Effects of Complement Activation

• Opsonization or immune adherence: Enhanced phagocytosis
• Membrane attack complex: Cytolysis
• Attract phagocytes

Classical Pathway of Complement Activation

1. $C1$ is activated by binding to antigen-antibody complexes.
2. Activated $C1$ splits $C2$ into $C2a$ and $C2b$, and $C4$ into $C4a$ and $C4b$.
3. $C2a$ and $C4b$ combine and activate $C3$, splitting it into $C3a$ and $C3b$.

Alternative Pathway of Complement Activation

1. $C3$ combines with factors B, D, and P on the surface of a microbe.
2. This causes $C3$ to split into fragments $C3a$ and $C3b$.

Lectin Pathway of Complement Activation

1. Lectin binds to an invading cell.
2. Bound lectin splits $C2$ and $C4$.
3. $C2a$ and $C4b$ combine and activate $C3$.

Complement Activation

• All three pathways activate complement protein $C3$, which produces $C3a$ and $C3b$.
• $C3b$ binds to the surface of the target cell and then works with other complement proteins to cleave $C5$ into $C5a$ and $C5b$.
• $C5b$ binds to the cell surface and recruits $C6$ through $C9$ to form the membrane attack complex (MAC).
• MAC punches through the cell membrane, causing the cell to swell and burst.

Some Bacteria Evade Complement

• Capsules prevent C activation.
• Surface lipid-carbohydrates prevent the formation of the membrane attack complex (MAC).
• Enzymatic digestion of $C5a$.

Cytokine Communication

• Autocrine, paracrine, and endocrine actions describe which cells are targeted by cytokines and how far the cytokines must travel.

Interferons (IFNs)

• IFN-$α$ and IFN-$β$: Cause cells to produce antiviral proteins that inhibit viral replication.
• Gamma IFN: Causes neutrophils and macrophages to phagocytize bacteria.

Antiviral Actions of Interferons

1. Viral RNA from an infecting virus enters the cell.
2. The infecting virus replicates into new viruses.
3. The infecting virus induces the host cell to produce interferon mRNA (IFN-mRNA), which is translated into alpha and beta interferons.
4. Interferons bind to receptors on uninfected neighboring host cells, inducing them to synthesize antiviral proteins (AVPs).
5. New viruses released by the virus-infected host cell infect neighboring host cells.
6. AVPs degrade viral mRNA and inhibit protein synthesis, interfering with viral replication.

Interferons

• Interferons are cytokines released by a cell infected with a virus.
• Interferon-$α$ and interferon-$β$ signal uninfected neighboring cells to inhibit mRNA synthesis, destroy RNA, and reduce protein synthesis.
• Also promote apoptosis in cells infected with the virus.
• Interferon-$γ$ alerts neighboring immune cells to an attack.

Case Study Part 2

• Angela is treated with antihistamines and corticosteroids through an inhaler.
• Her condition does not improve.
• Allergy testing is conducted.
• Blood analysis is ordered to check cytokine levels.
• A sputum sample is sent to the lab for microbial staining, culturing, and identification of pathogens.
• Questions:
  • Which aspects of the innate immune system could be contributing to Angela’s airway constriction?
  • Why was Angela treated with antihistamines?
  • Why would the doctor be interested in levels of cytokines in Angela’s blood?

Chemical Defenses of Nonspecific Innate Immunity

Chemical Defenses of Nonspecific Innate Immunity – Cont.

Cellular Defenses

• Hematopoiesis: All the formed elements of the blood arise by differentiation of hematopoietic stem cells in the bone marrow.

Hematopoiesis

• Formed elements of blood include erythrocytes (red blood cells), leukocytes (white blood cells), and platelets.

Summary Table of Formed Elements, Numbers, Appearance and Functions

Granulocytes

• Granulocytes can be distinguished by the number of lobes in their nuclei and the staining properties of their granules.

Mast Cells

• Mast cells function similarly to basophils by inducing and promoting inflammatory responses.
• Unlike basophils, mast cells migrate from the blood into various tissues.

Components of Lymphatic System

• Tonsil, Thymus, Heart, Lymphatic vessel, Large intestine, Red bone marrow, Thoracic duct, Spleen, Small intestine, Peyer's patch, Lymph node

The Lymphatic System

• Relationship of lymphatic capillaries to tissue cells and blood capillaries, Interstitial fluid, Lymph

Case Study – Part 3

• Angela’s tests are negative for common allergens and respiratory pathogens.
• She has elevated levels of inflammatory cytokines and a mildly elevated white blood cell count, but normal antibody levels.
• She has a lower-than-normal level of the complement protein C4.
• Questions:
  • What does this new information reveal about the cause of Angela’s constricted airways?
  • What are some possible conditions that could lead to low levels of complement proteins?

Agranulocytes: Natural Killer Cells

• Natural killer (NK) cells are inhibited by the presence of the major histocompatibility cell (MHC) receptor on healthy cells.
• Cancer cells and virus-infected cells have reduced expression of MHC and increased expression of activating molecules.
• NK cells recognize decreased MHC and increased activating molecules, they will kill the abnormal cell.

Agranulocytes: Monocytes

• Monocytes are large, agranular white blood cells with a nucleus that lacks lobes.
• When monocytes leave the bloodstream, they differentiate and become macrophages with tissue-specific properties.

Macrophages Found in Various Body Tissues

Pathogen Recognition and Phagocytosis

• Phago: From Greek, meaning eat
• Cyte: From Greek, meaning cell
• Ingestion of microbes or particles by a cell, performed by phagocytes

Phagocytosis

• Neutrophils
• Fixed macrophages
• Wandering macrophages

Phases of Phagocytosis

1. Chemotaxis and adherence of microbe to phagocyte
2. Ingestion of microbe by phagocyte
3. Formation of a phagosome
4. Fusion of the phagosome with a lysosome to form a phagolysosome
5. Digestion of ingested microbe by enzymes
6. Formation of residual body containing indigestible material
7. Discharge of waste materials

Extravasation (Diapedesis) of Leukocytes

• Damaged cells and macrophages release cytokines that are proinflammatory and chemotactic for leukocytes.
• Activation of complement at the site of infection results in production of the chemotactic and proinflammatory C5a.
• Leukocytes exit the blood vessel and follow the chemoattractant signal of cytokines and C5a to the site of infection.
• Granulocytes such as neutrophils release chemicals that destroy pathogens.
• They are also capable of phagocytosis and intracellular killing of bacterial pathogens.

Pathogen Recognition

• Phagocytic cells contain pattern recognition receptors (PRRs) capable of recognizing various pathogen-associated molecular patterns (PAMPs).
• PRRs can be found on the plasma membrane or in internal phagosomes.
• When a PRR recognizes a PAMP, it sends a signal to the nucleus that activates genes involved in phagocytosis.
• This includes cellular proliferation, production and secretion of antiviral interferons and proinflammatory cytokines, and enhanced intracellular killing.
• Leukocyte extravation, Leukocyte rolling

Pathogen Degradation

• The stages of phagocytosis include the engulfment of a pathogen, the formation of a phagosome, the digestion of the pathogenic particle in the phagolysosome, and the expulsion of undigested materials from the cell.

Microbial Evasion of Phagocytosis

• Inhibit adherence: M protein, capsules (Streptococcus pyogenes, S. pneumoniae)
• Kill phagocytes: Leukocidins (Staphylococcus aureus)
• Lyse phagocytes: Membrane attack complex (Listeria monocytogenes)
• Escape phagosome (Shigella, Rickettsia)
• Prevent phagosome-lysosome fusion (HIV, Mycobacterium tuberculosis)
• Survive in phagolysosome (Coxiella burnettii)

Leishmania

• Cutaneous leishmaniasis is a disfiguring disease caused by the intracellular flagellate Leishmania tropica, transmitted by the bite of a sand fly.

Inflammation and Fever

• Acute-phase proteins activated (complement, cytokine, and kinins)
• Vasodilation (histamine, kinins, prostaglandins, and leukotrienes)
• Redness
• Swelling (edema)
• Pain
• Heat

The Process of Inflammation

• Chemicals such as histamine, kinins, prostaglandins, leukotrienes, and cytokines are released by damaged cells.
• Blood clot forms.
• Abscess starts to form.

Phagocyte Migration and Phagocytosis

• Margination- phagocytes stick to endothelium.
• Diapedesis- phagocytes squeeze between endothelial cells.
• Phagocytosis of invading bacteria.

Tissue Repair

• Scab, Blood clot, Regenerated epidermis (parenchyma), Regenerated dermis (stroma)

Acute Inflammation

• Mast cells detect injury to nearby cells and release histamine, initiating an inflammatory response.
• Histamine increases blood flow to the wound site, and increased vascular permeability allows fluid, proteins, phagocytes, and other immune cells to enter infected tissue.
• These events result in the swelling and reddening of the injured site, and the increased blood flow to the injured site causes it to feel warm.
• Inflammation is also associated with pain due to these events stimulating nerve pain receptors in the tissue.
• The interaction of phagocyte PRRs with cellular distress signals and PAMPs and opsonins on the surface of pathogens leads to the release of more proinflammatory chemicals, enhancing the inflammatory response.

Chronic Inflammation

• A tubercle is a granuloma in the lung tissue of a patient with tuberculosis.
• White blood cells have walled off a pocket of tissue infected with Mycobacterium tuberculosis.
• Granulomas also occur in many other forms of disease.

Chronic Edema - Elephantiasis

• Elephantiasis (chronic edema) of the legs due to filariasis.

Fever

• Abnormally high body temperature.
• Hypothalamus normally set at 37°C.
• Gram-negative endotoxin cause phagocytes to release interleukin–1 (IL–1)
• Hypothalamus releases prostaglandins that reset the hypothalamus to a higher temperature.
• Body increases rate of metabolism and shivering; this raises temperature.
• Vasodilation and sweating cause body temperature to fall (crisis).

Fever - Advantages and Disadvantages

• Advantages:
  • Increases transferrins
  • Increases IL–1 activity
  • Produces Interferon
• Disadvantages:
  • Tachycardia
  • Acidosis
  • Dehydration
  • $44–46°C$ fatal

The Role of the Hypothalamus

• Macrophages recognize pathogens in an area and release cytokines that trigger inflammation.
• The cytokines also send a signal up the vagus nerve to the hypothalamus.

First Line of Defense: Skin and Mucous Membranes - Physical and Chemical Factors

Physical Factors:

Chemical Factors: