JOURNAL OF ENDODONTICS I VOL 3, NO 9, SEPTEMBER 1977
I m p o r t a n c e of t h e l e u k o c y t e to
d e n t a l and p u l p a l h e a l t h
H. R. Stardey, DDS, MS, Gainesville, Fkt
All of us have been intrigued by the
esoteric scientific story of the detailed
activities of the leukocyte as described
by Dr. Goldstein. You have heard a
few bad things about leukocytes that
can alarm you. Yet, in perspective,
one cannot live without them and
there is much in dentistry that
could not be successful without them.
Keep in mind how few patients there
are with these strange immunologic
diseases (rheumatoid arthritis, poly-
arteritis nodosa, systemic lupis erythe-
matosus, glomerulonephritis, serum
sickness, and emphysema) as com-
pared with the total population. 1
Evidently one must take the good
with the bad. If the leukocyte does
what it is supposed to do, everything
is fine. If it does not, then there is
trouble.
I want to discuss for a few moments
the good things of leukocytes. Outside
of your blood stream your contact
with leukocytes is minimal. They
come into your saliva from the gingi-
val crevices and they coat your bron-
chi and gut, acting as protective sol-
diers. Of course, you are exposed to a
lot of dead ones everytime you drink
milk, about 2,500,00 in a half pint of
milk. 2
As you have heard previously, in
the combat against infection the leuko-
cytes constitute the first line of de-
fense, s.4 Phagocytosis (the process of
cells eating) is the essence of this de-
334
fensive system, and the overall man-
ner in which it functions can be di-
vided into several stages: In the first,
the bone marrow produces and mobi-
lizes leukocytes in prodigious num-
bers. Second, bacterial products or in-
flammatory mediators interact with
serum factors, including complement,
to attract phagocytes into injured or
invaded areas by chemotaxis. Third,
factors in normal serum, particularly
gamma globulin and the first four
components of complement, opsonize
microbes, rendering them tasty to the
phagocytes. Fourth, the phagocyte in-
gests opsonized microorganisms, encas-
ing them within phagocytic vesicles.
Fifth, cytoplasmic structures, as de-
scribed by Dr. Goldstein, that contain
hydrolytic enzymes fuse with the
phagocytic vesicles, secrete their con-
tents therein, and disappear--a proc-
ess called degranulation. Sixth, at the
same time, the phagocytes generate
hydrogen peroxide, the most impor-
tant antimicrobial agent within the
phagocytic vesicles. Therefore, peroxi-
dation is the major determinant lead-
ing, finally, to microbial killing. 3
However, the first problem is to get
enough leukocytes to the site of in-
jury as soon as possible. In order to do
this, you need a leukocyte reserve.
The production of leukocytes occurs
in the bone marrow, an organ that,
if totally combined, would be about
the size af a liver. Every hour the
bone marrow produces about 5 billion
leukocytes5 or about 126 billion leu-
kocytes per day in a 70 kg (154 lb
man4). If you packed all these white
cells together, they would weigh about
80 gm a (5 oz or about the weight of
three packs of cigarettes). This vast
number of new cells is necessary to
maintain normal circulatory levels
(4,000-11,000/cu mm) because the
half-life of the mature leukocyte in the
blood is only six to seven hours. 4,7
Leukocytes in the standby reserve
can be quickly released in response to
chemotactic signals. One can imagine
the swarming leukocytes riding down
a vascular channel, in response to sig-
nals from the bone marrow, to a site
of infection like microscopic missiles
homing in on an enemy target. 5
Approximately half of the leuko-
cytes are rolling along and circulat-
ing freely, and the others are adhering
to the walls of the capillaries (Fig 1,
top left) by a process called margina-
tion. Margination is a function of cell
stickiness, and sticking to endothelial
surfaces is the first step in getting out
of the blood and into the tissues. 6
The slightest injury or irritant caus-
es a prompt and marked increase in
the number of leukocytes sticking to
the endothelium and passing through. 8
Where the leukocytes are needed in
the tissues, they simply crawl through
the capillary wall (so-called diape-
desis) out of the bloodstream and

into the combat zone 5 (Fig 1, top
right, bottom left).
The process of coating particles
with serum proteins, which accelerates
phagocytosis, is called opsonization
(to prepare for eating). Even George
Bernard Shaw in his play The
Doctor's Dilemma pointed out that
phagocytes won't eat the microbes
unless the microbes are nicely buttered
for them, the butter being globulin.
The patient manufactures the butter
for himself all right; but the manu-
facturing of that butter, which is
called opsonin, goes on in the system
sporadically with many ups and
downs. The one genuinely scientific
treatment for all diseases is to stimu-
late the phagocytes. The major clini-
cal cause of defective ingestion of
microorganisms is subnormal opsonic
activity in the serum. 4
Leukocytes kill bacteria by pro-
ducing such substances as superoxide
and hydrogen peroxide. The genera-
tion of such chemicals is collectively
termed the respiratory burst, s Leuko-
cytes rapidly render bacteria incapable
of multiplying, but they have only
30 seconds to kill the microorganism
or the leukocyte itself will be de-
stroyedP Metchinkoff wrote as early
as 1891 that leukocytes are able to
ingest many microbes, but do not
necessarily kill and digest all the
microbes they englobe. He pointed
out that some microbes actually
multiply within leukocytes and then
invade the whole body. lo
Any malfunction of a step or steps
in this framework of the defensive
system leads to an increased "suscepti-
bility to infection." Any derangement
produces a characteristic clinical pic-
ture, and whether the leukocyte or
the macrophage is involved, or both,
dictates its degree of clinical severity. 3
There are many diseases where the
patients are obviously sickly and there
is no problem understanding their in-
creased susceptibility to infection.
Such patients may have congenital neu-
JOURNAL OF ENDODONTICS I VOL 3, NO 9, SEPTEMBER 19';7
t
I cated by margination (H&E, orig mag
it\
!
11
$ p 114.)
o
tropenia4,11; cyclic neutropenia4,7,1z;
chronic granulomatous disease (the
leukocytes are unable to generate
hydrogen peroxide)a,s,12; Di George's
syndrome, no thymus gland or con-
genital aplasiala,~4; agammaglobulin-
emia, no plasma ceils or anti-
bodies1~ sickle-cell anemiaS~
neoplastic diseases6,17; rheumatoid
arthritislS; dermatomyositis; vitiligo;
regional ileitus; thrombocytopenialS;
alcoholic cirrhosis3,17,19,2~ and auto-
immune disease syndrome. ~8
But the question is this: When is
the average, reasonably healthy ap-
pearing individual's capacity for
Fig 1--Top left: Leukocytes (arrows)
have accumulated along intima o/
injured vessel wall (stickiness indi-
x450). (Reprinted, by permission,
from Morrey and Nelsen, Dental
Science Handbook, Washington, US
Government Printing Office, 1970,
p 113.) Top right: Leukocytes
(arrows) push through dilated vascular
wall (diapedesis) (H&E, orig mag
x 400). Bottom left: Leukocytes
(arrows) have escaped through injured
vessel wall and are located outside
vessel in connective tissue (H&E,
orig mag x450). (Reprinted, by per-
mission, from Morrey and Nelsen,
phagocytosis so malfunctioning or de-
ficient that organisms can gain a foot-
hold and multiply?
In life, even under the worst cir-
cumstances, people have always been
of relatively minor interest to the vast
microbial world. The production of
disease is not the rule. Disease usually
results from inconclusive negotiations
for symbiosis, an overstepping of the
line by one side, the microorganism,
or the other, the h o s t - - a biologic
misinterpretation of borders. 17,~1 It is
apparent that humans become infected
with only a small fraction of the many
microorganisms to which they are ex-
335

Fig 2--Low-power view of dense,
chronic, inflammatory cell in[iltrate
(H&E, orig mag x35). (Reprinted,
by permission, [rom Stanley, Swerd-
low, and Buonocore, JADA 73:132
July, 9 1967 by American Dental
Association.)
posed, and that a still smaller per-
centage of such host-parasite inter-
action ever results in disease. 22
But what leads to this imbalance or
misinterpretation of borders in a
healthy individual? One frustrating
dental problem is related to what
finally decides that a tooth will un-
dergo an episode of clinical acute ir-
reversible pulpitis. Certainly condi-
tions remain pretty much the same
most of the time, but then one day
"all hell breaks loose."
Since the study of Kakehashi,
Stanley, and Fitzgerald 2a on germfree
animals, dentists have come to be-
lieve that ultimately infection is the
chief cause of pulp death. Numerous
events and circumstances make the
pulp susceptible to infection, but it is
probably never a direct one-to-one re-
lationship, that is, a direct infection
of a normal pulp that leads to pulp
death.
Experience in examining thousands
of pulps indicates that a pure, acute
inflammatory lesion seldom exists ex-
cept following severe traumatic epi-
sodes or cutting a cavity preparation
in a normal tooth. In the majority of
336
JOURNAL OF ENDODONTICS I VOL 3, NO 9, SEPTEMBER 1977
Fig 3--Severe response
o/dental pulp to intruding
bacteria invading repara-
tive dentin (H&E, orig mag
x63) (.from Reeves and
StanleyST).
cases, the demise of the pulp starts
with a chronic lesion that has become
acutely exacerbated with the appear-
ance of leukocytes.
In cutting a cavity preparation in a
normal tooth, a typical inflammatory
response of varying degree routinely
occurs and lasts 10 to 30 days. The
acute inflammatory phase with leuko-
cytes predominating peaks somewhere
between three and five days, but soon
mononucleated cells predominate. By
15 days the cellular response is
diminishing; by 30 days, 90% of all
the inflammatory cells have de-
parted .24
But suppose you start with a tooth
possessing an established chronic
lesion of a severe degree (Fig 2) due
to caries or previous restorative pro-
cedures, especially involving unlined Fig 4---Colonies of cariogenic
composites. The lesion is intensely in- streptococcal microorganisms
within individual dentinal tubules of
filtrated with chronic inflammatory
rat molar (orig mag (Re-
cells, too many to count. This is not printed, by permission, [rom Morrey
unusual in a diseased tooth requiring and Nelsen, p 123.)
restoration even in the absence of
clinical symptoms. Nature may have
established a level of chronic inflam- pulpal lesion with dilated capillaries
mation within a pulp that is accepta- may permit the escape of micro-
ble, asymptomatic, and in balance; organisms into the pulp tissue, so-
however, if you raise that level of called anachoresis. After escaping,
irritation further with restorative pro- these microorganisms are usually de-
cedures, such a tooth may become stroyed. Technically, the pulp with a
acutely exacerbated and symptomatic. chronic lesion can be exposed to a
Every ,time you clench your teeth bacteremia at least a dozen times a
together or chew, a flood of micro- day. For the next hour or so the
organisms leaves your gingival tissues, leukocytes, with the help of macro-
enters your blood stream and creates phages, are phagocytizing these micro-
a transient bacteremia. During such organisms until the tissues are made
an episode of bacteremia a chronic free of them again. So nothing is ap-

parent clinically. That chronic lesion,
regardless of its cause, is under the
control of the pulp tissues locally and
the body systemically, a sort of
"detente." But if things go wrong,
escaped microorganisms begin to
multiply and a tooth develops an acute
pulpitis.
What conditions may have occurred
recently or may presently exist that
could produce phagocytic defective-
ness in a normal appearing healthy
individual and make him more sus-
ceptible to infection are listed as
follows:
--previous splenectomy17,2~;
--previous radiation therapy17,26;
- - d r u g intake: cytotoxic drugs for
implants, 27 colchicine for gout and
familial Mediterranean fever, z7 ste-
roids for many diseased condi-
tions,6,17, 2r'29 salicylates taken in large
quantities,6, 2s and epinephrine6;
--infections of various types17; hep-
atitis 17,3o; severe pneumoeoecal pneu-
moniaZl; mycoplasma infections4,3~-a4;
gram-negative infections33; an over-
whelming focal infection of organisms
of any kind, greater than 100,000
bacteria per gram of tissueZS; influ-
enzas A and B, varicella (chicken
pox), herpes simplex, and measles
(these infections create a lymphopenia
due to the production of lymphocyto-
toxic antibodies); and rubella (Ger-
man measles) ;34
--legal drunkenness ( 150-rag
ethanol/per 100 ml)6,2r,zs;
--extreme exercise--reduces sticki-
ness of leukocytes6;
--hemodialysis---all leukocytes pool
in lungs6; and
- - a g i n g - - o v e r 70 years, ae
Also, there are dental conditions
that possibly can lead to phagocytic
defectiveness. Examples of such con-
ditions are caries, reduction in pulp
size by secondary dentin and repara-
tive dentin formation, and reduction
in pulp vasculature by pulp stones,
dystrophic calcifications and sear
tissue.
JOURNAL OF ENDODONTICS VOL 3, NO 9, SEPTEMBER 1977
Fig 5--Top le[t: Large
pulp in premolar o[ lO-
year-old white girl; only
primary dentin is present
(H&E, orig mag x4). (Re-
printed, by permission, [rom
Stanley and Ranney, Oral
Surg 15:1396 Nov, 9
1962 by C. V. Mosby Co.)
Top right: Pulp narrowed
in size by [ormation o[
secondary (S) dentin and
reparative (R) dentin
(H&E, orig mag x35).
(Courtesy o[ Dr. Harold
Berk.) Bottom right: Pulp
greatly reduced in size by
[ormation o[ reparative
(R) dentin (H&E, orig mag
x35). (Reprinted, by per-
mission, ]rom Thomas,
Stanley, and Gilmore,
JADA 78:788 April, 9
1969 by American Dental
Association.)
It has been said that for every pulp by reparative dentin formation
microorganism you see in a micro- (Fig 5, bottom right), pulp stones
scopic section, there are 25,000 un- (Fig 6, top left and right), dystrophic
seen. When caries reaches within 0.75 calcification (Fig 6, bottom left and
mm of the pulp, the sheer borden of right), and scarring (Fig 7) offers a
numbers of microorganisms sitting reasonable explanation for inefficient
over and on the pulp is overwhelm- phagocytosis. Most certainly, it is not
ing. 37 No doubt the buildup of lactic unreasonable to believe that if you
acid is also a factor here (Fig 3, 4). create an imbalance by adding trauma
From my experience the main fac- to a pulp of this type, nature may
tor in the balance and control of pulp not be able to handle it. Consequent-
survival is the 'bigger the pulp, the ly, the dentist must strive to minimize
more vascular the tissue and the more the trauma and irritation of all opera-
with which nature has to work. How- tive procedures so that nature can rid
ever, the capacity of the pulp to deal the pulp of any new lesion as soon
with future episodes of disease and as possible and help eliminate any old,
trauma is being continuously com- established lesion that might be
promised. With increasing age of a present, especially in an asymptomatie
patient, the pulp is normally being pulp.
continuously reduced in size by the Certainly, the evidence for lysosom-
almost daily deposition of a few al damage is convincing. An instance
microns of secondary dentin (Fig. 5, where this lysosome problem is very
top left and right). The added diminu- evident in dentistry is in the man-
tion of size and circulation of the agement of aphthous lesions (Fig 8).
337
 Fig 7--Top: Progressive scarring.
Notice prominent longitudinal bundles
of collagen (H&E, orig mag
(Courtesy of Dr. Harold Berk.) Bot-
tom: Extreme scarring of pulp; most
of true pulp tissue is replaced by
dense collagen (H&E, orig mag
x l O0).

Fig 6--Top left: Great number of

pulp stones scattered throughout an
otherwise normal pulp (H&E, orig mag
(Reprinted, by permission,
from Tiecke, Oral pathology, New
York,@ McGraw-Hill Book Co.,
1965, p 112.) Top right: Giant pulp
stone replacing 75% of coronal pulp
tissue (H&E, orig mag x35). (Re-
vrinted by permission, from Sandell,
Stanley, and White, Oral Surg 25:579
April, 9 1968 by C. V. Mosby Co.)
Bottom left: Massive formation of
dystrophic calcification replacing
80% of pulp tissue of extirpated vital
pulp (H&E, orig mag Bottom
right: Higher magnification of Figure
12 shows detailed formations of
dystrophic calcifications (Von Kossa,
orig mag

Fig 8--,4phthous lesion (arrow) in

white girl with medical history of
aphthous-ma]or stomatitis
(Sutton's disease).
888

Fig 9--Top: Premonitory
aphthous lesion, approxi-
mately six hours old, shows
mononuclear cells filtering
into surrounding epithelium
from affected capillaries
within connective tissue
papillae (orig mag
(from StanleySS). Bottom:
Preulcerative aphthous
lesion approximately 36
hours old. Lamina propria
is edematous and its capil-
laries dilated; some leuko-
cytes have escaped at top oJ
papillae, but predominant
cells are mononuclear, both
in the lamina propria and
in the epithelium, filtering
as edge canals become
wider (H&E, orig mag
(/rom StanleySS).
JOURNAL OF ENDODONTICS VOL 3, NO 9, SEPTEMBER 1977
It appears that aphthous stomatitis is
a localized hypersensitivity (hyperim-
mune) phenomenon where the first
tissue changes represented by a burn-
ing, tingling, wormy sensation coin-
cide with the infiltration of mono-
nucleated cells beneath the epithe-
lium (Fig 9).
Coinciding with this infiltration,
degenerative changes appear within
the covering epithelium. At a certain
point the epithelium lifts off, creating
an ulcer (Fig 10). At that time, the
leukocytes become the predominant
cell both on the surface and in the
superficial tissues. In some cases the
lesions persist for as long as six
months.3S-41
In these cases, so-called Sutton's
disease, a necrotic plug develops
within the ulcer that contains a frame-
work of dead cells, including leuko-
cytes; the necrotic plug is marginated
by a collar of lymphoid cells (Fig 11 ).
Nature makes no attempt to push in
endothelial cells and fibroblasts to re-
move the necrotic plug. In fact, it
appears that any cells that attempt to Fig lO--Top: Aphthous
do so immediately die and help en- lesion approximately 24
large the necrotic plug. hours old. Breach has oc-
However, with systemic steroid curred in epithelium, and
leukocytes /ill in breach.
therapy, such invading cells can sur-
Marginating epithelium
vive the approachment to the necrotic undergoes edematous
plug, produce new and healthy granu-
changes and appears to
lation tissue, and the plug begins to separate at connective tissue
disappear (Fig 12). 41 Evidently the junction. Edematous
steroid prevents the further escape of changes in deeper tissues
lysosomes from the leukocytes already separate collagen bundles
present, and the permeability of the (H&E, orig mag 63).
cellular membrane of the regenerating, Bottom: Higher-power view
invading cells is decreased so that they of lesion shown in Figure
can survive .the killing irritants of the 10, top. Notice that leuko-
necrotic plug, much like wearing an cytes /ill in epithelial
breach, and edematous
asbestos suit to a fire: 2 I do not know
changes within adjacent
what dentists would do without ste- epithelium. Notice number
roids in the management of such
o/filtering inflammatory
severe cases of aphthous stomatitis. cells in epithelium (H&E,
As you can see, Dr. Goldstein is orig mag (from
opening a door to a better under- Graykowski and othe rs4~
standing of the functions and mechan- 9 1966 by American
isms of the leukocyte and its contents. Medical Association).
339

Fig l l - - W e d g e o] tissue [rom large
palatal aphthous lesion typical o/
Sutton's disease, in which a prominent
necrotic plug (NP) sits on sur[ace o/
lesion with lymphoid collar subjacent
(arrows) ([rom DriscoU and othersSg).
With this kind of endeavor, new in-
formation may result and chemicals or
drugs be prescribed to correct the
phagocytic defects of certain patients.
Just recently, it has been shown that
latex particles, less than a micron in
size, when coated with glucose oxidase
and then incorporated by phago-
cytosis within deficient leukocytes of
patients with chronic granulomatous
disease correct the genetic defect.
They can induce the development of
the respiratory burst with HzOz
production. *z
In summary, therefore, the dentist
should be cognizant of the past and
present systemic condition of his pa-
tient. To ask pertinent questions and
to obtain relevant data are most im-
portant. T o consider all the conditions
that can contribute to a lowered resis-
tance or a reduced phagocytic attack
is critical and helps decide whether
to postpone treatment or provide ap-
propriate therapeutic coverage.
Dr. Stanley is chairman, department of
oral medicine, College of Dentistry, Uni-
versity of Florida, Gainesville, 32610.
Requests for reprints should be directed
to Dr. Stanley.
840
JOURNAL OF ENDODONTICS I VOL 3, NO 9, SEPTEMBER 1977
Fig 12--Aphthous lesion in process o]
healing. Notice organizing granulation
tissue with prominent vascular net-
work that has replaced necrotic plug.
New epithelium has covered this
particular area (orig rnag x130).
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