Innate Immunity & Inflammation

Innate immunity

Defense mechanisms present at birth, provide initial response to invasion and injury. Includes natural barriers and inflammation.

Innate barriers

Form the first line of defense at the body's surfaces, prevent damage by the environment and thwart infection by pathogenic infection.

Inflammatory response

The second line of defense, protects the body from further injury, fights infections, and promotes healing.

Adaptive immunity

The third line of defense (aka, acquired/specific immunity), induced through slower and more specific process, and targets particular invaders and diseased tissues. Also has memory for rapid response for future infection by the same invader.

Physical barriers

Epithelial cells of skin, linings of gastrointestinal, genitourinary, and respiratory tracts.

Lysozyme

Make up perspiration, tears, and saliva; attack the cell walls of gram-positive bacteria.

Defensins

Antimicrobial peptides produced by neutrophils and epithelial cells that defend against bacterial infection by disrupting bacterial membranes.

Collectins

Soluble glycoproteins that facilitate the ability of marcophages to recoginze and kill pathogenic microorganisms and can active the lectin pathway of the complement system.

Opportunistic pathogens

Microorganisms that are harmless in normal conditions, but can cause disease in immunocompromised individuals.

Inflammation

A dynamic process programmed to respond to cellular tissue damage irrespective of the location or condition of the tissue. Rapid initiation of the humoral and cellular response.

Inflammatory response characteristics

1. Only occurs in vascularized tissues 2. Activation is rapid after damage occurs 3. Response includes both cellular and chemical components 4. The response is nonspecific

Cardinal signs of inflammation (5)

1. Rubor (redness, erythema) 2. Calor (heat) 3. Tumor (swelling) 4. Dolor (pain) 5. Functio laesa (loss of function)

Lymphangitis

Inflammation of lymph vessels. May become secondarily inflamed.

Lymphadenitis

Inflammation of nodes. Can present as enlarged, painful lymph nodes.

Protective functions of inflammation (4)

1. Prevention of infection and further damage by invading microorganisms 2. Limitation of the scope of the inflammatory process 3. Preparation of injury for healing and repair 4. Facilitation of the development of adaptive immunity

Three key plasma protein systems?

1. Complement system 2. Clotting system 3. Kinin system

Complement system

Intensifies or complements the capacity of antibodies and phagocytes to clear pathogens and damaged cells and active inflammation. Has C3b, C5a, and C3a + C5a.

C3b

Antibodies and ____ serve as opsonins which coat the surface of bacteria, increasing their susceptibility to phagocytosis by inflammatory cells

C5a

Chemotactic factor by diffusing from a site of inflammation, and attracts leukocytes

C3a + C5a

Anaphylatoxins, induce rapid degranulation of mast cells to release histamines (induce vasodilation and increases capillary permeability)

Membrane attack complex (MAC)

Composed of elements C6 through C9; leads to bacterial destruction and tissue injury by creating pores in the outer membranes of cells/bacterias. Pores facilitate water into cells and leading into cell death.

Classical pathway

Activated by antibodies, components of the adaptive immune system. Antibodies bind to their target. Antigens are typically proteins/carbs produced by infectious microorganisms.

Antibodies active which complement?

C1; then trigger C3 and C5 which triggers inflammation

Alternative pathway

Activated directly by substances found on the surface of infectious microorganisms. Induces endotoxins found on zymosans.

Which pathway uses factor B, factor D, and properdin to activate complement proteins C3 and C5?

Alternative pathway

Lectin pathway

Independent of antibodies and is activated by several plasma proteins, specifically mannose-binding lectin (MBL)

Pathways result in 1 of 4 protective functions:

1. Opsonization (C3b) 2. Anaphylatoxic activity from mast cell degranulation (C3a + C5a) 3. Leukocyte chemotaxis (C5a) 4. Cell lysis (C5b-C9 & MAC)

Blood clot

Meshwork of fibrin strands and platelets, the primary cellular initiator of clotting. Hemostasis. Prevents spread and provide framework for future repair.

When wall of blood vessel is injured, what happens?

1. Tissue factor (extrinsic) pathway: activated by tissue factor (TF), also called tissue thromboplastin 2. Contract activation (intrinsic) pathway: activated when vessel wall damage occurs, contact with Hageman factor. BOTH converge at factor X.

Kinin system

Interacts closely with the clotting system. Bradykinin causes dilation of blood vessels; acts with prostagladins to induce pain, trigger smooth muscle contraction, increase vascular permeability

Mast cells

Mediators of inflammation. Blood cells divided into erythrocytes, platelets, and leukocytes. Lymphocytes are an innate response through NK cells, and the adaptive B and T cells.

PAMP

Pathogen associated molecular patterns, expressed by infectious agents

DAMP

Damage associated molecular patterns, produced from cell damage

Cytokines

Large family of small soluble intracellular signaling molecules; some are pro or anti inflammatory. Some are fever inducers (endogenous pyrogens).

Interleukins (IL)

Are cytokines produced by macrophages and lymphocytes in response to stimulation of PRRs; expressed by WBCS

TNF-α

Interacts with IL-1 and IL-6. Plays role to any injury or infection. Has induction of fever, increased liver synthesis of serum proteins, muscle wasting, and intravascular thrombosis.

IL-1

Growth factor for many cells. Fever causing (endogenous pyrogens). Reacts with receptors on the hypothalamus which causes the fever.

Il-6

Directly induces hepatocytes in the liver to produce proteins for inflammation. Stimulates growth and differentiation of blood cells in bone marrow and growth of fibroblasts for wound healing.

Proinflammatory cytokines

TNF-α, IL-1, IL-6

Antiinflammatory cytokines

IL-10, TGF-β

IL-10

Produced by lymphocytes, suppresses activation and proliferation of other lymphocytes, limits production of proinflammatory cytokines

TGF-β

Suppresses activity of lymphocytes and downregulates the production of proinflammatory cytokines by macrophages

Interferons (IFNs)

Protect against viral infections and modulate the immune response. A CYTOKINE.

IFN-α and IFN-β

Type 1, produced and released by virally infected cells; do not kill viruses

IFN-γ

Type 2, produced by lymphocytes, activates macrophages and increases their capacity to detect and process invaders

Histamine

Potent effects on other cells, control the circulation of H1 and H2

H1 receptor

Proinflammatory. Present in smooth muscle cells of the bronchi.

H2 receptors

Antiinflammatory. Suppresses leukocyte functions.

H2 blockers

Group of medicines that reduce gastric acidity

Local manifestations of acute inflammation

Swelling, pain, heat, redness and sometimes loss of function; can produce exudates

Serous exudate

Watery, few plasma proteins/leukocytes. Ex: fluid in a blister

Fibrinous exudate

Thick and clotted, seen in more serious or advanced inflammation. Ex: Exudate found in patients with pneumonia

Purulent exudate

Pus, accumulation of a large number of leukocytes in bacterial infections. Ex: Walled of lesions/cysts/abcesses

Hemorrhagic exudate

When bleeding occurs, becomes filled with erythrocytes

Systemic manifestations of acute inflammation

1. Fever 2. Leukocytosis 3. Increased plasma protein synthesis

Fever causers?

IL-1 and TNF-α

Acute inflammation time?

Less than 14 days

Chronic inflammation time?

2 weeks or longer

Chronic inflammation

Sometimes caused by unsuccessful acute inflammation; pus formation, suppuration, and incomplete wound healing

Granuloma

Body walls off and isolates the infected area, occurs when macrophages are unable to protect; TB, listerosis, brucellosis, etc cause. MEDIATED BY TNF-α

Wound healing is what?

Regeneration, resolution, repair

Regeneration

Damaged tissue replaced with healthy tissue

Resolution

Can take up to 2 years, function almost back to normal

Repair

When resolution is not viable, replacement of tissue with scar tissue

Primary intention

Clean cut, minimal time to heal (quick)

Secondary intention

Severe burns, takes a lot longer time to heal

Wound healing phases

Phase 1: Hemostasis/coagulation; Phase 2: Inflammation; Phase 3: Proliferation & new tissue formation; Phase 4: Remodeling & maturation

Phase 1 of healing?

Hemostasis/coagulation

Phase 2 of healing?

Inflammation

Phase 3 of healing?

Proliferation & new tissue formation

Phase 4 of healing?

Remodeling & maturation

Hypertrophic scars

Raised, but remains in the same origin of where the injury first was

Keloid scar

Extends from site of original injury, occurs after surgical removal; impacts African Americans

Dehiscence

Suture complications, occurs 5-12 days after initial suture; 1/2 of incidences occur from wound infection, the remainder is caused by strain

Contracture

Anatomic deformity from excessive healing