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Immunohistological Expression of Interleukin 16 in Human Tonsils
Matthias F. Kramer, MD;
Brigitte Mack;
Gerd Rasp, MD
Arch Otolaryngol Head Neck Surg. 2001;127:1120-1125.
ABSTRACT
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Background Interleukin 16 (IL-16) acts highly chemotactic on CD4-bearing cells.
Besides chemotaxis, IL-16 has numerous immunomodulatory effects, and not only
on T cells.
Objective To determine IL-16 expression in human tonsils.
Methods Tonsillar follicles were immunohistologically characterized to elicit
a possible cellular source of IL-16 expression.
Results The mantle zone of immature and mature B cells was CD22 immunoreactive
(ir), whereas the germinal center of activated B cells was CD23-ir. Plasma
cells that were CD38-ir were observed extrafollicularly beneath the epithelium
and within the germinal center. T cells were found most frequently in the
extrafollicular space, with a majority of CD4 cells. CD68-ir macrophages were
predominantly found within the germinal center. Immunostaining of anti–IL-16
revealed strong cytoplasmatic reactivity of extrafollicular cells and of cells
at the outer rim of the mantle zone. Numerous cells adherent to the stratified
squamous epithelium were IL-16-ir as well. Double immunostaining identified
CD4+ T cells as the major cellular source of IL-16 expression.
Furthermore, a population of CD22+ B cells at the outer rim of
the mantle zone expressed IL-16 as well.
Conclusions Interleukin 16 was mainly expressed in a typical CD4-like pattern in
human tonsils. Our data strongly suggest that CD4+ lymphocytes
constitute the major cellular source for IL-16. We hypothesize that the double-immunostained
CD4-ir and IL-16-ir cells represent activated T cells. Because CD22+ B cells at the outer rim of the mantle zone expressed IL-16 as well,
we conclude that this area might constitute the locus of IL-16–mediated
B-cell differentiation.
INTRODUCTION
INTERLEUKIN 16 (IL-16) is synthesized as a precursor molecule of 68
kd (pro–IL-16) that is processed by caspase-3. The cleavage results
in a 13-kd carboxy terminal peptide, which constitutes the bioactive form
of IL-16.1 Interleukin 16, a proinflammatory
and immunomodulatory cytokine formerly known as lymphocyte chemoattractant
factor, acts highly chemotactic on CD4-bearing cells. Effects of IL-16 are
transmitted by its surface receptor CD4.2
Effects of IL-16 on CD4+ T cells include chemotaxis, cell
adhesion, induction of HLA-DR, induction of cytokine synthesis, and induction
of IL-2 receptor expression (CD25).2-4
Furthermore, IL-16 is known as a CD4+ T-cell growth factor because
it is capable of inducing a G0 to G1 cell cycle change.3
The cumulative effects of these functions on CD4+ T cells are increased
CD4+ cell recruitment, priming for IL-2–responsive proliferation,
and protection against Fas-mediated apoptosis.2-3
Besides affecting T cells, IL-16 also acts on other inflammatory cells.
It is chemotactic on eosinophils and monocytes and induces HLA-DR expression
in the latter.2 Furthermore, IL-16 might constitute
an important mediator in cell-cell interactions of various inflammatory cells
such as dendritic, mast, or B cells.5-8
Most work to date has focused on the chemotactic activities of IL-16
and therefore on diseases characterized by tissue infiltration of CD4+ cells. In individuals with atopic asthma, IL-16 represents a major
source of lymphocyte chemotactic activity early after antigen challenge in
which the major cell of origin is the epithelium, although mast cells, CD8
and CD4 cells, and eosinophils were described as additional sources.9 Kaser and coworkers,8
on the other hand, suggested that activated T cells are a cellular source
of IL-16 expression. Dendritic cells were described recently as another source
of IL-16.8
Interleukin 16 is released from CD4+ T cells in response
to antigen, mitogen, histamine, or anti-CD3 stimulation. Interleukin 16 messenger
RNA and pro–IL-16 are constitutively expressed by CD4+ and
CD8+ T cells. But different from CD8+ T cells, processing
and release of bioactive IL-16 by CD4+T cells is activation dependent.1
An increased level of IL-16 after challenge has been described in asthma9-10 and in allergic rhinitis,11 in which IL-16 expression correlated with CD4 influx.
Recently, Kramer et al12 identified IL-16 as
a characteristic cytokine expressed in late-phase response after antigen challenge
in allergic rhinitis. Increased expression of IL-16 was demonstrated in other
chronic inflammatory processes characterized by CD4+ T-cell influx,
such as atopic dermatitis, or granulomatous inflammation, such as sarcoidosis
or tuberculosis,2, 13 multiple
sclerosis,14 and acquired immunodeficiency
syndrome.15 Even autoimmune diseases such as
systemic lupus erythematosus are characterized by increased levels of IL-16,
which correlate with disease activity.16
To our knowledge, IL-16 expression by tonsillar tissue has not been
studied to date. Tonsillar follicles belong to the organized mucosa-associated
lymphoid tissue of the Waldeyer ring.17 Their
B-cell and T-cell areas are the locus of lymphocyte differentiation and initiation
of mucosal immune responses. Intense B-cell– T-cell interactions take
place, suggesting a relevant role for IL-16 here.
Tonsils are locations of intense cell-cell interactions while promoting
immune responses. As described in the previous paragraphs, IL-16 has far more
immunomodulatory effects on various inflammatory cells than chemotaxis.
The aim of this study was to determine IL-16 expression in human tonsils.
Tonsillar follicles were immunohistologically characterized to elicit a possible
cellular source of IL-16 expression.
MATERIALS AND METHODS
Tonsils were obtained from 5 patients (mean ± SD age, 6.4 ±
1.4 years) undergoing routine tonsillectomy for recurrent tonsillitis without
acute exacerbation. An allergic condition was ruled out by in vivo (skin test)
and in vitro (Sx1 [identical to Phadiatop]; Pharmacia & Upjohn, Freiburg,
Germany) tests to exclude possible effects of an atopic disease.
Tonsillar follicles were immunohistologically characterized to elicit
a possible cellular source of IL-16 expression. B-cell differentiation and
activation occur during migration from the outer mantle zone toward the germinal
center.5 As a marker for immature and mature
B cells, we chose anti-CD22, as described previously.18
Expression of CD23 in B cells is associated with immunoglobulin isotope switching.
Therefore, CD23+ B cells are generally accepted to constitute activated
B cells.18 Anti-CD38 was taken for detection
of plasma cells.19 T-cell populations were
detected by anti-CD3 (pan T-cell marker), and T-cell subpopulations were identified
by anti-CD4 and anti-CD8. For detection of macrophages we chose anti-CD68
(clone KP1), as described elsewhere.20
IMMUNOHISTOCHEMISTRY
Specimens were shock frozen in liquid nitrogen and stored at –20°C.
Cryostat sections (5 µm) were postfixed with acetone for 10 minutes.
Thereafter, sections were rinsed in 0.05M phosphate-buffered saline solution
(pH 7.4). Endogenous peroxidases were blocked by incubation in 0.3% hydrogen
peroxide for 30 minutes. Nonspecific binding was minimized by incubation with
fetal calf serum (1:20) for 20 minutes. The avidin-biotin-peroxidase complex
method was used for detection of immunostaining, as described elsewhere.21 Briefly, the following antibodies were used: monoclonal
(mc) anti-CD3 (1:200), mc anti-CD4 (1:100), mc anti-CD8 (1:200), mc anti-CD22
(1:100), mc anti-CD23 (1:3000), mc anti-CD38 (1:2000), mc anti-CD68 (clone
KP1, 1:10 000, all mouse) (Dako, Glostrup, Denmark), and polyclonal anti–IL-16
(1:100, goat) (R&D, Wiesbaden, Germany). Slides were incubated with the
primary antibody for 1 hour. After washing, slides were incubated with a biotinylated
secondary antibody for 30 minutes (1:200) (Vector Lab, Burlingame, Calif).
An avidin-biotin-peroxidase complex (Vector Lab) was added for 30 minutes
after washing. Finally, peroxidase reaction was performed using 0.01% 3-amino-9-ethylcarbazole
(Sigma, Munich, Germany) as chromogen. Omission of the primary antibody abolished
the immunohistological staining completely. Haemalum staining was performed
as the last step of the procedure to counterstain the nuclei.
A "Zeiss Standard 25" light microscope (Carl Zeiss, Oberkochen, Germany)
was used. Photographs were taken on Kodak 160T film (Eastman Kodak, Rochester,
NY).
DOUBLE IMMUNOSTAINING
Double immunostaining was performed with anti–IL-16 using the
avidin-biotin-peroxidase complex (red) and alkalic phosphatase–antialkalic
phosphatase (blue) methods for the other previously mentioned antibodies as
described elsewhere.22 The avidin-biotin-peroxidase
complex method was carried out as described in the previous subsection. Briefly,
the alkalic phosphatase–antialkalic phosphatase method was carried out
via incubation of the primary antibody. A rabbit anti–mouse immunoglobulin
antibody (1:25) (Dako) was used as the secondary antibody. A 0.05M Tris-buffered
saline solution (pH 7.6) was taken instead of phosphate-buffered saline solution
as washing solution. Alkalic phosphatase–antialkalic phosphatase complex
(1:50) (Dako) was added thereafter. Fast Blue BB salt (Dako) was used as the
final staining substrate.
RESULTS
B-CELL AREA
The mantle zone of immature and mature B cells was CD22 immunoreactive
(ir), whereas the germinal center of activated B cells was CD23-ir. CD38-ir
plasma cells were observed extrafollicularly beneath the epithelium and within
the germinal center (Figure 1, Figure 2, and Figure 3).
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Figure 1. Immature and mature B cells of
the mantle zone of the tonsillar secondary lymph follicle are CD22 immunoreactive
(avidin-biotin-peroxidase complex method, Haemalum counterstain, x200).
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Figure 2. Staining by anti-CD23 detected
activated B cells in the germinal center of the tonsillar secondary lymph
follicle (avidin-biotin-peroxidase complex method, Haemalum counterstain,
x100).
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Figure 3. Anti–CD38 antibody–stained
plasma cells. Plasma cells were found extrafollicularly beneath the epithelium
and, as shown here, within the germinal center of the follicle (avidin-biotin-peroxidase
complex method, Haemalum counterstain, x200).
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T-CELL AREA
T cells (CD3+) were found most frequently in the extrafollicular
space, with a majority of CD4 cells. CD4-ir lymphocytes were observed in the
mantle zone of the follicle too, whereas CD4-ir cells were only occasionally
found in the germinal center (Figure 4, Figure 5, and Figure 6).
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Figure 4. CD3+ T cells were found
in the extrafollicular space of the tonsillar tissue. Diapedesis of the stratified
squamous epithelium by CD3+ T cells is shown (avidin-biotin-peroxidase
complex method, Haemalum counterstain, x200).
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Figure 5. Staining by anti-CD4 revealed
T-helper cells mainly in the extrafollicular space. Note few CD4+
T cells within the mantle zone and the germinal center (avidin-biotin-peroxidase
complex method, Haemalum counterstain, x200).
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Figure 6. CD8+ T cells were basically
restricted to the extrafollicular space. Comparing anti-CD8 with anti-CD4
staining showed that most T cells are CD4 immunoreactive (avidin-biotin-peroxidase
complex method, Haemalum counterstain, x200).
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MACROPHAGES
CD68-ir macrophages were inhomogeneously distributed within the tonsillar
tissue, with a predominance in the germinal center (Figure 7).
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Figure 7. Double immunostaining with anti-CD68
(clone KP1, blue) and anti–interleukin 16 (red) revealed an inhomogeneous
distribution of macrophages, with a predominance in the germinal center (avidin-biotin-peroxidase
complex: red; alkalic phosphatase–antialkalic phosphatase: blue; x200).
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EPITHELIUM
Invaginated stratified squamous epithelium formed tonsillar crypts.
Diapedesis of the epithelium by CD4-ir and CD8-ir cells was observed. Cells
adherent to the epithelium were CD4-ir and could be detected regularly.
IL-16 IMMUNOSTAINING
Immunostaining of anti–IL-16 revealed strong cytoplasmatic reactivity
of extrafollicular cells and of cells at the outer rim of the neighboring
mantle zone. Only a few cells within the germinal center were IL-16-ir (Figure 8). Several cells adherent to the
stratified squamous epithelium were IL-16-ir as well.
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Figure 8. Interleukin 16 (IL-16)–immunoreactive
cells were found mainly extrafollicularly and within the mantle zone of tonsillar
secondary lymph follicle. Only a few cells within the germinal center were
IL-16+ as well (avidin-biotin-peroxidase complex method, Haemalum
counterstain, x200).
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DOUBLE STAINING
Double immunostaining identified CD4+ T cells as the major
cellular source of IL-16 expression. Most IL-16-ir cells were also CD4-ir,
but not all CD4-ir T cells expressed IL-16. Furthermore, a population of CD22+ B cells at the outer rim of the mantle zone expressed IL-16 as well
(Figure 9, Figure 10, and Figure 11).
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Figure 9. Double immunostaining with anti-CD4
(blue) and anti–interleukin 16 (IL-16) (red) showed that the pattern
of IL-16 expression is similar to the expression of CD4+ T cells.
Most cells within the extrafollicular space appear double stained (dark brown).
These IL-16 and CD4-immunoreactive cells are suggested to constitute activated
T cells (avidin-biotin-peroxidase complex: red; alkalic phosphatase–antialkalic
phosphatase: blue; double stained: dark brown; x200).
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Figure 10. Double immunostaining with anti-CD4
(blue) and anti–interleukin 16 (IL-16) (red) at a high magnification.
Most cells within the extrafollicular space appear double stained (dark brown).
Note that within the extrafollicular space no cells other than CD4+
express IL-16, whereas not all CD4-immunoreactive T cells express IL-16. Interleukin
16 and CD4 double-immunoreactive cells are suggested to constitute activated
T cells (avidin-biotin-peroxidase complex: red; alkalic phosphatase–antialkalic
phosphatase: blue; double stained: dark brown; x400).
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Figure 11. Double immunostaining with anti-CD22
(blue) and anti–interleukin 16 (IL-16) (red) at a high concentration.
Presented is the mantle zone of a tonsillar secondary lymph follicle. Extrafollicular
cells at the upper parts of the figure are IL-16 immunoreactive (red), whereas
B cells of the mantle zone were CD22 immunoreactive (blue, compare with Figure
1). Note the double-stained cells (dark brown) at the outer rim of the mantle
zone. This zone is suggested to constitute the locus of IL-16–mediated
B-cell differentiation (avidin-biotin-peroxidase complex: red; alkalic phosphatase–antialkalic
phosphatase: blue; double stained: dark brown; x400).
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COMMENT
Immunohistological characterization of human tonsillar follicles displayed
the well-known structure of secondary lymph follicles: The mantle zone of
immature and mature B cells was CD22-ir, whereas the germinal center of activated
B cells was CD23-ir. The precursors of germinal center B cells are believed
to be mantle B lymphocytes.5 Germinal centers
represent antigen-dependent B-cell compartments responsible for proliferative
expansion of memory clones and differentiation to immunoglobulin-producing
immunocytes.5 CD38-ir plasma cells were observed
extrafollicularly beneath the epithelium and within the germinal center. T
cells were found most frequently in the extrafollicular space. CD4+
cells were dominant. CD4-ir lymphocytes were observed in the mantle zone of
the follicle too, whereas CD4-ir cells were only occasionally found in the
germinal center. CD68-ir macrophages were inhomogeneously distributed within
the tonsillar tissue, with a predominance in the germinal center. All this
is in accordance with results of other researchers5, 18
who described human tonsillar follicles using immunohistochemical analysis.
Immunostaining of anti–IL-16 revealed strong cytoplasmatic reactivity
of extrafollicular cells and of cells at the outer rim of the neighboring
mantle zone. Only a few cells within the germinal center were IL-16-ir. Several
cells adherent to the stratified squamous epithelium were IL-16-ir too. Double
immunostaining identified CD4+ T cells as the major cellular source
of IL-16 expression. Most IL-16-ir cells were also CD4-ir, but not all CD4-ir
T cells expressed IL-16. Furthermore, a population of CD22+ B cells
at the outer rim of the mantle zone expressed IL-16 as well. This immunohistological
distribution of IL-16-ir CD4+ T cells and IL-16-ir CD22+
B cells suggests that the outer rim of the mantle zone constitutes the location
of IL-16–mediated B-cell differentiation.
Immunohistological examination of IL-16 expression in human lymphoid
organs other than tonsils revealed similar results: examination of human lymph
nodes showed that IL-16 is immunohistologically expressed in lymphocytic cytoplasm
within T-cell zones extrafollicularly and only occasionally in lymphocytes
of the germinal center.23
Interleukin 16 was mainly expressed in a typical CD4-like pattern in
human tonsils. Unlike atopic airways, our data strongly suggest that CD4+ lymphocytes constitute the major cellular source of IL-16 in human
tonsils. Furthermore, and unlike atopic airways, CD8+ T cells,
the epithelium, or macrophages did not express IL-16, at least not by means
of immunohistochemistry. In addition, we found IL-16-ir CD22+ B
cells. These B cells might contribute to the observed IL-16 expression as
well.
Double immunostaining clearly identified CD4+ cells as the
major cellular source of IL-16 expression. Comparison with anti-CD3 staining
led us to believe that most of these CD4+cells are T cells. However,
CD4-bearing cells other than lymphocytes under this IL-16-ir cell population
cannot be excluded in the end but seem unlikely to be of relevant amounts.
Tonsillar T cells are suggested to enter the extrafollicular tonsillar
area through so-called postcapillary or high-endothelial venules from the
blood.5 Their extravasation and chemoattractance
are not understood.  ß-Leukointegrins are suggested to constitute
selective adhesion receptors.24 Our data suggest
chemotactic effects of IL-16 on these CD4+ T cells.
As described earlier in this article, IL-16 has far more immunomodulatory
effects on various inflammatory cells than chemotaxis. Interleukin 16 further
promotes cell adhesion, HLA-DR induction, and induction of cytokine synthesis
on T cells and acts as a T-cell growth factor.2-3
Induction of IL-2 receptor expression (CD25) is mediated by IL-16 as well,
leading to a synergistic activation of CD4+ T cells by IL-16 and
IL-2.4 The cumulative effects of these functions
on CD4+ T cells are increased CD4+ cell recruitment
and priming for IL-2–responsive proliferation.2-3
Tonsillar T lymphocytes have striking peculiarities: most are activated, express
IL-2 receptor (anti-Tac positive), and respond to IL-2 stimulation.5, 25 Furthermore, most of these activated
T lymphocytes are T-helper cells5, 26
and are localized mainly extrafollicularly.27
Results of in vitro studies5 have indicated
that these IL-2–activated T cells are involved in differentiation of
tonsillar B cells to plasma cells, which is indirectly supported by our data.
Furthermore, tonsillar B and T cells are characterized by more frequent DR
expression compared with blood lymphocytes.5
The abundant intrafollicular DR expression (B cells, T cells, dendritic cells,
etc) probably serves to modulate local interactions between antigen-presenting
cells, T cells, and B cells.5 Taken together,
our data point to IL-16 as a relevant factor in the immune response of human
tonsils. Different from CD8+ T cells, processing and release of
bioactive IL-16 by CD4+T cells is activation dependent.1 Therefore, our data might be interpreted as showing
that the observed IL-16-ir and CD4-ir cells constitute activated T cells.
Triple staining with IL-2 receptor promises to be a challenging but interesting
target for a future study.
Besides affecting T cells, IL-16 acts on other inflammatory cells too.
It is chemotactic for eosinophils and monocytes and induces HLA-DR expression
in the latter.2 Furthermore, IL-16 constitutes
an important mediator in cell-cell interactions of various inflammatory cells:
T cells and mast cells interact bidirectionally in various aspects of immune
response, in which IL-16 plays an important role,7
and T-cell–dendritic cell interactions also depend on IL-16.8 Interleukin 16 is important in B-cell–T-cell
interactions as well. For instance, B-cell precursors need IL-16 for their
maturation,6 which again is supported by our
finding of IL-16-ir CD22+ B cells. All these interactions are pivotal
parts in initiating and promoting an immune response and point to IL-16 as
a relevant factor.
CONCLUSIONS
Interleukin 16 is mainly expressed in a typical CD4-like pattern in
human tonsils. Our data strongly suggest that CD4+ lymphocytes
constitute the major cellular source for IL-16. We hypothesize that the double-immunostained
CD4-ir and IL-16-ir cells represent activated T cells. CD22+ B
cells at the outer rim of the mantle zone expressed IL-16 as well, leading
us to conclude that this area might constitute a locus of IL-16–mediated
B-cell differentiation.
AUTHOR INFORMATION
Accepted for publication February 7, 2001.
Corresponding author and reprints: Matthias F. Kramer, MD, Department
of Oto-Rhino-Laryngology/Head and Neck Surgery, Ludwig-Maximilians-University,
Klinikum Grosshadern, Marchioninistr.15, 81377 Munich, Germany (e-mail:
mkramer{at}hno.med.uni-muenchen.de).
From the Department of Oto-Rhino-Laryngology/Head and Neck Surgery,
Ludwig-Maximilians-University, Munich, Germany.
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