Some Immunological Aspects of
Various Types of
Specific Acquired Deficient
Immune Status (SADIS) following
Various Kinds of Microbial Infection
- 3. the leukemia type .(Lk-type) of SADIS
R.A. Handojo*, Anggraeni Ingg rid Handojo**
* The Indonesian Association of Pulmonologists
** The TB Centre of Surabaya
Like the Tb-type of SADIS, the leukemia-type (Lk-type) of
SADIS may produce primary malignancies and unlike the Tb-
type of SADIS, the Lk-type of SADIS may produce hematologic
malignancies located in tissues of organs of the host.
The primary hematologic malignancies as disease expres-
sion of the Lk-type of SADIS are characterized by the existence
of malignant proliferation of immuno-competent cells. Depend-
ing on location of the proliferating cells, the Lk-type of SADIS
produces leukemia when malignant proliferation of cells takes
place in blood, often also in bone marrow, and malignant lym-
phomas when malignant proliferation of cells occurs in lym-
phatic organs such as lymph nodes.
The diagnosis of hematologic malignancies can be based on
cytologic examination of smear preparation obtained from blood
or bone marrow and on histopathologic examination of biopsy
tissue obtained from lymph nodes- or bone marrow
(1)
. The
leukemias are characterized by the existence of neoplastic pro-
liferation of one of the blood-forming cells
(2)
and of abnormal
maturation and accumulation of white blood cells
(3)
. The differ-
ent types of leukemia are classified according to the cell type
involved and as acute or chronic depending on the duration of the
disease
(2)
.
Leukemias can be divided into the acute and chronic
leukemias also on the basis of clinical and hematologic features.
A block in maturation of lymphoid or granulocytic cells at the
primitive blast stage is characteristic for the acute leukemias.
These cells accumulate in bone marrow, peripheral blood and at
times in other tissues
(3)
. Chronic leukemias are also disorders of
maturation of cells resulting in accumulation of abnormal leukemic
cells in bone marrow, lymph nodes, peripheral blood, liver,
spleen and occasionally in other organs. These abnormal cells in
chronic leukemias are better differentiated than are the abnormal
cells in acute leukemias from morphological and functional
Naskah ini merupakan lanjutan dari naskah berjudul soma yang telah dimuat
dalam Wellcome Journal of Health edisi no. 5, Januari 1993 dan edisi nio. 6,
Mares 1993.
points of view
(3)
. Chronic lymphocytic leukemias are charac-
terized by the existence of progressive accumulation of small
lymphocytes that have abnormally long lifespan in blood, lymph
nodes, bone marrow, spleen and in other tissues
(3)
. The leukemic
cells in chronic lymphocytic leukemia most often appear as small
but otherwise normal lymphocytes which have low mitotic rates.
In about 95% of cases, the leukemic cells are B-lymphocytes
and in the remainder these cells are T-lymphocytes
(3)
. There is
evidence that abnormal cells in B-cell cases of leukemia derive
from a single clone. Abnormalities of both B- and T-cell func-
tions have been observed in patients suffering from chronic
lymphocytic leukemia
(3)
.
The human T-cell lymphotropic virus type I (HTLV-I) is the
prototype of microbial pathogens that may produce the Lk-type
of SADIS. This virus was discovered by the group led by Gallo
at the National Cancer Institute in 1980. This human oncogenic
RNA-virus which is also termed the adult T-cell leukemia virus
is a member of the retroviruses (Scheffer 1984; quoted from
Daenen S: Nederl. Tijdschr. v. Geneesk. 1984, 128, 957-960).
This RNA-virus was isolated from lymphocytes of a patient that
had a T-cell lymphoma located in the skin in 1980
(4)
. Retroviruses
are characterized by the possession of the enzyme "reverse
transcriptase". By means of this enzyme, a DNA copy can be
produced from viral genome during the replication cycle which
in this way can be integrated into the genome of the infected
cell
s
(). The oncogenic retroviruses are at present classified into
the B-type, the C-type and the D-type. The C-type of viruses are
the most important. These C-type of viruses are discovered as the
causative agents for several kinds of leukemia, lymphomas and
sarcomas in animals. The HTLV-I is a retrovirus of the C-type.
(Scheffer 1984: quoted from Daenen S: NTvG 1984, 128, 957-
960). There have been numerous reports on finding of type C
virus particles as based on electron microscopic examination in
plasma pellets or tissues obtained from patients suffering from
leukemia
(3)
.
Shortly after the discovery of HTLV-I in 1980 by Gallo et al.,
the adult T-cell leukemia virus (ATLV) was discovered in Japan
in patients suffering from an endemic form of leukemia. This
ATLV is now considered to be the same as or strongly related to
the HTLV-I. Striking concentrations of ATLV are detected in
some islands in south-west Japan (Scheffer 1984; quoted from
Daenen S: NTvG 1984, 128, 957960). Soon after the isolation
of HTLV-I as the first retrovirus, a causal relationship can be
established between the virus and an aggressive form of leukemia,
the socalled "adult T-cell leukemia"
(6)
.
Beside the adult T-cell
leukemia, HTLV-I is associated with the development of the
"tropical spastic paraparesis", which is a consequence of a
progressive myelopathy caused by the virus
(7)
. The development
of myelopathy has been described a few months following
seroconversion
(8)
. The concomitant appearance of tropical spastic
paraparesis and the adult T-cell leukemia in one patient is rare
but has been described
(9)
. The incubation period is estimated to be
1520 years
(8)
.
Assuming that immune spectrum of individual cases of
HTLV-I disease is (almost) identical to that of individual cases of
tuberculosis, acute HTLV-I disease represents the L-type
immune status, chronic form of HTLV-I disease the K-type
immune status and the adult T-cell leukemia the KK-type
immune status, which is termed the Lk-type of SADIS. (fig. 1).
Fig. 1 The Immune Spectrum of individual cases of HTLV-I disease
Immune status
LL
L
K
KK
Stage of disease:
Disease express:
acute
HTLV-I
disease
acute
HTLV-I
disease
spastic
paraparesis
chronic
HTLV-I
disease
among others:
tropical
Lk-type
of
SADIS
adult T-cell
leukemia
It is interesting to note that adult T-cell leukemia as disease
expression of the Lk-type of SADIS is found in only 14% of
HTLV-I infected individuals over their life time (Gallo; quoted
from Asian Med. News, August 8, 1989). The risk to contract the
disease following infection with HTLV-I is estimated to be about
4% when seroconversion has taken place before the age of 20
years". This implies that the greater part of HTLV-I infected
individuals maintain their LL-type, their L-type or their K-type
immune status over their life time and that a few may show
progression of their K-type immune status to the Lk-type of
SADIS, resulting in the development of the adilt T-cell leukemia.
Contributory factors to this down-grading reaction in the
immune spectrum of HTLV-I disease are reported to be ionizing
radiation and some chemicals
(7)
.
There are numerous reports on the finding of an increased
incidence of acute non-lymphocytic leukemia in patients with
non-neoplastic diseases that have been put under treatment with
cytotoxic drugs especially alkylating agents
(3)
. The risk of con-
tracting the acute non-lymphocytic leukemia appears to be
greater with combined irradiation plus chemotherapy
(3)
. The
above finding indicates also that progression of HTLV-I disease
following primary infection to the development of the adult
T-cell leukemia is a multistep process. Antibodies against
HTLV-I are detected in various populations in seesawing rates.
A relatively high seroprevalence was observed among others in
many parts of Africa where seroprevalence is seesawing between
520%
(11)
.
In approximately 100% of a group of Japanese patients
suffering from the adult T-cell leukemia, antibodies against
HTLV-I were found in serum°
)
and in 2050% of their healthy
relatives as well. Antibodies against various parts of the virus
have, as can be expected, the same pattern of dissemination as the
virus itself. In endemic areas in Japan, 30% of the adult popula-
tion have antibodies against the virus (Scheffer 1984; quoted
from Daenen S.: NTvG 1984, 128, 957960).
Observations done to date indicate that HTLV is not a
ubiquitary virus that is transmitted vertically through germ cells.
It was reported that although the route of transmission is not clear,
horizontal transmission of the disease to healthy subjects has to
be considered possible. Intimate contact is needed for trans-
mission, and direct cell to cell contact is crucial for the spread of
the virus
(12)
. Transmission of HTLV-I takes place through sexual
contact, by means of blood
(13)
and from mother to child
(7)
. It has
to be noted that HTLV-I has been isolated in patients from cell
culture of mononuclear cells from blood and from cerebrospinal
fluid
(14)
.
It is interesting to note that HTLV-I can be detected only in
T-cells, Neither the virus nor its RNA or proviral RNA has been
detected in the B-cells (Scheffer 1984; quoted from Daenen S.:
NTvG 1984, 128, 957960). There is long period of latency of the
disease. Being infected doesn't necessarily mean that a malignant
lymphoma will develop
(15)
.
Patients with the adult T-cell leukemia from Japan
(16)
and the
West Indies
(17)
had similar disease expression but almost all had
lymphadenopathy. There were often several patients found in
one family suffering from the adult T-cell leukemia
(16)
. Patients
dually infected with the human immunodeficiency virus type 1
(HIV-1), formerly designated the human T-cell lymphotropic
virus type III (HTLV-III), and HTLV-I tend to develop frank
AIDS more rapidly (Gallo; quoted from Asian Med. News,
August 8, 1989).
A few years following the discovery of HTLV-I by Robert
Gallo in 1980, a related virus was isolated from a patient suffering
from the "hairy cell leukemia", designated the human T-cell
lymphotropic virus type II (HTLV-II)
(18)
. The pathway through
which the HTLV-II produce the Lk-type of SADIS is supposed
to be similar to that of HTLV-I (fig. 2).
Hairy cell leukemia also termed leukemic reticuloendo-
theliosis is a chronic leukemia. This RNA-virus affects mainly
older adult males with presenting symptoms such as fatigue,
malaise, pancytopenia, splenomegaly and at times lymphade-
nopathy
(3)
. Pathologic findings are mainly found in bone marrow,
Fig. 2 The Immune Spectrum of individual cases of HTLV-II disease
Immune status
LL
L
K
KK
Stage of disease:
Disease express:
acute
HTLV-lI
disease
acute
HTLV-II
disease
chronic
HTLV-11
disease
Lk-type
of
SADIS
hairy cell
leukemia
liver, spleen and peripheral blood. Abnormal cells are found in
peripheral blood. Light microscopic examination reveals the
presence of irregular fingerlike projections of cytoplasm from
which the term hairy cell leukemia originates. These findings are
confirmed by electron microscopy
(3)
.
Disease expression of the Lk-type of SADIS other than
leukemia, is the malignant lymphoma. The prototype of micro-
bial pathogen that may produce the Lk-type of SADIS that gives
rise to the development of malignant lymphoma is the Epstein-
Barr virus (EBV) (fig 3). Like the adult T-cell leukemia and the
hairy cell leukemia, the malignant lymphomas brought about by
EBV are primary hematologic malignancies which means that
EBV is the causative microbial pathogen of the mentioned
malignancy. Primary infection with EBV results in the develop-
ment of acute mononucleosis infectiosa, which may occur at any
age. The vast majority of population are infected with this EBV
during childhood or adolescence. This EBV-infection often
doesn't produce any symptoms, but in approximately 50% of
adolescents and young adults, infection with the virus gives rise
to the development of infectious mononucleosis, also known as
the disease of Pfeiffer
(17)
. This virus infects preferably the B-
lymphocytes. Like other herpes viruses, this EBV shows lifelong
persistence in EBV-infected individuals, particularly in the B-
cells, the glandula parotis and the nasopharynx
(19)
.
Fig. 3 The Immune Spectrum of individual cases of EBV-disease
Immune status
LL
L
K
KK
Stage of disease:
Disease express:
acute
EBV-
disease
acute
mononucleo-
sis infect.
acute
EBV-
disease
acute
mononucleo-
sis infect.
chronic
EBV-
disease
chronic
mononucleo-
sis infect.
Lk-type
of
SADIS
NHL*
HD**
Note :
* NHL = Non-Hodgkin lymphoma
** HD = Hodgkin's disease
Acute infectious mononucleosis has fever, headache, pha-
ryngitis, generalized lymphadenopathy, splenomegaly, myalgia
and articular swelling as characteristic symptoms and signs
(16)
.
Peripheral blood examination reveals the existence of absolute
T-celland B-cell lymphocytosis. Atypical lymphocytes are found
up to 56% in peripheral blood
(16)
. Mononucleosis is a name
derived from the atypical mononuclear cells in blood like those
which were described for the first time by Downey and Mc-
Kintey
(20)
. These cells are especially related to a primary infection
with EBV, although they are also found in cytomegalo virus
disease, influenza B disease
(21)
. Beside the lymphocytosis,
neutropenia is found in approximately two third of patients
suffering from mononucleosis infectiosa
(22)
. Superinfection in
mononucleosis infectiosa could be accounted for by the
neutropenia together with T-cell suppression
(22)
.
Oedema of the
eyelids plus painful swollen fingers which might be observed
during the early stage of the disease are unusual manifestation
of mononucleosis infectiosa
(23)
.
Histologic examination reveals the presence of marked
lymphoproliferation in almost all lymphoid tissues which is
secondary to the entry of EBV into B-cells. This induces a short-
lived increase in B-lymphocytes which is followed by a marked
and prolonged T-lymphocyte response
(3)
.
Elevation of soluble CD25 (sCD25) levels are used to assess
the degree of lymphocyte activation in patients
(24)
. Stimulation of
T-lymphocytes in vitro gives rise to a rapid increase in CD25
membrane expression
(24)
. Nelson and coworkers showed in 1985
that in vitro activated T-lymphocytes also produce a soluble form
of CD25
(25)
. Soluble CD25 is the soluble fragment of Interleukin-
2 receptor also known as the soluble membrane receptor. It can
be shown by means of ELISA that the in vitro production of
sCD25 is a reflection of the degree of T-cell activation
(24)
. In
serum of patients with infectious mononucleosis elevated soluble
CD25 levels are encountered
(26)
. In serum of healthy individuals,
low levels of sCD25 can be found which are considered products
of a normally functioning immune system. The normal values of
sCD25 are in a rather narrow range of 325-405 U/ml
(24)
. Macro-
phages and B-lymphocytes produce sCD25 only in small amounts
in vitro
(24)
.
In patients with the adult T-cell leukemia, the hairy cell
leukemia and the non-Hodgkin lymphoma, there is a strong
CD25 expression on the cell membrane and the molecule is
continuously excreted in large amounts
(27)
. Serum levels up to
15000 U/mI have been reported
(24)
.
There is decreased delayed skin hypersensitivity to antigens
during the acute phase of mononucleosis infectiosa
(3)
. Recent
studies suggest that the T-cell lymphocytosis which is found in
response to primary EBV-infection of B-cells is a suppressor T-
cell response thereby limiting the proliferation of B-cells and
possibly preventing the development of malignant transforma-
tion
(3)
.
Following infection with EBV, antibodies of the IgG and the
IgM classes are produced against the viral capside antigen
(EBVCA)
(16)
. The presence of IgM antibodies against the capside
antigen ofEBV indicates that primary infection with the virus has
taken place
(21)
. The 1gM antibodies disappear following primary
infection; IgG antibodies on the other hand, show lifelong persis-
tence
(16)
. Antibodies against the early antigen complex (EBVEA)
are also found following infection with EBV. This early antigen
complex consists of proteins which are synthesized by the virus
during primary infection
(16)
. Most interesting to note is the
persistent presence of antibodies against EBVEA, often in high
titers. Positive EBVEA titers are found in patients who have the
Burkitt lymphoma and some forms of nasopharynx carcinoma.
Also in healthy individuals, positive titers of EBVEA can be
observed in periods of decreased immunoprotective capacity,
such as in the elderly, during pregnancy or during the advent of
immunosuppressive agents
(20)
. Antibodies against the nuclear
antigen (EBVNA) are synthesized late following primary infec-
tion. These antibodies are produced in the nucleus of EBV-
infected B-lymphocytes and remain lifelong in the body of the
hose
(16)
.
The diagnosis of mononucleosis infectiosa is confirmed by
the presence of striking lymphocytosis with atypical lympho-
cytes as a rule, the presence of specific heterophyl antibodies
(reaction of Paul Bunnell) and the presence of specific antibodies
against the viral antigens (EBVCA, EBVEA, EBVNA)
(28)
.
In general, spontaneous recovery from EBV-disease has
been observed in the vast majority of patients suffering from
primary mononucleosis infectiosa. In a few however, symptoms
of primary EBV-disease may persist for several months to
several years. Members of families with the recessive immu-
nodeficiency syndrome, the Duncan syndrome which is an
x-linked immunodeficiency syndrome, die due to overwhelming
infection during the acute stage of mononucleosis infectiosa, or
they get agammaglobulinemia subsequently, or malignant
lymphoma many years later
(29)
.
Multiple and repeated endogenic and/or exogenic reinfec-
tions with EBV following primary acute EBV-disease, may give
rise to the development of a downgrading reaction in the immune
spectrum of the disease, resulting in the progression from the L-
type to the K-type and further to the KK-type immune status
which may be either the Tb-type or the Lk-type of SADIS. It is
int
r
iguing to speculate that when smoking is the contributory
factor for immune status of chronic EBV-disease to progress to
the Tb-type of SADIS, ionizing radiation and some chemicals are
the potential contributory factors for immune status of chronic
EBV-disease to progress to the Lk-type of SADIS. Disease
expression of the Tb-type of SADIS due to EBV is the epithelial
malignancy known as the nasopharynx carcinoma and that of
the Lk-type of SADIS due to EBV is the lymphoid malignancy
which may be either the non-Hodgkin lymphoma (NHL) or the
Hodgkin's disease (HD). Chemotherapy using cyclosporine may
in the long run lead to the development of malignancies due to
aspecific immunosuppression
(30)
. Of the 661 patients with
nephrotic syndrome under treatment with cyclosporine, five
were found to contract malignancy
(31)
. Of the five patients that
contracted malignancy following- prolonged treatment with
cyclosporine for nephrotic syndrome, two had the Hodgkin's
disease and three had carcinoma
(31)
.
Lymphoid malignancy or lymphoma malignum is a malig-
nant disease of the lymphoid .system which comprises the non-
Hodgkin lymphoma, the Hodgkin's disease and the multiple
myeloma. The adult T-cell leukemia is a variant of the lymphoma
malignum
(15)
. Non-Hodgkin lumphoma is defined as auto-
nomously growing and clonal proliferation of lymphocytes
(32)
.
The NHLs are a heterogeneous group of malignancies which
primarily involve lymphoid tissue. Relation between EBV and
the malignant lymphoma was established
(15)
. It appears that there
is an association between a form of NHL in Africa, the Burkitt
lymphoma and evidence of infection with EBV
(33)
. There is high
incidence of antobodies to EBV antigens especially the EBV
early antigen (EBVEA) in Burkitt lymphoma
(3)
. Positive EBVEA
titers are also found in patients suffering from some forms of
nasopharynx carcinoma
(20)
.
There are NHLs of the B-cell as well as of the T-cell type.
The greater part of NHLs are of the B-cell type
(33)
and that most
of the B-cell lymphoma derive from lymphocytes which are
present in the follicle centre of the cortex of lymph nodes
(34)
. Non-
Hodgkin lymphomas are reflections of the stages of differentia-
tion of T- and of B-cells
(35,36)
. The prognosis of T-cell lymphomas
is in general poorer than that of B-cell lymphomas
(34)
.
In order to know whether NHL is of B-cell or of T-cell type,
immunophenotyping has to be carried out beside the histopa-
thologic examination of the malignancy
(21)
. Phenotyping of tumors
of the lymphatic system is based on the insight that they consist
pretty much of uninhibited growing cells which belong to one
clone (monoclonal proliferation), that cells of this clone are
almost all in the same stage of maturation (differentiation arrest)
and that this stage can be located somewhere in the normal
development of the lymphatic system
(1)
.
It is sometimes difficult to differentiate between a reactive
process and a malignancy based on histopathologic abnormality
in lymph node follicles. Tumors are (almost always) monoclonal
and the existence of a monoclonal pattern is of direct diagnostic
value
(1)
. There are nodal and extranodal locations of NHL, i.e. in
central nervous system and the gastro-intestinal tract
(33)
.
Approximately 40% of NHLs are located extranodally
(37)
. The
median survival is best for patients with B-cell lymphoma, less
for patients with T-cell lymphoma and least for patients with non-
T-non-B- cell lymphoma
(38)
. The Burkitt lymphoma is a B-cell
lymphoma
(3)
. There is strong expression of CD25 on cell
membrane in patients with NHL; this molecule is continuously
excreted in great numbers
(27)
. Serum levels of sCD25 is a reflec-
tion of the total tumor mass and that serum levels decrease to
normal values following successful cytostatic therapy
(24)
.
Hodgkin's disease (HD) is a lymphoproliferative disorder
which means there is neoplas tic proliferation in lymph nodes
(39)
.
The cause of HD is unknown, but a number of features point to
a viral aetiology perhaps with altered protective immunity. At
present, the most likely causative agent appears to be the Epstein-
Barr virus
(39)
. The disease is characterized histopathologically by
the presence of the Reed-Sternberg cells. It is generally accepted
that the malignant cell is the Reed-Sternberg cell
(39)
. The origin
of the Reed-Sternberg cell and its mononuclear variants remains
controversial. Different investigators have presented evidence
implicating the T- and the B-cell and the macrophage-monocyte
as the cell of origin in Hodgkin's disease. Current evidence
favours the macrophage-monocyte as the primary malignant
cell(
3
). Cabanillas et al. suggested that the malignant cell of HD
is a B-cell(
40
). The Reed-Sternberg cell is also reported to be
lymphocytic in origin and may be of T-cell or of B-cell pheno-
type
(39)
.
Lymphocyte predominance which may be diffuse or no-
dular, is encountered in about 10% of cases of Hodgkin's disease.
The nodular form of HD has now been shown to be a B-cell
lymphoproliferative disease. Depletion of lymphocytes is com-
paratively rare in Hodgkin's disease
(39)
. Lymphocyte predomi-
nance type is encountered in younger patients, is usually limited
in extent and has an excellent prognosis. Most investigators
believe that the lymphocytic infiltrate found in histopathologic
lesions of HID represents host cellular immune response against
the tumor and correlation with a favourable prognosis. Patients
with lymphocytic predominance therefore have a strong host
immune response against the tumor
(3)
.
Lymphocyte depletion type is at the opposite end of the
spectrum of HD, usually presenting with widespread disease and
constitutional symptoms and having a poor prognosis. Patients
with the lymphocyte depletion type of HD show a failure of
response of the immune system to the tumor
(3)
.
In the spectrum of chronic infectious diseases which may
progress to SADIS, the lymphocyte depletion type of HD is
located nearer to the leprosy-type of SADIS than to the tuber-
culosis-type of SADIS. (fig. 4). Defects in cell-mediated immu-
nity are found in HD which can be demonstrated by doing skin
testing and in vitro transformation testing in response to mitogens
and antigens
(3)
.
Fig. 4 The spectrum of various types of SADIS
Microbial
pathogen
Type of
SADIS
Disease
expression
Lympho-
cytes
M. tuberc.
Helicob. pylori
EBV, HBV, HCV,
HPV, HSV
HTLV-I, HTLV-U
EBV
HTLV-III(HIV-1)
M. leprae
Tb-type
Tb-type
Lk-type
Lk-type
Lp-type
Lp-type
epithelial
carcinoma
epithelial
carcinoma
leukemia
NHL*
Hodgkin
'
s dis.:
AIDS**
LL-type leprosy
predominance
predominance
predominance
predominance
predominance
depletion
depletion
depletion
* NHL = Non-Hodgkin Lymphoma
** AIDS = Acquired Immuno Deficiency Syndrome
It is important to note that patients must be tested before
chemotherapy and radiotherapy which are themselves immuno-
suppressive
(3)
, especially when dealing with patients suffering
from HD of the lymphocyte depletion type. The defect in
advanced HD includes a disproportionate excess of suppressor
lymphocytes despite tje existence of overall lymphocyte deple-
tion with frequent lymphopenia
(3)
.
As was postulated by Boveri in 1914, transition of normal to
malignant proliferation of cells is brought about by chromosome
aberrations
(41)
. There are a lot of correlations between specific
chromosome abnormalities and disease characteristics in the
NHL and the disease of Hodgkin
(42)
. It can be assumed that
aberrations found in both the disease of Hodgkin and the non-
Hodgkin lumphoma play a role in the emergence of unregulated
growth in general and that aberrations found in either one of the
above diseases play a role in the development of the ultimate
phenotype of the disease, either in the direction of NHL or in the
direction of the disease of Hodgkin
(42)
. The chances of survival of
HD are much better than that of non-Hodgkin lymphoma
(34)
.
Disease expression of the Lk-type of SADIS is the primary
hematologic malignancy located in tissues of organs of the host.
The development of primary hematologic malignancy is based
on the existence of malignant proliferation of immunocompetent
cells. Like in the solid malignancy as disease expression of the
Tb-type of S ADIS which has lymphocyte predominance, entrap-
ment of microbial pathogens in the histopathologic lesions of the
malignancy likely occurs in the primary hematologic malignan-
cies which makes the disease not any more infectious except
probably in the lymphocyte depletion tupe of Hodgkin's disease.
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Proper words in proper places make the true definition of a style