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Skin response to intradermal dna and rna in systemic lupus erythematosus.

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1284
SKIN RESPONSE TO INTRADERMAL DNA AND RNA
IN SYSTEMIC LUPUS ERYTHEMATOSUS
YRJO T. KONTTINEN, ERKKI TOLVANEN, EIJA JOHANSSON, SAKARI REITAMO,
and OTTO WEGELIUS
The local response of 18 patients with active
systemic lupus erythematosus to 0.1 ml of intradermally
injected 0.1% polymerized calf thymus DNA and synthetic double-stranded polyinosinic-polycytidylic acid
was studied. In 14 patients positive for DNA, 61 f 8%
of the inflammatory cells in the subepidermis at 24
hours were acid alpha-naphthyl acetate esterase-positive T lymphocytes. A leukocytoclastic vasculitis was
observed in the deeper dermis. Rheumatoid arthritis
patients and acne patients had negative responses. These
results indicated an abnormal cellular and humoral in
vivo response by patients with systemic lupus to DNA. It
is suggested that the epidermal Langerhans cells were
responsible for the topographic dichotomy of the local
DNA response. Test results were positive for polyinosinic-polycytidylic acid in 12 patients, for DNA in 14
patients, and for both in 9 patients. In the 9 patients
with positive results for both tests, comparison of responses to each test indicated that the reaction intensity
was dependent on the patient and not on the type of
polynucleotide acid that was injected.
From the Fourth Department of Medicine and the Department of Dermatology, University of Helsinki, Helsinki, Finland.
Supported by the Sigrid Juselius Foundation, Finska
Lakaresallskapet, Finnish Foundation For Rheumatic Diseases and
Finnish Foundation For Allergic Diseases.
Y j o T. Konttinen, MD: Postdoctoral Fellow, Fourth Department of Medicine, Helsinki University Central Hospital; Erkki
Tolvanen, MD: Research Assistant, Fourth Department of Medicine, Helsinki University Central Hospital; Eija Johansson, MD:
Postdoctoral Fellow, Department of Dermatology, Helsinki University Central Hospital; Sakari Reitamo, MD: Postdoctoral Fellow,
Institute of Cancer Research, College of Physicians & Surgeons,
Columbia University, New York; Otto Wegelius, MD: Professor of
Internal Medicine, Fourth Department of Medicine, Helsinki University Central Hospital.
Address reprint requests to Y j o Konttinen, MD, Fourth
Department of Medicine, Helsinki University Central Hospital,
Unioninkatu 38, SF-00170 Helsinki 17, Finland.
Submitted for publication November 2, 1981; accepted in
revised form June 1, 1982.
Arthritis and Rheumatism, Vol. 25, No. 11 (November 1982)
Some tissue damage in systemic lupus erythematosus (SLE) is mediated via circulating or locally
formed immune complexes (1,2). However, clinically
normal SLE skin also has immunoglobulin-complement deposits in the epidermal-dermal border (3), and
in ultraviolet light-induced skin lesions, the lupus
band test first becomes positive long after the appearance of skin lesions (4). These findings cast some
doubt on the relevance of these local immune complexes to the pathogenesis of SLE skin lesions.
A feature more characteristic of SLE skin lesions is the presence of a mononuclear cell infiltrate
(5). In addition, increased blast transformation, cell
proliferation, and lymphokine production as a response to nuclear antigens in vitro have been observed
in SLE (6-10). These in vitro responses are dependent
on the type and quantity of the antigenic stimulus, type
of serum used in the culture medium, and other culture
conditions (9). In addition, in vitro and in vivo responses to the same initiating stimulus can be different
(7). The concentration or even absence of antinuclear
antibodies in seronegative lupus does not correlate
with the expression of cellular immunity ( 8 , l l ) . Because the extrapolation of in vitro findings to the in
vivo situation may be difficult, we decided to study the
local inflammatory responses in SLE patients to intradermally injected native calf-thymus DNA and a synthetic double-stranded RNA polymer, polyinosinicpolycytidylic acid (poly I poly C).
-
MATERIALS AND METHODS
Patients. Eighteen patients in the study had 4 or more
of the preliminary criteria of the American Rheumatism
Association for SLE (12). Patients receiving antimalarial
treatment were excluded because they show a decreased
skin response to native DNA (13). The control group includ-
DNA AND RNA SKIN TESTS IN SLE
Figure 1. Alpha-naphthyl acetate esterase staining of a subepiderma1 infiltrate in a DNA skin test at 24 hours. Most of the inflammatory cells in this infiltrate are T pattern lymphocytes (arrows).
(Original magnification x 1,000.)
ed 10 patients with classic or definite rheumatoid arthritis
according to the criteria of the American Rheumatism Association (14), and 5 patients with acne.
Performance of the DNA and RNA skin tests. We
injected intradermally into each patient's thigh at 2 separate
sites at least 10 cm apart 0.1 mg of polymerized calf thymus
DNA (Calbiochem, Lucerne, Switzerland) and synthetic,
double-stranded poly I poly C (Miles Laboratories, Elkhart, IN) in 0.1 ml of phosphate buffered saline (pH 7.4),
0.1M NaCl; 0.1 ml of phosphate buffered saline was used as
a control. The calf thymus DNA contained not less than 85%
DNA and less than 5% RNA. The protein content was less
than 1% (15), and the relative viscosity was approximately
2.0 when a solution of 0.5 mg DNA/ml in 0.015M sodium
citrate/O.14M NaCl (pH 7.1) was used. The viscosity of this
solution, measured in an Ostwald viscometer at 23°C after
being heated for 1 hour at 76"C, relative to the viscosity of
the buffer differed by not more than 2% from that before
heating. For poly I poly C , S20 was 11.03 in 0.05M phosphate buffer (pH 7.0, O.1M NaCI); hmax was 266 nm, 280
nm/260 nm 0.62, 250 nm/260 nm 0.94 in 0.1M phosphate
buffer, pH 7.0; Tm 64°C in 0.05M phosphate buffer, 0.1M
NaC1, H 7.0, p 260 nm; hyperchromicity, 30%; Ep260,
5 . 2 10
~ in 0.1M phosphate buffer, pH 7.0; ratio I:C=50:50.
The results of the DNA test were regarded as positive when the diameter of the induration at 24 hours was 6
mm or more. The results of the RNA test were positive when
the induration was 10 mm or more. In all positive cases
reactivity-in the form of erythema and induration-was
evident at 6 hours, although it could often be detected as
early as 3 hours after the injection of the nucleic acid
solution. The reaction reached a peak at 24 hours and
subsided within 48-72 hours after the injection. Excision
-
P
1285
biopsies were taken from the sites of DNA, poly I . poly C,
and phosphate buffered saline injection at 24 hours in 14 SLE
patients, at 48 hours in 1 patient, and at 6 and 48 hours in 3
patients.
Identification of cells from tissue sections. Biopsies
were fixed in Baker's fluid (22 hours), rinsed in Holt's
solution (24 hours), dehydrated in acetone (9 hours), and
cleared in xylene (22 hours), all at 4"C, before being embedded in paraffin at 55°C for 2 hours. Alpha-naphthyl acetate
esterase (ANAE) activity survives quantitatively during this
kind of processing (16). For the histochemical demonstration
of ANAE, tissue specimens deparaffinized in xylene and
then acetone (10 minutes each at 4°C) were incubated in a
medium consisting of 40 ml of 0.067M phosphate buffer (pH
5.3), 2.4 ml of hexazotized pararosaniline, and 10 mg of
ANAE (Sigma, St. Louis, MO) in 0.4 ml of acetone. The
mixture was adjusted to pH 5.8 with the use of 1M NaOH.
The incubation time was 4 hours at 25°C (17).
Tissue sections were counterstained in a 1% aqueous
solution of toluidine blue. Lymphocytes displaying 1 or more
distinct cytoplasmic dots were recorded as T pattern cells;
large mononuclear cells displaying a diffuse cytoplasmic
ANAE activity, as M pattern cells; and round cells (morphologically lymphocytes), displaying no ANAE whatsoever, as
non-T, non-M pattern cells. Granulocytes were identified by
morphology alone.
Counting of cells in tissue sections. Inflammatory cell
subclasses were counted from 6 p tissue sections with the use
of an ocular counting square (20 squares x 20 squares) and
an oil immersion objective ( x 1,000 magnification). The
ocular counting square was calibrated with a stage micrometer. At least 200 inflammatory cells were counted in each test
reaction. The investigator counting the cells did not know
the source (SLE or control group; DNA, poly I * poly C, or
phosphate buffered saline) of the sample.
RESULTS
The biopsy specimens from the 10 rheumatoid
arthritis patients and 5 acne patients, from the injection sites of phosphate buffered saline in SLE patients,
and from the SLE patients who had clinically negative
results showed either no infiltrates o r only infiltrates
containing less than 50 cells in the largest infiltrate in a
6pthick tissue section. These infiltrates were considered negative. There was no nonperivascular dermis in
any negative response.
At 24 hours, the inflammatory cell infiltrates
produced as a response to DNA or RNA in SLE
patients showed less than 10% variation between
different areas in the subepidermis and perivascular
areas deeper in the dermis. The inflammatory cell
density in the nonperivascular dermis (dermal background) was usually 20-50 cells/10,000p2at 24 hours.
The dermal background consisted of granulocytes (4080%) and M pattern cells (20-60%).
DNA and RNA skin tests at 24 hours. The T
KONTTINEN ET AL
1286
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NON-M
GR
Figure 2. Composition of a subepidermal infiltrate in 24-hour DNA
skin tests in 9 patients. Values are given for T pattern lymphocytes
(TI,M pattern cells (M), non-T non-M pattern lymphocytes (NON-T,
NON-M), and granulocytes (GR). Most of the inflammatory cells in
the subepidermis are T pattern cells.
pattern cell was the dominant cell type (Figures 1 and
2, Table 1) in 9 patients with subepidermal infiltrate at
24 hours. One of the patients had had only a leukocytoclastic vasculitis. The perivascular infiltrate deeper
in the dermis contained mainly granulocytes (Table 1,
Figure 3).
At 24 hours in the RNA skin tests, the subepidermal infiltrate contained mainly T pattern cells,
whereas the perivascular infiltrate in the deeper dermis contained mainly granulocytes (8 patients , Table
2).
- _
M
T
NON-T
NON-M
Figure 3. Composition of the perivascular infiltrates in the deeper
dermis in 24-hour DNA skin tests in 10 patients. Granulocytes make
up the largest cell group at these sites, but the composition of the
infiltrate shows large variation between individual patients. See
Figure 2 for definitions.
At 24 hours the perivascular infiltrates in the
deeper dermis were highly variable between individual
patients. There was a negative correlation, however,
between the total lymphocyte percentage and the
extent of the perivascular infiltrate in the deeper
dermis in both the DNA and RNA skin tests (data not
shown). A high total lymphocyte percentage was associated with a low granulocyte percentage and vice
versa.
Comparison of DNA and RNA skin test results:
response kinetics. In 9 of the patients studied, results of
both the DNA and RNA tests were positive. In spite of
Table 1. Inflammatory cells in DNA skin test reactions at 24 hours for 9 patients with systemic lupus
erythematosus
Percentage of infiltrating cells*
Site of infiltrate
Subepidermis
Perivascular dermis
Pt
* Mean
T
M
Non-T,
non-M
61 ? 8
31 2 26
22 2 5
24 +- 13
12 2 3
7 2 4
<0.01
<0.5
CO.01
standard deviation; T = T lymphocytes; M
ANAE negative round cells; G r = granulocytes.
t Student’s t-test.
f
GR
=
Gr
5 2 7
38 2 31
<0.01
mononuclear phagocytes; non-T, non-M
=
DNA AND RNA SKIN TESTS IN SLE
1287
Table 2. Inflammatory cells in RNA skin test reactions at 24 hours for 8 patients with systemic lupus
erythematosus
Percentage of infiltrating cells*
Site of infiltrate
Subepidermis
Perivascular dermis
Pt
* See Table 1 for definitions.
t Student’s t-test.
T
M
62 2 I 1
33 f 31
<0.05
21 k 5
24 t 12
<0.5
large variations between patients and between the
subepidermis and deeper dermis in individual patients,
the responses to DNA and RNA were similar in
individual patients at 6, 24, and 48 hours. (The differences for all kinds of cells identified in the present
study were usually less than 10% and always less than
20%.) Because of these similarities, the values of both
DNA and RNA responses could be used for response
kinetics curves.
In the subepidermis the infiltrate was rich in
granulocytes (47 & 42%) at 6 hours, but at 24 and 48
hours, T pattern cells were the dominant inflammatory
cell (61 t 10% and 60 f 14%, respectively, Figure 4).
80v)
1
d
0
60-
1
J
a
8
40-
c3
w
13 2 3
6 2 4
<0.01
Gr
4 k 9
36 k 33
<0.01
In the perivascular infiltrates deeper in the dermis,
granulocytes were the dominant cell at 6 and 24 hours
(75 k 10% and 38 31%, respectively), but at 48
hours, there was a clear M pattern cell dominance
(66 k 22%, Figure 5). In both the DNA and RNA skin
tests this perivascular infiltrate in the deeper dermis
was associated with disappearance of endothelial cells
or fibrinoid degeneration of the vessel wall, leukocytoclasis, and erythrocyte extravasation. In these infiltrates, hematoxylin bodies and even LE cells were
observed. The subepidermal infiltrates and perivascular infiltrates deeper in the dermis were similar at 6
hours; they differed significantly from each other when
T pattern cells, non-T, non-M pattern cells, and granulocytes were compared at 24 hours (Tables 1 and 2).
They also differed significantly from each other when
T pattern lymphocytes ( P <0.01, Student’s t-test) or M
pattern cells ( P <0.01, Student’s t-test) were compared at 48 hours (Figures 4 and 5).
Clinical pattern of SLE compared with skin test
results. Some comment on the clinical patterns of the
SLE patients with positive and negative results on
their skin tests is given in Table 3. At 24 hours the deep
dermal infiltrate contained 18 k 11% T pattern cells in
patients with severe SLE and in those with only
serologic signs of active disease and 49 29% T
pattern cells for the rest of the patients (P<0.05,
Student’s t-test). Values for granulocytes at 24 hours
were 50 20% and 25 2 34% for the respective
groups (PC0.5, Student’s t-test).
*
*
W
a
Iz
Non-T,
non-M
*
20-
0
U
DISCUSSION
W
a
0
6
24
TIME (hours)
48
Figure 4. The time course of the subepidermal response to intradermally injected DNA and poly I * poly C. Mean values for T pattern
lymphocytes ( O ) , M pattern cells (A),non-T non-M pattern cells
(O),
and granulocytes (A) are given at 6, 24, and 48 hours.
Those lymphocytes that display T pattern
ANAE staining are T lymphocytes (17-19), whereas
only up to 10% of lymphocytes that display surface
immunoglobulin display ANAE (17). In vitro activation of T lymphocytes by different mitogens or in
mixed lymphocyte culture diminishes the T pattern
staining among the activated lymphoblasts to a
able degree, depending on the stimulus and other
1288
KONTTINEN ET AL
801
'
6
24
T I M E (hours)
48
Figure 5. The time course of the perivascular response to intradermally injected DNA and poly I poly C. Mean values for T pattern
lymphocytes (O), M pattern cells (A), non-T non-M pattern cells
(O),
and granulocytes (A)are given at 6, 24, and 48 hours.
assay conditions (20). Histochemical ANAE staining
does not exclude simultaneous morphologic studies of
individual cells, however. We have also shown that in
rheumatoid synovial eluate, S-(2-aminoethyl) isothiuronium bromide-hydrobromide aminoethyl isothiuronium bromide-hydrobromide-sheep red blood cell
(AET-SRBC), rosette-forming lymphocytes correlate
well with T pattern lymphocytes (21).
The original observation about the restriction of
T pattern staining to T lymphocytes bearing receptors
for the Fc part of the IgM molecule (22) has recently
been confirmed (23). T p cells provide assistance for B
cell proliferation in response to pokeweed mitogen,
but the correlation with T helper cells, as recognized
by monoclonal hybridoma antibodies, is poor (24). We
have recently shown that 69% of AET-SRBC-rosetting enriched rheumatoid synovial T lymphocytes are
ANAE positive, whereas only 29% are F c p positive
(25).
Bennett and Holley (26) observed both mononuclear cells and granulocytes in the local response to
intradermally injected leukocytes in SLE. The present
study shows a dual pattern in the response of SLE
patients to intradermally injected polynucleotide,
probably representing a combined abnormal cellular
and humoral response of the SLE patients to the
injected polynucleotides. These responses proceed
simultaneously, but with different response kinetics
and preferentially at different sites.
The skin response probably begins as an interaction between injected polynucleotide and preformed
circulating antibodies. In the subepidermis this is
replaced by a cell mediated response, but in the deeper
dermis a prolonged Arthus type response is observed.
This is especially evident in patients with severe SLE
and with extensive infiltration of deep dermis. This
response is probably caused by a slow release of a
large amount of viscous antigen material (27). Recruited blood monocytes observed at 48 hours probably
have a scavenger-cell function at the site of such tissue
damage.
The timing of the biopsy could explain why
Ores and Mandel (28) observed granulocytes at 8-12
hours after the intradermal injection of DNA, whereas
biopsy samples taken 24 hours after the DNA injection
showed mononuclear cell infiltrates. This could also
explain why only mononuclear cells were observed in
studies of 3 patients by Fardal and Winkelmann (29)
and in 2 patients studied by Goldman et al (7).
The reason for the topographic dichotomy of
Table 3. Clinical pattern of 18 patients with systemic lupus erythematosus (SLE) compared with skin-test results at 24 hours
Type of skin test
Number of patients with:
Positive skin test
Clinically severe SLE*
Only serologic signs of
active SLEt
DNA or RNA
DNA
RNA
DNA and RNA
Onlv DNA
Onlv RNA
13
4
2
10
4
2
8
1
5
5
3
1
3
0
0
1
1
1
* Nephritis and/or central nervous system manifestations or 3 or more of the following: pleuritis, pericarditis, myocarditis, pneumonitis with
disc atelectasis, Ieukopenia, thrombocytopenia.
'!All of the following: antinuclear antibodies 21:1000, high DNA antibodies, cryoglobulins, and low serum C3, C4 or both.
DNA AND RNA SKIN TESTS IN SLE
-
the DNA and poly I poly C responses is not known,
but epidermal Langerhans cells might be responsible
for this phenomenon. First, exogenous antigens applied to clinically normal skin in allergic dermatitis
evoke a cell-mediated delayed hypersensitivity response where the cutaneous mononuclear cell infiltrate is rich in ANAE-displaying T lymphocytes
(30,31). Second, ultraviolet light irradiation of SLE
skin results in a lymphocyte infiltrate in the upper
dermis (4). The membrane attack complex C5b-9,
located specifically in lupus skin lesions (32), could
also be responsible for local release of DNA and other
potentially antigenic cellular components. Both exogenously applied and intraepidermally released endogenous antigens would come into contact with the Langerhans cells of the epidermis and thus provoke a cellmediated response.
The natural skin lesions in SLE are of this type,
containing 56 & 15% ANAE-displaying T lymphocytes from all cells (33,34). Only a minor part of the
DNA released from skin by ultraviolet light, even after
heavy irradiation, reaches the circulating blood (35).
When DNA or other antigenic material is injected
intradermally , however, it escapes the Langerhans cell
barrier in the epidermis and the epidermal-dermal
basement membrane and evokes an Arthus type reaction around the blood vessels in the deeper dermis.
Simultaneously, a part of the material intradermally
injected could diffuse to the epidermis and be processed there by Langerhans cells to provoke a cellmediated response containing ANAE-displaying T
lymphocytes (61 +- 9% of all cells), as was observed in
this study.
Because DNA and poly I poly C were injected
directly into the dermis in skin tests, access to the
systemic circulation and some adverse systemic responses could result. The test solution used, 0.1 ml of
0.1% polynucleotide, evoked an intense local response, but was not enough to evoke any adverse
systemic (clinical or serologic) effects whatsoever. We
did not perform DNA skin tests on patients with
seronegative lupus, however, because of the possibility of sensitizing these patients to DNA. Theoretically,
it would be of interest to test such patients with the
present skin test method to learn whether they display
signs of a cell-mediated immune response to DNA in
spite of negative serology. This would be especially
interesting because such patients show in vitro signs of
cell-mediated immune response to DNA ( 8 , l l ) . In this
context, it is also interesting to note that 1 patient in
the present series displayed an Arthus type response
-
1289
without any mononuclear cell infiltrate in the subepidermis whatsoever.
The positivity in the DNA and poly 1 poly C
skin tests did not totally overlap. Several antigens
would probably have to be injected if a skin test profile
were to be evaluated in the same manner because
several serologic tests are used for the serologic profile. The results of skin tests for DNA and/or poly
I * poly C were positive in almost every patient with
SLE, but the control patients showed negative results.
We concluded that the combined use of these
skin tests is a useful diagnostic tool for the detection of
SLE. All patients with clinically and/or serologically
severe disease had positive results on the DNA skin
test. All patients with positive results only on the RNA
test were clinically and serologically in a quiescent
phase of the disease. In addition, patients with a
clinically and/or serologically severe disease usually
had positive results only on the DNA test. Because of
the small number of patients, however, these observations can at best serve as a useful working hypothesis
for future research. The positivity of the skin test
results and the intensity of the responses were dependent on the patient and not on the type of polynucleotide injected. This type of phenomenon could be the
reason for the diversity of clinical findings, even in
SLE patients with similar serologic or skin test profiles.
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