The Lectin Pathway Originates with Host Proteins Binding Microbial Surfaces

Lectin: proteins that bind to a carbohydrate

MBL (mannose-binding lectin) :

- a protein which binds to mannose residues on glycoproteins or carbohydrates on the surface of microorganisms (structurally similar to C1q)

MASP-1 & MASP-II: MBL-associated serine protease

( structurally similar to C1r and C1s )

- MBL is induced during inflammatory responses.

-After MBL binds to the surface of a microbe, MBL-associated serine proteases, ) MASP-1 and MASP-2,( bind to MBL.

-The MBL-MASP-1&II complex mimics the activity of C1r and C1s, and causes cleavage and activation of C4 and C2.

-Thus, the lectin pathway is Ab-independent.

-It is an important innate defense mechanism comparable to the alternative pathway, but utilizing the elements of the classical pathway, except for the C1 proteins.

Q2: Why doesn’t mannose-binding lectin (MBL) bind to host carbohydrates?

A2: Mammalian cells normally have sialic acid residues covering the sugar groups

recognized by MBL and are not a target for binding.

Biological Effects Mediated by Complement

1 .Cell lysis

The membrane-attack complex can lyse a broad spectrum of cells:

G(-) bacteria parasites

viruses erythrocyte

nucleated cells (tumor cells)

Because the activation of alternative and lectin pathways is

Ab-independent, these pathways serve as important innate immune defenses against infectious microorganisms.

2 .Inflammatory response - Various peptides generated during activation of

complement play a role in the development of an effective inflammatory response.

- C3a, C4a, C5a (called anaphylatoxin) bind to

complement receptors on mast cells and basophils and induce degranulation with release of histamine

and other mediators.

- The anaphylatoxins also increased vascular permeability, extravasation, and chemoattraction (induced by

C5a, C3a, and C5b67)

3 .Opsonization -C3b is the major opsonin of the complement

system, although C4b also have opsonizing activity.

binds to the surface of microbes

Opsonization by Ab and complement

4 .Viral neutralization

-Formation of larger viral aggregates reduces the net number of infectious viral particles.

-The deposits of Ab and complement on viral particle neutralizes viral infectivity by

blocking attachment to susceptible host cells and

facilitates binding of the viral particle.

5 .Clearance of immune complexes

Innate Immunity: Complement

Comparison of 3 Pathways

Inflammation:Inflammation is non specific response to tissue damage resulting from a variety causes, including heat, chemicals, ultraviolet light, cuts and pathogens.

-There are two types:

Acute inflammation: develops quickly and is short lived, is typically beneficial and result in the elimination of whatever condition precipitated.

Chronic inflammation: develops slowly, lasts a long time, and can cause damage to tissue, resulting in disease .

Acute inflammation is an important part of the second line of defense because it results in:

1) dilatation and increases permeability of blood vessels.

2) migration of phagocytes ( diapedesis).

3) tissue repair

Components of Innate Immunity Inflammation

• Non-specific, physiologic reaction of vascular tissue to injury and microbial invasion.

• The inflammatory process can be divided into two sequential steps:

– Vascular Phase - dilation and increased permeability of blood vessels with the accumulation of fluid and cells at the site of injury.

– Cellular Phase - the activation of specialized blood and

connective tissue cells that destroy or wall off injurious agents and clear debris so that tissue repair can take place.

Cells important to inflammation include neutrophils, basophils, eosinophils, lymphocytes, monocytes, and platelets.

• In the skin, inflammation is recognized by the presence of

redness, swelling, heat, and pain.

• Without inflammation and repair, infections would go unchecked and wounds would never heal.

SIGNS OF ACUTE INFLAMMATION

Heat Redness Swelling Pain Loss of Heat Redness Swelling Pain Loss of functionfunction

Cytokines• An important group of small molecular weight

polypeptides that are produced by lymphocytes, macrophages, and other connective tissue cells.

• The function of cytokines is to regulate growth and differentiation of blood, lymphoid, and connective tissue cells.

• They help to orchestrate many aspects of innate and acquired immunity as well as wound healing, and the production of blood cells.

Inflammatory cytokines: Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF)

• induce the fever, fatigue, and decreased appetite. • Activate leukocytes and other

inflammatory cells, • increase vascular permeability.• Activate tissue-degrading enzymes. • Activate the connective tissue cell

involved in tissue repair.

Stages of Inflammation: 1. Vascular Phase

• Vasoconstriction - Immediately following injury, tightening of blood vessels

• Complement activation and mediator release – – Activated complement opsonize microbes/injured tissue and

release of histamine and serotonin from nearby mast cells– Formation of bradykinin and initiation of synthesis of

prostaglandins and leukotrienes • Vasodilation –

– Histamine, and other vasodilators, cause relaxation of smooth muscle in arteriolar and capillaries walls.

– Vessels dilate providing increased blood flow to the injured tissue.

– Causes redness/heat

Increased vascular permeability –

endothelial cells lining blood vessels contract slightly creating gaps between the cells that allow plasma to escape into surrounding tissues.

Plasma delivers antibodies and other antimicrobial substances to the site of injury.

Fibrinogen from plasma also clots and serves as a temporary barrier to bacterial invasion.

Stages of Inflammation:2. Cellular Phase

• Adhesion – white blood cells (WBC’s) stick to inner surface of blood vessel walls

• Diapedesis WBC's then to squeeze between the contracted endothelial cells and migrate in an ameba-like fashion into the extravascular space

• Chemotaxis - Once in tissue, the WBC's begin to migrate towards the site of injury or microbial invasion. WBC's are attracted by chemotactic agents that have been released at the site of injury. WBC's apparently have surface receptors for chemotactic agents which cause them to move in the direction of increasing concentrations of the chemotactic substance.

Phagocytosis –

When WBC's arrive at the site of tissue injury or microbial invasion they become very active and begin engulfing bacteria (or other foreign) that have been opsonized by complement or antibodies; through various mechanisms, bacteria and other foreign substances are destroyed and degraded after phagocytosis

Increase permeability during inflammation

MECHANISMS OF INFLAMMATION

Emigration of NeutrophilsEmigration of Neutrophils

Inflammation Outcome - ResolutionChronic

Inflammation

Abscess

SinusFistula Ulcer

Acute

InflammationHealing

Injury

Fever :

is a body temperature more than 37 ºC.

- Fever results due the presence of chemicals called pyrogens.

- Pyrogens trigger the hypothalamic thermostat to reset at high temperature.

Pyrogens include:

-bacterial toxins- cytoplasmic contents of bacteria that are released upon lysis Ab-Ag complexes.

-interleukin-1 a pyrogen released by phagocytes that have phogocytized bacteria

Steps of fever

Determinants of innate immunity

Innate immunity is genetically controlled and varies widely with species, race and to less extent between individuals.

a)Species and race: -Man and guinea pigs are highly susceptible to

diphtheria while rats are not. -Man is susceptible to common cold while dogs

are not. -American Indian and Negro are more susceptible

to tuberculosis than white races.

B) Individual differences: Age: the very young and aged are particular liable to infection.

Nutrition: Malnutrition and starvation predispose to infection by decreasing the total white cell count and phagocytosis.

Hormones: Some endocrine diseases cause a decrease in resistance to infection such as diabetes mellitus, hypothroidism and adrenal dysfunction.