Chapter 1: Introduction and Natural Immunity

IMMUNITY AND IMMUNIZATION

IMMUNOLOGY- defined as the study of a host’s reactions when foreign substances are introduced into the
body.

A foreign substance that induces such an immune response is called an ANTIGEN.

Immunology as a science has its roots in the study of immunity, the condition of being resistant to infection.

1500s- Chinese developed a practice of inhaling powder made from smallpox scabs in order to produce
protection against this dreaded disease. This practice of deliberately exposing an individual to material from
smallpox lesions was known as variolation.

1700s- Edward Jenner discovered a remarkable relationship between exposure to cowpox and immunity to
smallpox. He proved that immunity to cowpox, a very mild disease, provided protection against smallpox. This
procedure of injecting cellular material became known as vaccination, from vacca, the Latin word for “cow.”

Louis Pasteur In working with the bacteria that caused chicken cholera accidentally found that old cultures
would not cause disease in chickens. Subsequent injections of more virulent organisms had no effect on the
birds that had been previously exposed to the older cultures. In this manner, the first attenuated vaccine was
discovered. Attenuation, or change, may occur through heat, aging, or chemical means, and it remains the
basis for many of the immunizations that are used today.

CELLULAR VERSUS HUMORAL IMMUNITY

In 1800, Elie Metchnikoff, a Russian scientist, observed that foreign objects introduced into transparent
starfish larvae became surrounded by motile cells that attempted to destroy these invaders. He called this
process phagocytosis, meaning cells that eat cells. He hypothesized that immunity to disease was based on
the action of these scavenger cells. The theory of humoral immunity was thus born, and this set off a long-
lasting dispute over the relative importance of cellular versus humoral immunity.

In 1903, Almoth Wright English physician linked the two theories by showing that the immune response
involved both cellular and humoral elements. He observed that certain humoral, or circulating, factors called
opsonins acted to coat bacteria so that they became more susceptible to ingestion by phagocytic cells. These
serum factors include specific proteins known as antibodies and nonspecific factors called acute-phase
reactants that increase nonspecifically in any infection.

NATURAL, OR INNATE, IMMUNITY is the ability of the individual to resist infection by means of normally
present body functions.

These are considered non adaptive or nonspecific and are the same for all pathogens or foreign substances to
which one is exposed.

No prior exposure is required, and the response does not change with subsequent exposures.
Many of these mechanisms are subject to influence by such factors as nutrition, age, fatigue, stress, and
genetic determinants.

ACQUIRED IMMUNITY, in contrast, is a type of resistance that is characterized by specificity for each
individual pathogen, or microbial agent, and the ability to remember a prior exposure, which results in an
increased response upon repeated exposure.

NATURAL DEFENSE SYSTEM is composed of two parts:

1. External defense system

2. Internal defense system

The external defense system is designed to keep microorganisms from entering the body. If these defenses
are overcome, then the internal defense system must clear invaders as quickly as possible.

INTERNAL DEFENSES can be categorized into:

1. Cellular mechanisms
2. Humoral factors

~Both of these systems work together to promote PHAGOCYTOSIS, which results in the destruction of foreign
cells and organisms.

~The process of INFLAMMATION brings cells and humoral factors to the area in need of healing. If the healing
process is begun and resolved as quickly as possible, the tissues are less likely to be damaged.

EXTERNAL DEFENSE SYSTEM

~Structural barriers that prevent most infectious agents from entering the body.

First and foremost is the unbroken skin and the mucosal membrane surfaces. Not only does the skin serve as
a major structural barrier, but also the presence of several secretions discourages the growth of
microorganisms.

Lactic acid in sweat, for instance, and fatty acids from sebaceous glands maintain the skin at a pH of
approximately 5.6. This acid pH keeps most microorganisms from growing.

In the respiratory tract, mucous secretions and the motion of cilia lining the nasopharyngeal passages clear
away almost 90 percent of the deposited material.

The flushing action of urine, plus its slight acidity, helps to remove many potential pathogens from the
genitourinary tract.

Lactic acid production in the female genital tract keeps the vagina at a pH of about 5, another means of
preventing invasion of pathogens.

In the digestive tract, acidity of the stomach, which is due to production of hydrochloric acid, keeps the pH as
low as 1 and serves to halt microbial growth.
Lysozyme is an enzyme found in many secretions such as tears and saliva, and it attacks the cell walls of
microorganisms, especially those that are gram-positive.

In many locations of the body, there is normal flora that often keeps pathogens from establishing themselves
in these areas. This phenomenon is known as competitive exclusion.

INTERNAL DEFENSE SYSTEM

~Both cells and soluble factors play essential parts.

~Designed to recognize molecules that are unique to infectious organisms.

~This typically involves recognizing a carbohydrate such as mannose that is found in microorganisms and is not
evident on human cells.

White blood cells seek out and destroy foreign cells by participating in phagocytosis, which is the engulfment
of cells or particulate matter by leukocytes, macrophages, and other cells. This process destroys most of the
foreign invaders that enter the body, and it is the most important function of the internal defense system.

Phagocytosis is enhanced by soluble factors called ACUTE PHASE REACTANTS.

ACUTE-PHASE REACTANTS:

Are normal serum constituents that increase rapidly by at least 25 percent due to infection, injury, or trauma
to the tissues.

Some of the most important ones are C-reactive protein, serum amyloid A, complement components,
mannose-binding protein, alpha1-antitrypsin, haptoglobin, fibrinogen, and ceruloplasmin.

They are produced primarily by hepatocytes (liver parenchymal cells) within 12 to 24 hours in response to an
increase in certain intercellular signaling polypeptides called cytokines

These cell messengers, most notably interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-
alpha (TNF-α) are mainly produced by monocytes and macrophages at the sites of inflammation.

A. C-REACTIVE PROTEIN

C-reactive protein (CRP) is a trace constituent of serum originally thought to be an antibody to the c-
polysaccharide of pneumococci. It increases rapidly within 4 to 6 hours following infection, surgery, or other
trauma to the body. Levels increase dramatically as much as a hundredfold to a thousand fold, reaching a peak
value within 48 hours.

CRP acts somewhat like an antibody, as it is capable of opsonization (the coating of foreign particles),
agglutination, precipitation, and activation of complement by the classical pathway.

Monitoring CRP may be an important preventative measure in determining the potential risk of heart attack or
stroke, although only automated, high-sensitivity tests for CRP are useful for this purpose.

B. SERUM AMYLOID A
Serum amyloid A is the other major protein whose concentration can increase almost a thousand fold, as is
the case in CRP. It is an apolipoprotein that is synthesized in the liver and has a molecular weight of 11,685
daltons. Normal circulating levels are approximately 30ug/ml.

In plasma, it is associated with HDL cholesterol, and it is thought to play a role in metabolism of cholesterol. By
removing cholesterol from cholesterol-filled macrophages at the site of tissue injury, serum amyloid A
contributes to the cleaning up of the area.

This also facilitates recycling of cell membrane cholesterol and phospholipids for reuse in building membrane
of new cells required during acute inflammation.

It has been found to increase significantly more in bacterial infections than in viral infections.

C. COMPLEMENT

~Series of serum proteins that are normally present and whose overall function is mediation of inflammation.

There are nine such proteins that are activated by bound antibodies in a sequence known as the classical
cascade; an additional number are involved in the alternate pathway that is triggered by microorganisms.

Major functions:

1. opsonization,
2. chemotaxis, and
3. lysis of cells.
D. MANNOSE-BINDING PROTEIN

~Also called mannosebinding lectin, is a trimer that acts as an opsonin, which is calcium-dependent.

It is able to recognize foreign carbohydrates such as mannose and several other sugars found primarily on
bacteria, some yeasts, viruses, and several parasites. It is widely distributed on mucosal surfaces throughout
the body. It has many similarities to the complement component C1q, as binding activates the complement
cascade and helps to promote phagocytosis. Normal concentrations are up to 10 ug/ml.

Lack of MBP has been associated with recurrent yeast infections.

E. ALPHA1-ANTITRYPSIN

~Major component of the alpha band when serum is electrophoresed.

Although the name implies that it acts against trypsin, it is a general plasma inhibitor of proteases released
from leukocytes, especially elastase. Elastase is an endogenous enzyme that can degrade elastin and collagen.

In chronic pulmonary inflammation, lung tissue is damaged because of its activity. Thus, alpha1-antitrypsin
acts to “mop up” or counteract the effects of neutrophil invasion during an inflammatory response.

It also regulates expression of pro inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1,
and interleukin-6, mentioned previously.
Alpha1-antitrypsin deficiency can result in premature emphysema, especially in individuals who smoke or who
are exposed to a noxious occupational environment. In such a deficiency, uninhibited proteases remain in the
lower respiratory tract, leading to destruction of parenchymal cells in the lungs and to development of
emphysema or idiopathic pulmonary fibrosis.

F. HAPTOGLOBIN

~Is an alpha2-globulin with a molecular weight of 100,000 daltons.

Its primary function is to bind irreversibly to free hemoglobin released by intravascular hemolysis.

Once bound, the complex is cleared rapidly by Kupffer and parenchymal cells in the liver, thus preventing loss
of free hemoglobin.

The rise in plasma haptoglobin is due to de novo synthesis by the liver and does not represent release of
previously formed haptoglobin from other sites.

A twofold to tenfold increase in haptoglobin can be seen following inflammation, stress, or tissue necrosis.

Early in the inflammatory response, however, haptoglobin levels may drop because of intravascular hemolysis,
consequently masking the protein’s behavior as an acute-phase reactant. Thus, plasma levels must be
interpreted in light of other acute-phase reactants. Normal plasma concentrations range from 40 to 290
mg/dL.

Haptoglobin plays an important role in protecting the kidney from damage and in preventing the loss of iron
by urinary excretion.

However, its most important function may be to provide protection against oxidative damage mediated by
free hemoglobin, a powerful oxidizing agent that can generate peroxides and hydroxyl radicals.

G. FIBRINOGEN

~Most abundant of the coagulation factors in plasma, and it forms the fibrin clot.

The molecule is a dimer with a molecular weight of 340,000 daltons. Normal levels range from 100 to 400
mg/dL. A small portion is cleaved by thrombin to form fibrils that make up a fibrin clot.

This increases the strength of a wound and stimulates endothelial cell adhesion and proliferation, which are
critical to the healing process.

Formation of a clot also creates a barrier that helps prevent the spread of microorganisms further into the
body. Fibrinogen also serves to promote aggregation of red blood cells, and increased levels contribute to an
increased risk for developing coronary artery disease, especially in women.

H. CERULOPLASMIN

~Consists of a single polypeptide chain with a molecular weight of 132,000 daltons. It is the principal copper-
transporting protein in human plasma, binding 90 to 95 percent of the copper found in plasma by attaching six
cupric ions per molecule. Additionally, ceruloplasmin acts as a ferroxidase, oxidizing iron from Fe2+ to Fe3+.
This may serve as a means of releasing iron from ferritin for binding to transferrin.

A depletion of ceruloplasmin is found in Wilson’s disease, an autosomal recessive genetic disorder

characterized by a massive increase of copper in the tissues. Normally, circulating copper is absorbed out by
the liver and either combined with ceruloplasmin and returned to the plasma or excreted into the bile duct.
Wilson’s disease- copper accumulates in the liver and subsequently in other tissues such as the brain, cornea,
kidneys, and bones.

CELLULAR DEFENSE MECHANISMS

There are five principal types of leukocytes, or white blood cells, in peripheral blood:

1. Neutrophils
2. Eosinophils
3. Basophils
4. Monocytes
5. Lymphocytes

Some of these white blood cells participate in the process of phagocytosis; these are known as the myeloid
line and arise from a common precursor in the marrow.

These can be further divided into:

1. Granulocytes- Neutrophils, eosinophils, and basophils

2. Monocytes, or mononuclear cells.

Several cell lines that are found in the tissues, namely mast cells, macrophages, and dendritic cells contribute
to the process of natural immunity.

NEUTROPHILS

Neutrophil, or Polymorphonuclear Neutrophilic (PMN) leukocyte

~Approximately 50 to 70 percent of the total peripheral white blood cells.

These are around 10 to 15 μm in diameter, with a nucleus that has between two and five lobes.

They contain a large number of neutral staining granules, which are classified as primary, secondary, and
tertiary granules.

A. Primary granules, also called azurophilic granules, contain enzymes such as myeloperoxidase; elastase;
proteinase 3; lysozyme; cathepsin G; and defensins, small proteins that have antibacterial activity.
B. Secondary granules are characterized by the presence of collagenase, lactoferrin, lysozyme, reduced
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and other membrane proteins
normally associated with the plasma membrane.
C. Newly discovered: Tertiary granules contain gelatinase and plasminogen activator. Acid hydrolases are
found in separate compartments called lysosomes.
 Normally, half of the total neutrophil population is found in a marginating pool on blood vessel walls, while
the rest circulate freely for approximately 6 to 10 hours. There is a continuous interchange, however,
between the marginatingand the circulating pools. Marginating occurs to allow neutrophils to move from
the circulating blood to the tissues through a process known as diapedesis, or movement through blood
vessel walls.

Receptors known as selectins help make neutrophils sticky and enhance adherence to endothelial cells
that make up the vessel wall. Neutrophils then form pseudopods, which squeeze through junctions of the
endothelial cells. They are attracted to a specific area by chemotactic factors.

Chemotaxins are chemical messengers that cause cells to migrate in a particular direction. Factors that are
chemotactic for neutrophils include complement components; proteins from the coagulation cascade;
products from bacteria and viruses; platelet activating factor; and secretions from mast cells, lymphocytes,
macrophages, and other neutrophils.

Once in the tissues, neutrophils have a life span of about 5 days. Normally, the input of neutrophils from
the bone marrow equals the output from the blood to the tissues to maintain a steady state. However, in
the case of acute infection, an increase of neutrophils in the circulating blood can occur almost
immediately.

EOSINOPHILS

~Approximately 12 to 15 μm in diameter, and they normally make up between 1 and 3 percent of the
circulating white blood cells in a nonallergic person.

Their number increases in an allergic reaction or in response to many parasitic infections.

The nucleus is usually bilobed or ellipsoidal and is often eccentrically located. Eosinophils take up the acid
eosin dye, and the cytoplasm is filled with large orange to reddish orange granules.

Primary granules contain acid phosphatase and arylsulfatase, while eosinophil-specific granules contain
several different proteins: major basic protein, eosinophil cationic protein, eosinophil peroxidase, and
eosinophil-derived neurotoxin. These cells are capable of phagocytosis but are much less efficient than
neutrophils because of the smaller numbers present and their lack of digestive enzymes.

Their most important role is neutralizing basophil and mast cell products and killing certain parasites

BASOPHILS

~Representing less than 1 percent of all circulating white blood cells.

~The smallest of the granulocytes, they are between 10 to 15 μm in diameter and contain coarse, densely
staining deep-bluish purple granules that often obscure the nucleus.

Constituents of these granules are histamine, a small amount of heparin, and eosinophil chemotactic factor-A,
all of which have an important function in inducing and maintaining immediate hypersensitivity reactions.
 Histamine is a vasoactive amine that contracts smooth muscle, and heparin is an anticoagulant. IgE, the
immunoglobulin formed in allergic reactions, binds readily to basophil cell membranes,and granules release
their constituents when they contact an antigen. The granules lack hydrolytic enzymes, although peroxidase is
present. Basophils exist for only a few hours in the bloodstream.

MAST CELLS

~Resemble basophils, but they are connective tissue cells of mesenchymal origin. They are widely distributed
throughout the body and are larger than basophils, with a small round nucleus and more granules.

~Long life span of between 9 and 18 months.

The enzyme content of the granules helps to distinguish them from basophils, as they contain acid
phosphatase, alkaline phosphatase, and protease.

The mast cell, like the basophil, plays a role in hypersensitivity reactions by binding IgE.

MONOCYTES

Monocytes, or mononuclear cells

~Largest cells in the peripheral blood, with a diameter that can vary from 12 to 22 μm; they have an average
size of 18 μm.

One distinguishing feature is an irregularly folded or horseshoe-shaped nucleus that occupies almost one-half
of the entire cell’s volume. The abundant cytoplasm stains a dull grayish blue and has a ground-glass
appearance due to the presence of fine dustlike granules.

Two types of granules:

1. Contains peroxidase, acid phosphatase, and arylsulfatase; this indicates that these granules are similar
to the lysosomes of neutrophils.
2. Contain β-glucuronidase, lysozyme, and lipase, but no alkaline phosphatase.

Digestive vacuoles may also be observed in the cytoplasm.

These make up between 4 and 10 percent of total circulating white blood cells; however, they do not remain
in the circulation for long. They stay in peripheral blood for up to 70 hours, and then they migrate to the
tissues and become known as macrophages.

TISSUE MACROPHAGES

All tissue macrophages arise from monocytes, which can be thought of as macrophage precursors, because
additional differentiation and cell division takes place in the tissues. The transition from monocyte to
macrophage is characterized by progressive cellular enlargement to between 25 and 80 μm. As the monocyte
matures into a macrophage, there is an increase in endoplasmic reticulum, lysosomes, and mitochondria.
Unlike monocytes, macrophages contain no peroxidase.
Macrophages have specific names according to their particular tissue location. Some are immobile, while
others progress through the tissues by means of amoeboid action.

Macrophages in the lung are alveolar macrophages; in the liver, Kupffer cells; in the brain, microglial cells;
and in connective tissue, histiocytes. Macrophages may not be as efficient as neutrophils in phagocytosis,
because their motility is slow compared to that of the neutrophils. However, their life span appears to be in
the range of months rather than days.

The monocyte–macrophage system plays an important role in initiating and regulating the immune response.
Functions:

1. microbial killing,
2. tumoricidal activity,
3. intracellular parasite eradication,
4. phagocytosis,
5. secretion of cell mediators, and
6. antigen presentation.

Killing activity is enhanced when macrophages become “activated” by contact with microorganisms or with
chemical messengers called cytokines, which are released by T lymphocytes during the immune response

DENDRITIC CELLS

Dendritic cells are so named because they are covered long membranous extensions with that make them
resemble nerve cell dendrites.

Their main function is to phagocytose antigen and present it to helper T lymphocytes.

Classified according to their tissue location:

1. Langerhans cells are found on skin and mucous membranes;

2. Interstitial dendritic cells populate the major organs such as the heart, lungs, liver, kidney, and the
gastrointestinal tract; and
3. Interdigitating dendritic cells are present in the T lymphocyte areas of secondary lymphoid tissue and
the thymus.

After capturing antigen in the tissue by phagocytosis or endocytosis, they migrate to the blood and to
lymphoid organs, where they present antigen to T lymphocytes to initiate the acquired immune response.
They are the most potent phagocytic cell in the tissue.

TOLL-LIKE RECEPTORS

~ Recently discovered on certain cells is Toll-like Receptors.

Toll is a protein originally discovered in the fruit fly Drosophila, where it plays an important role in antifungal
immunity in the adult fly. Very similar molecules are found on human leukocytes and some non leukocyte cell
types, and these are called Toll-like receptors (TLRs).
The highest concentration of these receptors occurs on monocytes, macrophages, and neutrophils.

There are 11 slightly different TLRs in humans. Each of these receptors recognizes a different microbial
product.

TLR2 recognizes teichoic acid and peptidoglycan found in gram-positive bacteria

TLR4 recognizes lipopolysaccharide found in gram-negative bacteria

Once a receptor binds to its particular substance, or ligand, phagocytosis may be stimulated, or the cell
produces cytokines that enhance inflammation and eventual destruction of the microorganism.

PHAGOCYTOSIS

Four main steps:

1. Physical contact between the white cell and the foreign particle,
2. Formation of a phagosome,
3. Fusion with cytoplasmic granules to form a phagolysosome, and
4. Digestion and release of debris to the outside

Physical contact occurs as neutrophils roll along until they encounter the site of injury or infection. They
adhere to receptors on the endothelial cell wall of the blood vessels and penetrate through to the tissue by
means of diapedesis. This process is aided by chemotaxis, whereby cells are attracted to the site of
inflammation by chemical substances such as soluble bacterial factors, complement components, or C-reactive
protein.

Receptors on neutrophils or monocytes come into contact with the foreign particle surface, enhanced by
opsonins, a term derived from the Greek word meaning “to prepare for eating.” Opsonins are serum proteins
that attach to a foreign substance and help prepare it for phagocytosis. C-reactive protein, complement
components, and antibodies are all important opsonins.

Phagocytic cells have receptors for immunoglobulins and for complement components, which aid in contact
and in initiating ingestion. Opsonins may act by neutralizing the surface charge on the foreign particle, making
it easier for the cells to approach one another.

Once attachment has occurred, the cellular cytoplasm flows around the particle and eventually fuses with it.
An increase in oxygen consumption, known as the respiratory, or oxidative, burst, occurs within the cell as the
pseudopodia enclose the particle within a vacuole. The structure formed is known as a phagosome. The
phagosome is gradually moved toward the center of the cell.

Next, contact with cytoplasmic granules takes place, and fusion between granules and the phagosome occurs.
At this point, the fused elements are known as a phagolysosome. The granules then release their contents,
and digestion occurs. Any undigested material is excreted from the cells by exocytosis.

The actual process of killing is oxygen-dependent and results from the generation of bactericidal metabolites.
Heavily opsonized particles are taken up in as little as 20 seconds, and killing is almost immediate. Resting cells
derive their energy from anaerobic glycolysis; however, when phagocytosis is triggered, the respiratory burst
produces greater energy via oxidative metabolism.

The hexose monophosphate shunt is used to change nicotinamide adenine dinucleotide phosphate (NADP) to
its reduced form by adding a hydrogen. NADPH. NADPH then donates an electron to oxygen in the presence of
NADPH oxidase, a membrane-bound enzyme, which is only activated through conformational change
triggered by microbes themselves. A radical known as O2 – (superoxide) is formed. Superoxide is highly toxic
but can be rapidly converted to more lethal products. By adding hydrogen ions, the enzyme superoxide
dismutase (SOD) converts superoxide to hydrogen peroxide or the hydroxyl radical OH.

Hydrogen peroxide has long been considered an important bactericidal agent, and it is more stable than any
of the free radicals. Its effect is potentiated by the formation of hypochlorite ions. This is accomplished
through the action of the enzyme myeloperoxidase in the presence of chloride ions. Hypochlorite ions are
powerful oxidizing agents. All of these substances contribute to killing within the phagocyte

However, new evidence indicates that an electron transport system that alters the charge across the
membrane of the phagolysosome is more important than actual formation of oxygen radicals themselves.
NADPH oxidase may depolarize the membrane, allowing hydrogen and potassium ions to enter the vacuole.
When hydrogen combines with the superoxides, the pH increases, which in turn activates proteases that
contribute to microbial killing. NADPH oxidase is known to be central to the killing of microbes, because its
dysfunction causes chronic granulomatous disease. Patients with this disease suffer from recurring, severe
bacterial infections.

INFLAMMATION

~Overall reaction of the body to injury or invasion by an infectious agent

~Both cellular and humoral mechanisms are involved

~Each individual reactant plays a role in initiating, amplifying, or sustaining the reaction, and a delicate balance
must be maintained for the process to be speedily resolved.

The four cardinal signs or clinical symptoms: redness, swelling, heat, and pain.

Major events associated with the process of inflammation:

1. Increased blood supply to the infected area;

2. Increased capillary permeability caused by retraction of endothelial cells lining the vessels;
3. Migration of white blood cells, mainly neutrophils, from the capillaries to the surrounding tissue; and
4. Migration of macrophages to the injured area.

Chemical mediators such as histamine, which are released from injured mast cells, cause dilation of the blood
vessels and bring additional blood flow to the affected area, resulting in redness and heat.

The increased permeability of the vessels allows fluids in the plasma to leak to the tissues. This produces the
swelling and pain associated with inflammation.
Soluble mediators, including acute-phase reactants, initiate and control the response. Amplification occurs
through formation of clots by the coagulation system and then the triggering of the fibrinolytic system.

As the endothelial cells of the vessels contract, neutrophils move through the endothelial cells of the vessel
and out into the tissues. They are attracted to the site of injury or infection by the chemotaxins mentioned
previously.

Neutrophils, which are mobilized within 30 to 60 minutes after the injury, are the major type of cell present in
acute inflammation. Neutrophil emigration may last 24 to 48 hours and is proportional to the level of
chemotactic factors present in the area. Migration of macrophages from surrounding tissue and from blood
monocytes occurs several hours later and peaks at 16 to 48 hours. Macrophages attempt to clear the area
through phagocytosis, and in most cases the healing process is completed with a return of normal tissue
structure.

However, when the inflammatory process becomes prolonged, it is said to be chronic, and tissue damage and
loss of function may result. Specific immunity with infiltration of lymphocytes may contribute to the damage.
Thus, a failure to remove microorganisms or injured tissue may result in continued tissue damage.