BSI: Immunology Innate Immunity

Innate immunity is the non-specific responses of the body to invading pathogens.

• The immune system is essential to life. The innate response uses:
• (1) non-specific phagocytosis
• (2) inflammation

Some features of the innate response are also connected/shared with the acquired/adaptive response. This includes, for example, opsonization and utilization of the complement system/MAC to kill bacteria and phagocytosing macrophages which help activate lymphocytes (which are mediators of the acquired/adaptive response) by antigen presentation.

One must appreciate both innate and acquired/adaptive immune responses to fully understand how the immune system functions.

Autoimmune diseases are often the result of the immune system not functioning properly.

● We are constantly exposed to bacteria, viruses, fungi and parasites via the skin, mouth, GI tract, respiratory passages, eyes and urinary tract. Many of these pathogens can cause serious conditions if allowed to reach deeper tissues.

• ● There are two principal mechanisms/systems which protect our bodies from invasion (apart from physical barriers and secretions). These include:
• (1) phagocytosis which involves the ingestion and subsequent destruction/inactivation of invading organisms
• (2) the production of specific antibodies and
• sensitized lymphocytes.

● Innate immunity: we are born with the relatively non-specific ability to phagocytize foreign organisms, particles, some cancerous cells and exhausted/worn out cells such as old RBC's.

● Acquired or Adaptive Immunity: when the body is first exposed to an organism, a protein or other molecule whose “chemical profile” is recognized as foreign (an antigen/antigenic), a specific response is generated by the production of antibodies and memory cells which “remember” the antigen and are therefore able to respond faster and with a more effective response with subsequent exposure.

● Leukocytes (White Blood Cells: WBC's) are the mediators of innate immunity (phagocytosis).

• There are five types of Leukocytes (WBC's):
• Granulocytes (contain intracellular granules)
• ● Neutrophils: ~62% of total WBC's; multi-lobed nucleus; Life span is 6 hours to a few days; Destroys bacteria by phagocytosis.
• ● Eosinophils: ~2.3% of total WBC's; bi-lobed nucleus; red granules; Life span 8-12 days; Turns off allergic responses and kill parasites.
• ● Basophils: ~0.4% of total WBC's; bi-lobed nucleus; indigo granules; Life span few hours to a few days?; Release histamine and other mediators of inflammation.
• Agranulocytes (lacking granules)
• ● Lymphocytes: ~30% of total WBC's; spherical nucleus; Life span hours to years; Initiate immune response by direct cell attack (T Cells) or via antibodies (B Cells).
• ● Monocytes: ~5.3% of total WBC's; U or kidney-shaped nucleus; Life span is months; Phagocytosis; Develop into macrophages in tissues.

● Recall there are two categories of Leukocytes (WBC's): Granulocytes (which include Neutrophils, Eosinophils and Basophils) and Agranulocytes (which include lymphocytes and monocytes).

● Leukocytes move around the body via the blood and lymph. They are formed either principally in the bone marrow (which include granulocytes, monocytes and a few lymphocytes), or they form principally in lymphoid tissue (which include lymphocytes and plasma cells).

● Leukocytes move to the area of the body where they are needed. Granulocytes and monocytes seek out invading organisms by chemotaxis.

● Granulocytes together with the larger granule-free monocytes protect primarily by phagocytosis (innate) while lymphocytes and plasma cells act principally by the production of specific antibodies (acquired/adaptive).

A General Summary of the Function of Immune Cells:

• ● Neutrophils: A type of Leukocyte (WBC) produced in the bone marrow that has two functions:
• 1) Phagocytosis
• 2) Release chemicals involved in inflammation (vasodilators, chemotaxins, etc.)

● Basophils: A type of Leukocyte (WBC) produced in the bone marrow. Releases histamine and other chemicals involved in inflammation.

• ● Eosinophils: A type of Leukocyte (WBC) produced in the bone marrow that has two functions:
• 1) Destroy multicellular parasites
• 2) Participate in immediate hypersensitivity reactions

• ● Monocytes: A type of Leukocyte (WBC) produced in the bone marrow that has two functions:
• 1) carry out functions similar to macrophages, but on a smaller scale level
• 2) Enter tissues and transform into macrophages

• ● Macrophages: Produced in the bone marrow; reside in almost all tissues and organs; differentiate from monocytes. They have four main functions:
• 1) Phagocytosis
• 2) Extracellular killing via secretion of toxic chemicals
• 3) Process and present antigens to helper T cells
• 4) Secrete cytokines involved in inflammation, activation and differentiation of helper T cells, and systemic responses to infection or injury (the acute phase response)

• ● Macrophage-like cells ("Dendritic Cells"): Produced in almost all tissues and organs; microglia in the Central Nervous System. Serve the same functions as macrophages:
• 1) Phagocytosis
• 2) Extracellular killing via secretion of toxic chemicals
• 3) Process and present antigens to helper T cells
• 4) Secrete cytokines involved in inflammation, activation and differentiation of helper T cells, and systemic responses to infection or injury (the acute phase response)

●Mast Cells: Produced in bone marrow; differentiate from bone marrow cells; reside in almost all tissues and organs. Their function is to release histamine and other chemicals involved in inflammation.

• ● Eosinophils compose ~2.3% of all circulating WBC's. They exhibit chemotaxis but are poor at
• phagocytosis (insignificant compared to neutrophils or macrophages).

● They are however produced in  no. in response to parasitic infections when they are attracted by chemotaxis and release substances toxic to most parasites. These include hydrolytic enzymes from modified lysosomes, certain ROS's and the highly larvacidal polypeptide called Major Basic Protein.

● Eosinophils also migrate into tissues undergoing allergic responses. The primary cells involved in allergic response are Mast cells and basophils and these release an Eosinophil Chemotactic Factor which attracts eosinophils which may then detoxify certain substances involved in inflammation.

● Basophils compose ~0.4% of all circulating WBC's. They are similar to Mast cells found in tissues as both release heparin to inhibit coagulation. They both release histamine and small quantities of bradykinin and serotonin.

• ● As mentioned previously basophils and Mast cells are very important in some kinds of allergic responses as they bind to a particular type of antibody (IgE) that is produced under these conditions. These antibodies attach to the foreign substance (antigen) triggering the release of
•  amounts of histamine, bradykinin, serotonin, heparin, Slow-reacting Substance of Anaphylaxis and several lysosymal enzymes which cause local vasodilation and tissue reactions characteristic of allergic responses.

● The total WBC count is typically ~7,000/mL as compared to the much larger RBC count of ~5 x 106 RBC's/mL. Therefore WBC's are much smaller in number in comparison to RBC's. However, WBC's can increase dramatically in response to an infection or leukemia.

● Most WBC's are produced or have  production according to the need.

• ● WBC's begin from the same pluripotent
• hematopoietic stem cells (PHSCs) as RBC's and platelets. These PHSCs subsequently become committed to two principal cell lines:
• 1) myeloblasts (myelocytic) in the bone marrow which eventually produce granulocytes
• 2) monocytes and lymphoblasts (lymphocytic)
• in lymphoid tissue (lymph glands, spleen, thymus, tonsils, etc.) which eventually produce lymphocytes and plasma cells

● The majority of WBC's are actually stored in bone marrow or lymphoid tissue rather than circulating in the blood. This gives a “reserve” of ~6 days of WBC's.

● The typical lifespan of granulocytes is ~4-8 hours in the blood plus ~5-6 days in the tissues where needed. This can be reduced when fighting infections (they wear out!).

● Monocytes however spend ~10-20 hours in the blood before entering tissues where they enlarge and mature into active tissue macrophages which can survive for months while phagocytozing pathogens.

• The players of Phagocytosis
• ● There are two main types of cells that perform phagocytosis:
• 1) Neutrophils (A granulocyte Leukocyte)
• 2) Monocytes (An agranulocyte Leukocyte) which matures to a Macrophage

● Neutrophils and mature monocytes (tissue macrophages) attack and destroy invading pathogens by phagocytosis.

• The Process of Phagocytosis
• ● When tissue damage and inflammation occur, many substances are released which attract phagocytozing cells by chemotaxis.

• ● Once they have "sniffed" out their target, phagocytozing cells selectively ingest invading organisms via the following three mechanisms. [Two of the three mechanisms are innate all of the time, but the third mechanism could be innate or acquired immunity]:
• 1) Many pathogens have roughened surfaces which attract these cells (our cells are smooth!) [innate immunity]
• 2) Most pathogens lack the repellant protective coats that our cells possess [innate immunity]
• 3) Bacterial pathogens can be “labeled” through the complement system by either specific antibodies (via acquired/adaptive immunity) or without the involvement of antibodies during inflammation (via innate immunity) through the alternate complement pathway (another way of activating the complement pathway). This marks them for phagocytosis and/or other methods of destruction. [innate or acquired/adaptive immunity]
• ● Neutrophils enter tissues from the blood by diapedesis attracted by chemotactic stimuli and project pseudopodia around the pathogen so engulfing it. This invagination separates internally and becomes a phagocytic vesicle (also called a phagosome) in which the pathogen is normally destroyed.
• ● Once the invader is suspended and captured in a phagosome, numerous cytoplasmic granules fuse and release their contents (principally proteases) into the phagosome to digest the invader, which now creates a digestive vesicle.

Location of Immune Cells

● Neutrophils are found primarily in the blood whereas macrophages move into the tissues.

● Some macrophages become attached to the tissue they reside in where they function locally. With the right stimulus, they can release themselves and move around the body once more.

● The skin is usually impervious to infectious agents unless the skin is broken for whatever reason. If the skin is broken, ensuing local inflammation of subcutaneous tissue triggers local tissue macrophages (also known as histiocytes) to divide and phagocytize any invading organisms.

● The alveolar walls of the lungs contain many macrophages optimally located to phagocytize any inhaled organisms or particles. If these organisms are not digestible, sometimes a giant cell capsule is formed around them so hopefully isolating and inactivating them (like building a jail cell for the organism). Capsules are typically formed around tuberculosis bacilli which are difficult to kill, silica and carbon particles.

● The liver also contains many macrophages (known as Kupffer cells) which line the sinusoids between the hepatocytes (liver cells) through which blood carrying ingested substances from the GI tract passes (via the hepatic portal vein). These macrophages (Kupffer cells) are therefore perfectly positioned to filter out foreign cells and material entering from the GI tract.

The function of the Lymph System

● Anything not phagocytized must be removed via the lymph as it cannot cross the endothelium and enter the blood.

● Lymph circulates through the lymph nodes where these particles tend to become trapped by the reticular meshwork and then phagocytized by macrophages that line the lymph nodes or destroyed by various antibody/complement/etc. mechanisms.

● If an invading organism does manage to enter the blood despite the previously mentioned defenses, they can be removed as the blood passes through the reticular systems of the spleen and bone marrow by macrophages in a manner analogous to the “filtering” of lymph.

● In the spleen the capillaries are very “leaky” which allows whole blood, including RBC's, to squeeze through the so-called “cords of red pulp” which are lined with macrophages. This torturous path often ruptures old or abnormal RBC's allowing recycling.

Lymphocytes

● Recall a Lymphocyte is a Leukocyte or WBC that is an Agranulocyte that mounts the immune response by direct cell attack (T cells) or viaantibodies (B cells).

● Lymphocytes enter the blood via the lymph (formed in lymphoid tissues) where they circulate only to invade tissues and subsequently re-enter the lymph, and they cycle continues. Lymphocytes can continue this process for months depending on the need.

Other Mechanisms for Killing Pathogens

● Macrophages can release lipases which can attack the thickened membranes which some bacteria possess (note neutrophils do not posses lipases).

● Neutrophils and macrophages also contain certain bactericidal enzymes that can kill most types of bacteria even if they are resistant to digestion.

● Neutrophils and macrophages may contain certain oxidizing agents (Reactive Oxygen Species: ROS's) synthesized by membrane-bound enzymes or in a special organelle called a peroxisome. These agents include “superoxide” (O2-), hydrogen peroxide (H2O2) and hydroxyl ions (OH-).

● A lysosomal enzyme myeloperoxidase catalyzes the reaction between H₂O₂ and Cl^- ions to produce hypochlorite (“bleach”) which is extremely bacteriocidal. However, some bacteria can even resist these agents (the tuberculosis bacillus for example).

Opsonization

● Relatively nonspecific (as opposed to specific antibodies) interactions between microbial cell-surface carbohydrates and components of the complement system (specifically complement factor C3b) connect bacteria effectively to phagocytes. This is called opsonization.



MAC Attack

● After opsonization, recruitment of various complement proteins form the Membrane Attack Complex (MAC) which perforate bacterial membranes (forming a "channel") making them leaky and subsequently killing the bacteria.

• Chemicals: a way of communicating
• ● When tissue damage occurs many important substances are released:
• 1) histamine
• 2) bradykinin
• 3) serotonin
• 4) prostaglandins
• 5) complement system factors
• 6) factors involved in blood clotting (especially Tissue factor)
• 7) lymphokines from lymphocytes
• Responding to Chemicals released at the site of injury
• ● These substances produce the localized response known as inflammation. This is characterized by local vasodilation which  blood flow and together with  capillary permeability allows the leakage of:
• 1) plasma proteins
• 2) granulocytes (types of leukocytes or WBCs)
• 3) monocytes (immature macrophages)
• All of the above are attracted by chemotaxis into the extracellular fluid (ECF) of the affected tissue.

● Leakage of clotting factors (including fibrinogen) into the ECF allows it to clot so helping limit the spread of any pathogens or toxins.

The Role of Macrophages in the First Response

● Several of these substances activate macrophages which then start to phagocytize damaged cells.

• ● Very shortly after inflammation begins macrophages already present in the tissue enlarge and begin phagocytosis. This activation can cause previously attached macrophages to release and become the first response, also known as the innate response (<1 hour) which is extremely important.

Once a phagocytic cell has made contact with a microbe, the following things could happen:

1) Phagocytosis: intracellular killing of microbes (in other words, the phagocytic cell internalizes the microbe by endocytosis to kill it).

2) Chemical Secretion: the phagocyte could secrete chemicals to regulate the inflammatory process.

• 3) Chemical Secretion: the phagocyte could secrete chemicals to kill microbes extracellularly. This includes releasing:
• -Reactive Oxygen Species
• -Stimulating the alternate complement pathway via C3b
• -MAC attack
• -Opsonization

4) Chemical Secretion: the phagocyte could stimulate activation of clotting and anti-clotting pathways.

5) Chemical Secretion: the phagocyte could stimulate hormonal regulation of overall bodily responses to infection.

If a complement protein is activated, the following things could happen:

1) Direct destruction of invading microbes by membrane attack complex (MAC attack)

2) Vasodilation and increased permeability of capillaries and venules to proteins

3) Chemotaxis

4) Enhancement of phagocytosis (opsonization)

The following Mediators play a role in the First Response:

• 1) Kinins: generated from enzymatic action on plasma proteins; cause vascular changes & interact with pain receptors.
• 2) Complement: generated from enzymatic action on plasma proteins; involved mostly in the acquired/adaptive immunity.
• 3) Products of Blood clotting: generated from enzymatic action on plasma proteins; promotes hemostasis.
• 4) Histamine: secreted by mast cells and injured cells; increase vasodilation & permeability.
• 5) Eicosanoids: secreted by many cell types; involved in arachadonic acid pathways.
• 6) Platelet-activating Factor: Secreted by many cell types; promotes hemostasis.
• 7) Cytokines (including chemokines): Secreted by injured cells, monocytes, macrophages, neutrophils, lymphocytes, and several non-immune cell types (such as endothelial cells & fibroblasts); system regulators, chemotaxis, colony stimulating factors (CSFs), interferons, etc.
• 8) Lysosomal enzymes, nitric oxide, and other oxygen-derived substances: Secreted by injured cells, neutrophils, and macrophages; involved in enzymatic and Reactive Oxygen Species (ROS) degradation.

• Inflammation:
• Entry of bacteria into tissues; injury to tissue causes release of chemicals to initiate the following events:

1) Vasodilation of the microcirculation in the affected area, leading to increased blood flow.

2) Large increase in protein permeability of the capillaries and venules of the affected area, with resulting diffusion of protein and filtration of fluid into the interstitial fluid.

3) Chemotaxis: Movement of leukocytes from the venules into the interstitial fluid of the infected area.

4) Destruction of bacteria in the tissue either through phagocytosis or by other mechanisms.

Margination: A Way for Neutrophils to Stick

● Margination: The adhesion of white blood cells to the endothelial cells of blood vessels that occurs at the site of an injury during the early phases of inflammation.

● After ~1 hour,  no. neutrophils invade the inflamed tissues from the blood (chemotaxis). This is now possible because some of the substances released from damaged tissue alter the normally smooth endothelial surface so neutrophils can attach prior to leaving capillaries by diapedesis (this process is called margination).

● Margination is when certain adhesion molecules (a bit "Notch-like") make the cell surface rough so that neutrophils can loosely tether to the endothelial surface near the site of infection.

• Diapedesis: the migration to infection site
• ● Diapedesis: the outward passage of blood cells through intact vessel walls.

● The presence of chemoattractants are released from immune cells already responding at the site. The adjacent endothelial surface causes the expression/activation of high-affinity integrin adhesion molecules on the surface of attracted neutrophils that bind far more strongly. This allows stable adhesion with subsequent squeezing of the deformable neutrophils between endothelial cells to the site of infection; this is diapedesis.

● This process is further enhanced by a loosening of the intercellular connections between capillaries and venules (↓pressure end of capillaries as opposed to ↑pressure/arterioles).

● Lymphocyte cells (recall, a lymphocyte is a type of leukocyte that is an agranulocyte) are very mobile and are capable of amoeboid-like movement (rearrangement of their cytoskeletons) and can pass through “gaps” in the capillary endothelium to enter the tissues by a process called diapedesis and can follow chemical “trails” to the source by a process called chemotaxis.

The players involved are:

1) Integrins: According to Wikipedia, "Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the extracellular matrix (ECM). They also play a role in cell signaling and thereby define cellular shape, mobility, and regulate the cell cycle."

2) Selectins: are transmembrane glycoproteins that play a role in cell adhesion. They are expressed principally on leukocytes and endothelial cells, and they can, for example, mark the part of a blood vessel near an infection.

3) Chemokines: like selectins, are also present in the endothelial cells near the infection signaling to leukocytes where the site of infection is.

• Steps involved for margination & diapedesis:
• 1) Selectins are expressed on endothelial cells around the site of infection.

2) Leukocytes, such as neutrophils, express the ligand for selectins. The binding of the ligand with the selectin is weak, however, and cannot hold on for long because of the flow of blood, so the leukocyte continues to roll along.

3) Chemokines, like selectins, are also present in the endothelial cells near the infection. As the leukocyte is rolling along having weak interactions with selectins, the chemokine will eventually bind allowing integrin activation (from the low-affinity state to the high affinity state).

4) Once the integrin has been activated, there is stable adhesion between the leukocyte and a receptor.

5) The leukocyte is then able to migrate through the endothelium by margination and diapedesis to the site of infection.

6) The leukocyte is able to determine where the site of infection is by following the chemokine gradient. Chemokines such as TNF and IL-1 are released from macrophages to signal the site of infection.

● Chemicals released at the site of injury can also cause the release of  no. stored neutrophils from the bone marrow. This is termed neutrophilia and can result in x4 increase in circulating neutrophils.

● Immature monocytes enter the affected tissue and become functional macrophages (~8 hours) but their numbers are low initially. A full response requires several days.

● Finally a large  production of both granulocytes and monocytes occurs in the bone marrow; however, this requires ~3-4 days before these cells are released and able to respond. If inflammation persists can get  production for months and even years! (up to x20-50 normal).

● Although >24 substances have been implicated in the response to inflammation, five in particular that are released by activated macrophages are thought to be of prime importance and include:

1) Tumor necrosisfactor (TNF)

2) Interleukin-1 (IL-1)

3) Granulocyte-monocyte Colony-stimulating Factor (GM-CSF: stimulates production of all WBC's except lymphocytes)

4) Granulocyte Colony-stimulating Factor (G-CSF: only stimulates granulocyte production)

5) Monocyte Colony-stimulating Factor (M-CSF: only stimulates monocyte production)

The following are the most important cytokines:

• 1) Interleukin 1 (IL-1)
• Source: Antigen Presenting Cells (e.g. macrophages)
• Target Cells: are helper T cells, certain brain cells & numerous systemic cells.
• Major Function: to stimulate IL-2 secretion and receptor expression, induce fever, stimulate systemic responses to inflammation, infection & injury.

• 2) Tumor Necrosis Factor (TNF)
• Source: Antigen Presenting Cells (e.g. macrophages)
• Target Cells: are helper T cells, certain brain cells & numerous systemic cells.
• Major Function: to stimulate IL-2 secretion and receptor expression, induce fever, stimulate systemic responses to inflammation, infection & injury.

• 3) Interleukin 6 (IL-6)
• Source: Antigen Presenting Cells (e.g. macrophages)
• Target Cells: are helper T cells, certain brain cells & numerous systemic cells.
• Major Function: to stimulate IL-2 secretion and receptor expression, induce fever, stimulate systemic responses to inflammation, infection & injury.

• 4) Interleukin 2 (IL-2)
• Source: most immune cells
• Target Cells: helper T cells, cytotoxic T cells, NK cells, B cells
• Major Functions: to stimulate proliferation and promote conversion to plasma cells.

• 5) Interferons
• Source: most cell types
• Target Cells: most cell types
• Major Function: to stimulate cells to produce antiviral proteins (nonspecific response).

• 6) Interferon-gamma
• Source: NK cells & activated helper T cells
• Target Cells: NK cells & macrophages
• Major Function: Stimulate proliferation & secretion of cytotoxic compounds.

• 7) Chemokines
• Source: damaged cells, including endothelial cells.
• Target Cells: Neutrophils & other leukocytes
• Major Function: facilitate accumulation of leukocytes at site of injury & inflammation.

• 8) Colony Stimulating Factors
• Source: Macrophages
• Target Cells: Bone Marrow
• Major Function: Stimulate proliferation of neutrophils & monocytes.

● Interferons are a family of cytokines that nonspecifically inhibit viral replication inside host cells. When most cell types are infected, they secrete interferons which then act in an auto- and paracrine manner causing the synthesis of literally dozens of antiviral proteins in both infected and uninfected cells.

• ● As neutrophils and macrophages phagocytize bacteria and necrotic tissue they wear out and die. After several days, a cavity is formed which
• fills with these dead cells, as well as tissue and tissue fluid. This combination is called pus.

● Pus eventually autolyzes and is re-absorbed.

● Leukopenia is a clinical condition whereby the bone marrow starts to produce very ↓no. of WBC's.

● After ~2 days (when the previously circulating/not stored WBC's now dying), various infections start to occur and if not treated death can ensue <1 week!

● The prime cause of such a condition is damage to the bone marrow as caused by exposure to gamma or X-rays, chemicals such as benzene or anthracene and drugs such as chloramphenicol (an antibiotic), thiouracil (used to treat thyrotoxicosis) or even some barbiturates.

● Modest damage to the bone marrow will repair eventually (hyperplasia, defined as "abnormal increase in number of cells," may take weeks to months) if the patient is treated/supported appropriately during this time.

● Leukemia is when cancerous mutations of WBC precursor cells may result in uncontrolled production of WBC's.

• ● Just as there are two general types/classes of WBC's (granulocytes + monocytes vs. lymphocytes), there are two general types of leukemia:
• 1) myelogenous
• 2) lymphocytic

● Myelogenous leukemia originates in the bone marrow and subsequently spreads throughout the body especially to lymph nodes, spleen and liver. Cells are often undifferentiated with bizarre shapes.

● The more undifferentiated the cells are the less function they have. In acute cases, death can result in a few months if untreated (compare to Leukopenia where death could ensue in less than a week).

● Obviously in Leukemia, the WBCs have some function otherwise the patient would not survive that long (as with Leukopenia).

● If the cells are reasonably differentiated/have some significant function this results in a chronic form of this disease whereby it may develop slowly over 10-20 years.

● Lymphocytic leukemia usually develops in lymph nodes or other lymphoid tissues but spreads and develops in a similar fashion to myelogenous.

• ● The primary result of leukemia is the production of increased no. non-functional/partially functional WBC's in inappropriate areas of the body resulting in infection, severe anemia (↓no. RBC's) and a
• tendency to bleed due to thrombocytopenia (↓no. platelets).

● Both myelogenous and lymphocytic leukemia are conditions caused by the physical displacement of normally functioning bone marrow by the cancerous cells.

● However the most significant effect on the patient is often due to the very high metabolic demand placed on the body by these rapidly dividing cells. Other tissues can be starved and forced to rely on protein catabolism.

● In summary, Leukemia is the uncontrolled/cancerous production of WBC’s. Myelogenous leukemia originates in the bone marrow and then metastasizes while lymphocytic leukemia originates in lymphoid tissue (nodes) before spreading.

• ● The more undifferentiated the WBC’s produced,
• the less function they have and the more acute the condition (↓survival: as with leukopenia). In other words, victims can survive for years if WBC's have some function.

• Neutrophils
• Monocytes/Macrophages

• Local primary responders (such as "tissue macrophages") and damaged tissue at the site produce and release chemotaxins, thus stimulating chemotaxis.
• Chemotaxis attracts circulating phagocytes, which are secondary responders.

Phagocytosis followed by intracellular digestion.

• Innate immunity is generally nonspecific. There are two mechanisms that are nonspecific that are used by immune cells:
• 1) immune cells can "feel" rough surface of pathogens
• 2) pathogens have a "different coat" than body cells that the immune cells can recognize as different

Anything or any process that enhances phagocytosis by neutrophils and monocytes/macrophages.

• The Alternate Complement Pathway is part of the Complement Pathway that can be activated nonspecifically.
• This nonspecific activation happens when an upstream factor is activated (not the first factor of the pathway...not C1).
• This upstream factor is activated between a bacterium and a phagocyte.
• This causes opsonization and recruitment of other killing mechanisms.

Complement Factor C3b

• The Membrane Attack Complex. Other names meaning the same thing are:
• The MAC attack
• The Lytic System

• • The innate response to injury and/or
• infection is primarily that of inflammation. This includes:
• 1) vasodilation
• 2) ↑vascular permeability to important proteins
• 3) phagocyte chemotaxis
• 4) phagocytosis and/or destruction of the invading pathogen nonspecifically

• •Chemical mediators controlling/coordinating
• these processes are either released at the site or generated from plasma proteins.

• • The principal phagocytes are neutrophils,
• monocytes, macrophages and related cells. They also secrete many inflammatory mediators.

• •The complement system can be activated during
• nonspecific (innate) inflammation and adds to the response plus enhances phagocytosis and implementation of the MAC.