Clin.
exp.
Immunol.
(1968)
3,
509-523.
THE
THYMUS
IN
RHEUMATIC
HEART
DISEASE
KRISTIN
HENRY
The
Brompton
Hospital
for
Diseases
of
the
Chest;
and
the
Middlesex
Hospital
Medical
School,
London
(Received
25
January
1968)
SUMMARY
Thymic
biopsy
specimens
obtained
during
thoracic
surgery
from
113
patients
suffer-
ing
from
rheumatic
heart
disease,
congenital
heart
disease
and
certain
other
miscellaneous
diseases
were
studied
at
the
light
microscope
level.
Thymuses
from
patients
with
rheumatic
heart
disease
showed
certain
changes
consistent
with
the
effects
of
a
chronic
inflammatory
process,
and
which
included
in
370
%
of
the
cases,
formation
lymph
follicles
with
germinal
centres.
The
thymuses
of
adults
with
congenital
heart
disease
showed
a
much
lower
incidence
(10%)
of
such
follicles
as
compared
with
those
of
children
in
this
group,
250
of
which
showed
this
change.
However,
there
was
a
relative
absence
of
other
thymic
abnormalities
in
both
children
and
adults
with
congenital
heart
disease.
Patients
suffering
from
a
variety
of
other
diseases,
several
of
which
are
accepted
as
being of
an
autoimmune
nature
and
in
which
thymic
pathology
is
already
well
documented,
also
showed
a
high
incidence
(470
%)
of
germinal
centre
formation
within
the
thymus,
and
in
certain
instances
other
thymic
changes.
Lymph
follicles
with
germinal
centres
presumably
reflect
a
response
to
antigen,
and
it
is
suggested
that
these
structures
may
occasionally
arise
in
the
thymus
of
normal
individuals,
particularly
children
and
adolescents.
However,
in
rheumatic
heart
disease,
the
formation
of
increased
numbers
of
these
structures
within
the
thymus
occurring
in
association
with
the
other
changes
described,
are
interpreted
as
reflecting
a
chronic
inflammatory
process
or
'thymitis'.
The
possibility
is
discussed
that
this
might
represent
an
autoimmune
reaction
against
a
thymic
component,
and
that
this
reaction
could
be
triggered
off
by
a
common
antigenic
determinant
shared
with
a
streptococcus.
INTRODUCTION
In
recent
years
there
has
been
much
re-awakened
interest
in
the
thymus
with
regard
to
its
Correspondence:
Dr
K.
Henry,
Rheumatology
Research
Department,
Middlesex
Hospital
Medical
School,
London,
W.1.
509
510
Kristin
Henry
role
in
the
development
and
maintenance
of
normal
immune
competence,
and
its
relation-
ship
to
disease
processes
associated
with
disordered
immunological
function.
It
has
been
known
for
some
time
that
thymic
lesions
exist
in
patients
with
myasthenia
gravis,
thyro-
toxicosis
and
Addison's
disease
(Weigert,
1901;
Sloan,
1943;
Castleman
&
Norris,
1949),
and
in
the
last
decade
thymic
abnormalities
have
been
described
in
a
number
of
diseases
such
as
systemic
lupus
erythematosus
(SLE)
and
rheumatoid
arthritis
(Hutchins
&
Harvey,
1964;
Mackay
&
de
Gail,
1963),
many
of
the
immunological
deficiency
syndromes
(Hitzig
&
Willi,
1961;
Gitlin,
Vawter
&
Craig,
1964;
Peterson,
Cooper
&
Good,
1965),
and
in
haemo-
poietic
insufficiency
states
(Havard
&
Bodley-Scott,
1960).
However,
the
decision
as
to
whether
any
thymic
abnormality
present
is
relevant
to
the
disease
under
investigation
is
difficult,
for
not
only
does
the
thymus
undergo
normal
'age'
or
'physiological'
involution
following
puberty,
but
it
also
exhibits
extensive
and
often
extremely
rapid
involution
in
conditions
of
stress
such
as
serious
illness,
following
X-ray
therapy
and
the
administration
of
metabolically
active
steroids
and
radiomimetric
drugs,
and
in
pregnancy
and
lactation.
This
type
of
involution
is
called
'stress'
or
'accidental'
involution,
is
mediated
through
the
adrenal-pituitary
axis
(Selye,
1936),
and
is
due
to
massive
depletion
of
the
lymphoid
popula-
tion.
In
thyrotoxicosis,
the
thymus
may
show
hyperplasia
of
its
lymphoid
elements
without
any
other
change,
and
is
further
evidence
that
endocrine
control
mechanisms
may
affect
thymic
structure.
Failure
to
appreciate
hormonal
influences
and
the
effects
of
stress,
together
with
the
fact
that
there
is
a
wide
variation
in
thymic
weights
at
different
ages
(Hammar,
1926),
may
lead
to
an
erroneous
diagnosis
of
a
hyperplastic,
aplastic
or
per-
sistent
thymus.
Because
of
this
difficulty
in
evaluation
of
thymic
changes
in
patients
dying
in
hospital,
in
whom
age,
sex
and
nature,
duration
and
treatment
of
the
disease
must
be
considered,
and
in
whom
there
is
the
added
disadvantage
of
the
time
lapse
between
death
and
autopsy,
it
was
decided
to
investigate
thymic
biopsy
material
from
patients
undergoing
cardiopulmonary
by-pass
procedures
for
either
rheumatic
or
congenital
heart
disease.
These
patients
formed
an
ideal
study
group
for
the
following
reasons;
first,
rheumatic
heart
disease
is
a
condition
in
which
autoimmune
processes
are
thought
to
play
some
part
(Glynn
&
Holborow,
1965)
and
thus
of
interest
with
regard
to
changes
present
in
the
thymus;
second,
most
patients
were
at
the
time
of
operation
relatively
fit,
free
of
infection,
and
not
receiving
treatment
other
than
for
their
cardiac
condition,
and
third,
the
thymic
biopsies
obtained
from
the
congenital
heart
disease
patients
would
serve
as
controls.
In
addition,
by
also
studying
biopsy
material
obtained
from
patients
undergoing
thoracic
surgery
for
other
conditions,
it
was
hoped
to
determine
whether
there
were
changes
present
in
the
thymus
in
chronic
rheumatic
heart
disease
which
differed
from
those
occurring
in
other
conditions.
MATERIALS
AND
METHODS
A
total
of
120
thymic
biopsies
were
obtained,
of
which
113
were
satisfactory.
The
number
ob-
tained
from
patients
with
rheumatic
heart
disease
(RHD),
congenital
heart
disease
CHD),
and
with
a
variety
of
miscellaneous
diseases,
is
shown
in
Table
1.
The
biopsies
obtained
from
the
latter
two
groups
were
subdivided
into
those
obtained
from
adults
and
children,
since
there
were
no
children
in
the
RHD
group.
One
woman
with
RHD
and
six
patients
with
CHD
also
suffered
from
other
diseases,
and
Thymus
in
rheumatic
heart
disease
511
therefore
the
biopsies
obtained
from
these
patients
were
placed
in
the
miscellaneous
disease
group,
since
it
was
felt
that
the
additional
diseases
from
which
they
suffered
were
of
them-
selves
capable
of
inducing
thymic
changes.
With
three
exceptions
the
thymic
biopsies
were
performed
as
soon
as
the
chest
was
opened,
the
exceptions
being
patients
with
myasthenia
gravis
in
whom
material
was
taken
from
the
thymectomy
specimen.
Two
blocks
were
taken
from
each
biopsy
specimen
and
fixed
in
10%
neutral
formalin
and
formol
mercury.
An
average
of
six
sections
per
block
were
cut,
and
stains
included
haematoxylin
and
eosin,
and
methods
to
demonstrate
the
presence
and
type
of
mucin
secreted
by
the
thymic
epithelial
cells
(Henry,
1966).
TABLE
1.
Distribution
of
thymic
biopsy
material
Diagnosis
No.
of
patients
Age
(years)
Rheumatic
heart
disease
32
17-62
Congenital
heart
disease
62
43
1-12
19
15-59
Miscellaneous
diseases
19
2
7
and
11
17
16-71
The
sections
were
examined
for
the
presence
or
absence
of
lymph
follicles
with
germinal
centres,
changes
in
the
epithelial
cell
component,
the
numbers
of
plasma
cells,
eosinophils
and
PAS
cells
present,
and
degrees
of
hyperplasia
or
involution
inappropriate
to
the
age
of
the
patient.
Mucin
secretion
by
the
epithelial
cells
and
Hassall's
corpuscles
was
graded
quanti-
tatively
using
a
system
of
from
one
to
four
pluses,
three
plus
and
over
being
regarded
as
excessive.
In
all
cases
clinical
history,
treatment-in
particular
steroid
therapy-and
relevant
laboratory
tests
were
recorded.
OBSERVATIONS
Rheumatic
heart
disease
Typical
lymph
follicles
with
germinal
centres
were
present
in
the
medullae
of
twelve
out
of
the
thirty-two
thymuses
from
this
group
of
patients
(Figs.
1,
2
and
3).
There
were
usually
one
or
two
of
these
structures
in
each
section,
their
presence
was
not
related
to
the
degree
of
'age'
involution,
and
in
only
one
case
(Fig.
lb)
were
they
seen
in
large
numbers.
In
four
instances,
these
structures
were
the
only
significant
finding
but
in
the
other
eight
they
occurred
in
conjunction
with
epithelial
cell
abnormalities.
Not
infrequently
they
were
seen
with
islands
of
epithelial
cells
and
Hassall's
corpuscles
ranged
around
them
(Fig.
3a).
Changes
in
the
epithelial
cell
component,
present
either
alone
or
in
association
with
lymph
follicles
with
germinal
centres
were
found
in
twenty-six
out
of
the
thirty-two
RHD
biopsies.
The
changes
ranged
from
increased
numbers
of
epithelial
islands
and
slight
generalized
epithelial
cell
hyperplasia,
to
striking
and
often
widespread
areas
of
epithelium
usually
with
formation
of
cysts
and
clefts
(Figs.
3
and
4).
This
latter
process
is
referred
to
as
epithelializa-
tion.
In
biopsies
showing
lesser
degrees
of
epithelial
cell
change,
Hassall's
corpuscles
were
D
512
Kristin
Henry
numerous
and
often
cystic,
but
in
the
more
advanced
epithelialized
glands
containing
cysts
and
clefts,
Hassall's
corpuscles
were
few
in
number
and
often
absent
completely
as
recog-
nizable
structures.
Indeed,
the
process
of
cyst
and
cleft
formation
appeared
to
arise
from
FIG.
1.
Thymus
from
patients
with
chronic
rheumatic
heart
disease,
showing
typical
lymph
follicles
with
well
defined
germinal
centres
in
the
thymic
medulla.
All
sections
stained
with
haematoxylin
and
eosin.
(a)
Male
39
years.
x
120.
(b)
Male
30
years.
x
110.
(c)
Female
27
years.
x
90.
(d)
Male
24
years.
x
58.
gradual
cystic
enlargement
and
fusion
of
the
Hassall's
corpuscles.
Spindle
cell
change
in
the
epithelial
component
was
not
a
feature,
but
the
epithelial
areas
did
sometimes
resemble
the
elongated
'archipelagos'
found
in
thymuses
of
patients
with
SLE
(Hutchins
&
Harvey,
1964).
Thymus
in
rheumatic
heart
disease
513
In
one
thymus
examined
the
entire
gland
was
converted
into
a
system
of
ramifying
cystic
spaces
and
clefts
lined
by
squamous
epithelium,
the
surrounding
thymic
parenchyma
being
involved
in
a
fibrosing
chronic
inflammatory
process
(Fig.
4b).
In
this
case
too,
the
epithelial
lining
of
the
clefts
showed
infiltration
with
chronic
inflammatory
cells,
and
germinal
centre
formation
was
present
in
the
few
small
remaining
areas
of
recognizable
thymic
tissue.
Occasionally
the
degree
and
character
of
the
epithelial
cell
hyperplasia
mimicked
the
appearance
seen
in
some
predominantly
epithelial
thymomas
(Fig.
5),
the
abnormal
epithelium
showing
bizarre,
multi-nucleate
cells
but
few
mitotic
figures.
Increased
mucin
secretion
was
associated
with
hyperplasia
of
the
epithelial
cells
and
Hassall's
corpuscles,
FIG.
2.
Thymic
biopsy
from
a
62-year-old
female
with
chronic
rheumatic
heart
disease.
There
is
fatty
infiltration
due
to
normal
'age'
or
'physiological'
involution,
but
a
lymph
follicle
with
germinal
centre
(arrow)
can
be
seen
in
the
medullary
zone
of
the
thymic
lobule.
H
&
E,
x
120.
but
was
diminished
or
absent
in
the
grossly
epithelialized
glands
with
cysts
and
clefts.
Increased
numbers
of
plasma
cells
were
invariably
present
in
the
abnormal
glands
in
the
medulla
and
interstitial
tissues
(Figs.
3
and
4).
They
seemed
to
have
a
particularly
close
association
with
the
epithelial
cell
component,
for
they
were
often
seen
in
large
numbers
adjacent
to
epithelialized
areas
(Fig.
4)
and
in
the
tissues
surrounding
cystic
spaces
and
clefts.
Congenital
heart
and
miscellaneous
diseases
In
contrast
to
the
RHD
group,
only
two
of
the
nineteen
adults
with
CHD
showed
the
presence
of
lymph
follicles
with
germinal
centres
in
their
thymic
biopsies
(Fig.
6).
These
were
a
woman
of
27
and
a
man
of
30
with
atrial
septal
defect
(ASD)
and
ventricular
Kristin
Henry
r
-:
i
4f
aid
I
.1
e1
I'd
1~
troi
='
A-.d
)
.::
RA
.:
FIG.
3.
Varying
degrees
and
types
of
change
seen
in
the
epithelial
cell
component
of
thymuses
from
patients
with
rheumatic
heart
disease.
The
main
sites
of
mucin
secretion
are
indicated
by
arrows.
(a)
Thymic
medulla
showing
increased
numbers
of
epithelial
cells
and
Hassall's
corpuscles
ranged
around
two
lymph
follicles
with
germinal
centres
(g).
Mucin
secretion
is
pro-
minent.
Male
30
years.
Alcian-blue/PAS,
x
45.
(b)
Somewhat
involuted
gland
showing
a
fairly
extensive
epithelial
area.
The
Hassall's
corpuscles
are
tending
to
undergo
cystic
change
(h).
Female
19
years.
PAS,
x
63.
(c)
Moderately
advanced
epithelialization,
with
formation
of
clefts.
The
epithelium
is
becoming
squamous
in
character,
although
mucin
secretion
is
still
514
intend
`6
"'..
..
,2-
AL
Thymus
in
rheumatic
heart
disease
515
septal
defect
(VSD),
respectively.
However
of
the
forty-three
children
with
CHD
as
many
as
eleven
showed
this
change
(Fig.
6),
and
of
these
eleven
five
had
a
history
of
recurrent
upper
respiratory
tract
infection
and
tonsillitis.
The
follicles
and
germinal
centres
in
these
cases
tended
to
be
fewer
in
number
than
in
the
RHD
groups,
although
there
was
no
marked
difference
in
the
size
of
these
structures.
Thymuses
from
patients
with
miscellaneous
disease
showed
a
high
incidence
of
germinal
centre
formation,
this
feature
being
present
in
nine
out
of
nineteen
biopsy
specimens,
notably
three
out
of
three
biopsies
from
myas-
thenics,
two
out
of
three
from
patients
with
chronic
bronchitis
and
asthma,
two
out
of
three
from
those
with
bronchiectasis,
one
out
of
four
from
cases
of
carcinoma
of
bronchus,
and
the
one
biopsy
from
the
patient
with
a
suspected
toxic
goitre
(Table
2).
Only
in
the
TABLE
2.
Incidence
of
lymph
follicles
with
germinal
centres
in
the
miscellaneous
disease
group
Diagnosis
Incidence
Myasthenia
gravis
3/3
Rheumatoid
arthritis
0/1
Bronchiectasis
2/3
Chronic
bronchitis
and
asthma
2/3
Addison's
disease+
bronchitis
and
asthma
0/1
Carcinoma
of
bronchus
1/4
Suspected
toxic
goitre
1/1
Degenerative
cardiac
conditions
0/3
myasthenic
thymuses
were
these
structures
numerous,
their
numbers
in
the
miscellaneous
diseases
being
about
the
same
or
rather
less
than
in
the
RHD
group.
The
actual
number
and
percentage
of
germinal
centre
formation
in
all
three
disease
groups
is
given
in
Table
3.
TABLE
3.
Incidence
and
percentage
of
lymph
follicles
with
germinal
centres
in
all
disease
groups
Rheumatic
heart
Congenital
heart
Miscellaneous
disease
disease
diseases
Age
(years)
17-62
0-12
15-59
0-11
16-71
No.
of
patients
32
43
19
2
17
No.
and
percentage
with
follicles
12
11
2
1
8
(37%O)
(25%)
(10%.)
(47%.)
present.
Male
39
years.
Alcian-blue/PAS,
x
90.
(d)
Grossly
abnormal
thymus
showing
derange-
ment
of
normal
architecture.
There
is
formation
of
cysts
and
clefts,
and
extensive
infiltration
with
chronic
inflammatory
cells,
including
plasma
cells.
Intracellular
mucin
can
be
seen
within
the
epithelial
cells
including
those
lining
the
cystic
spaces.
Male
30
years.
Alcian-blue/PAS,
x
110.
Kristin
Henry
FIG.
4.
Chronic
inflammatory
changes
in
the
thymus
in
RHD.
All
sections
stained
with
haematoxylin
and
eosin.
(a)
In
addition
to
infiltration
of
the
thymic
parenchyma
with
lympho-
cytes
and
plasma
cells,
there
are
also
aggregates
of
these
cells
(see
inset)
in
the
surrounding
tissue.
The
well
demarcated
epithelial
island
(arrow)
is
somewhat
reminiscent
of
the
'archi-
pelagos'
of
epithelium
characteristic
of
SLE.
Male
42
years.
x
50.
(b)
Same
case
as
(a).
The
major
part
of
the
thymus
is
converted
into
a
system
of
communicating
cystic
spaces
lined
by
epi-
thelium
of
squamous
character.
This
abnormal
epithelium
(arrow)
and
the
surrounding
parenchyma
show
infiltration
with
chronic
inflammatory
cells
and
fibrosis.
Aggregates
of
516
Thymus
in
rheumatic
heart
disease
517
The
marked
epithelial
cell
changes
found
in
the
RHD
group
(Table
4)
occurred
in
none
of
the
children
with
CHD,
and
in
only
one
adult
with
CHD,
a
woman
of
thirty-two
with
FVER'''
b~w''
An
FIG.
5.
(a)
Abnormal
thymic
epithelium
in
a
woman
of
48
years
with
rheumatic
heart
disease.
The
epithelial
cells
are
hyperplastic,
with
many
bizarre
multinucleate
forms,
but
mitotic
figures
are
few.
Mucin
secretion
and
Hassall's
corpuscles
are
absent.
H
&
E,
x
305.
(b)
Section
from
a
mixed
epithelial
lymphocytic
type
of
thymoma
for
comparison.
H
&
E,
x
305.
sub-valvular
aortic
stenosis,
and
this
patient
gave
a
history
of
rheumatic
fever
and
arthritis
in
childhood.
In
the
miscellaneous
disease
group
two
biopsy
specimens
showed
fairly
extensive
epithelialization
but
without
cyst
or
cleft
formation,
and
were
obtained
from
a
woman
of
fifty-three
with
a
pulmonary
hamartoma
and
rheumatoid
arthritis,
and
a
man
of
seventy-one
with
a
retrosternal
goitre,
chronic
bronchitis
and
asthma
who
was
receiving
steroid
therapy.
A
slight
increase
in
the
epithelial
cell
component
either
alone
or
in
con-
junction
with
lymph
follicles,
was
seen
in
five
adults
and
three
children
with
CHD,
and
in
six
of
the
miscellaneous
disease
groups
(Fig.
7).
Chronic
inflammatory
changes
as
evidenced
by
increased
numbers
of
plasma
cells
and
medullary
lymphocytes
were
not
observed
in
the
non-rheumatic
biopsies,
with
the
exception
of
those
from
the
32-year-old
woman
with
sub-valvular
stenosis
already
referred
to,
a
woman
with
ASD
and
suspected
toxic
goitre,
a
16-year-old
boy
with
saccular
bronchiectasis
and
two
of
the
three
cases
of
myasthenia
gravis.
lymphoid
tissue
are
randomly
distributed,
there
are
no
recognizable
Hassall's
corpuscles
and
no
evidence
of
mucin
secretion.
x
50.
(c)
The
normal
cortico-medullary
relations
are
com-
pletely
destroyed.
There
is
extensive
infiltration
with
chronic
inflammatory
cells,
and
many
cystic
Hassall's
corpuscles
and
clefted
areas.
Female
31
years.
x
120.
Kristin
Henry
FIG.
6.
Germinal
centre
formation
in
otherwise
normal
thymuses
from
two
patients
with
congenital
heart
disease.
(a)
Child
9
years.
H
&
E,
x
140.
(b)
Adult
22
years.
H
&
E,
x
160.
FIG.
7.
Thymus
from
a
46-year-old
woman
with
suspected
toxic
goitre
showing
a
lymph
follicle
with
germinal
centre
adjacent
to
an
island
of
plump
ovoid
epithelial
cells.
H
&
E,
x245.
518
Thymus
in
rheumatic
heart
disease
519
Additionalfindings
in
all
disease
groups
Eosinophils
were
present
in
all
the
biopsies
except
the
71-year-old
man
with
the
retro-
sternal
goitre,
chronic
bronchitis
and
asthma
who
was
receiving
steroid
therapy.
The
eosinophils
were
located
mainly
in
the
interlobular
septa
and
medulla,
but
sometimes
also
within
Hassall's
corpuscles
and
were
present
in
largest
numbers
in
the
thymuses
from
chil-
dren.
Both
mature
and
immature
forms
were
seen,
and
there
was
no
correlation
with
germinal
centre
formation
or
epithelial
cell
change.
TABLE
4.
Changes
present
in
the
epithelial
cell
component
(including
Hassall's
corpuscles)
Degree
of
epithelial
change
No.
of
Increased
mucin
Diagnosis
patients
secretion
Slight
Moderate
to
severe
Rheumatic
heart
32
12
14
12
disease
Congenital
heart
disease
1-12
years
43
3
0
6
15-59
years
19
3
1
1
Miscellaneous
diseases
19
4
2
4
TABLE
5.
Increased
mucin
secretion
related
to
germinal
centre
formation
and
epithelial
cell
change
Both
epithelial
Diagnosis
No.
showing
Germinal
centre
Epithelial
cell*
cell
change
and
No
increased
secretion
formation
only
change
only
germinal
centre
abnormality
formation
Rheumatic
heart
12
0/4t
7/18
5/8
0/2
disease
Congenital
heart
disease
1-12
years
6
0/10
0/2
0/1
6/30
15-59
years
3
0/2
2/6
0/0
1/11
Miscellaneous
4
0/5
2/4
2/4
0/6
diseases
*
All
degrees.
t
Number
showing
increased
mucin
secretion/number
with
morphological
change
specified.
Mucin
secretion
was
present,
though
variable
in
amount,
in
all
but
the
most
severely
epithelialized
glands
of
the
type
seen
in
chronic
RHD,
in
which
the
epithelium
tended
to
be
of
an
epidermoid
character,
and
to
be
associated
with
evidence
of
chronic
inflammation.
From
the
results
of
a
study
of
mucin
secretion
by
the
thymic
epithelium
(including
Hassall's
520
Kristin
Henry
corpuscles)
the
mucin
was
found
to
be
an
acid,
probably
sulphated,
mucopolysaccharide
(Henry,
1966),
similar
to
other
epithelial
mucins.
The
number
of
thymuses
in
this
study
showing
increased
mucin
secretion
is
shown
in
Table
4,
and
by
reference
to
Table
5,
it
can
be
seen
that
although
there
is
no
correlation
between
increased
secretion
and
germinal
centre
formation,
there
is
perhaps
some
indication
of
a
positive
correlation
with
changes
in
the
epithelial
cell
component.
Six
children
with
CHD
however,
showed
increased
mucin
secretion
in
otherwise
normal
glands,
suggesting
that
increased
secretion
per
se
may
not
itself
be
abnormal,
but
might
represent
a
physiological
response.
DISCUSSION
In
most
accounts
of
the
histology
of
the
human
thymus,
it
is
generally
stated
that
lymph
follicles
with
germinal
centres
do
not
occur.
In
fact
Mackay
(1966)
states
that
the
normal
human
thymus
at
all
ages
characteristically
contains
no
germinal
centres.
Germinal
centre
formation
in
this
organ
together
with
increased
numbers
of
lympho-
cytes
in
the
medulla
was
first
described
in
cases
of
myasthenia
gravis
(Sloan,
1943),
the
incidence
of
these
structures
being
about
80%
in
non-neoplastic
glands
(Castleman,
1955).
Indeed,
it
was
the
microscopical
appearance
of
the
thymus
in
this
disease
and
its
resem-
blance
to
that
of
the
thyroid
in
Hashimoto's
disease
that
first
prompted
the
suggestion
that
myasthenia
gravis
was
of
an
autoimmune
nature
(Smithers,
1959).
The
subsequent
observa-
tions
that
germinal
centre
formation
took
place
in
the
thymuses
of
patients
with
other
autoimmune
diseases
(Burnet
&
Mackay,
1962;
Gunn,
Michie
&
Irvine,
1964)
including
autoimmune
thyroid
disease
led
to
the
suggestion
that
this
particular
finding
was
a
feature
of
autoimmune
disease
(Burnet
&
Mackay,
1965).
Sloan
(1943)
however,
found
lymph
follicles
with
germinal
centres
not
only
in
myasthenia
gravis
and
other
conditions
such
as
thyrotoxicosis
and
Addison's
disease,
but
also
in
fourteen
out
of
150
cases
of
sudden
death
in
presumed
normal
people.
Germinal
centres
have
also
been
noted
in
four
out
of
twenty
thymic
biopsies
obtained
from
children
with
congenital
heart
disease
(Bhathal
&
Campbell,
1965),
and
recently
Middleton
(1967)
has
recorded
the
incidence
of
lymph
follicles
with
germinal
centres
in
seventy-one
apparently
healthy
patients
killed
in
road
accidents
as
50%/,
rising
to
70%.
if
only
the
age
group
6-39
years
was
considered.
Furthermore,
he
states
that
in
714
hospital
deaths
the
overall
incidence
of
these
structures
in
the
thymus
was
5%/,
but
rose
to
31%
in
patients
dying
within
3
days
of
the
onset
of
their
illness.
Middleton
(1967)
interprets
these
findings
as
indicating
nothing
more
than
normal
immunological
processes
occurring
in
response
to
antigen,
and
in
no
way
implying
an
autoimmune
disease.
However,
it
should
be
borne
in
mind
that
clinical
details
were
not
available
in
the
cases
of
sudden
or
accidental
death,
the
individuals
merely
being
presumed
to
be
healthy,
that
when
these
structures
were
present
they
were
few
in
number
as
compared
with
diseases
such
as
myas-
thenia
gravis,
and
that
there
is
no
comment
on
the
epithelial
cells
in
these
thymuses.
Germinal
centres
are
regarded
as
the
morphologic
expression
of
antibody
production,
and
their
relative
absence
in
the
human
thymus
supports
the
results
of
various
experimental
procedures
which
show
that
the
thymus
is
not
normally
concerned
with
antibody
produc-
tion,
being
rather
the
lymphoid
centre
controlling
cellular
immunity
(Miller,
1964;
Good
et
al.,
1966).
Thus
the
presence
of
these
structures
alone
in
the
thymus
in
the
cases
reported
in
this
communication
is
of
interest,
although
not
necessarily
pathological,
or
suggestive
of
the
presence
of
an
autoimmune
disease,
since
it
indicates
that
antibody
is
being
produced
Thymus
in
rheumatic
heart
disease
521
in
response
to
available
antigen.
In
completely
healthy
individuals
it
is
a
possibility
that
occasional
germinal
centre
formation
could
be
a
normal
event,
since
it
has
been
amply
demonstrated
that
the
blood
thymus
barrier
proposed
by
Marshall
&
White
(1961)
is
by
no
means
complete
(Clark,
1964).
In
children
with
congenital
heart
disease,
in
whom
in
this
series
the
incidence
of
these
structures
is
25%,
a
continued
antigenic
stimulation
such
as
might
occur
in
recurrent
upper
respiratory
tract
infections
might
be
a
factor,
or
the
altered
circulatory
dynamics
present
in
these
heart
cases
might
lead
to
increased
permeability
of
the
blood
thymus
barrier
with
the
result
that
antigen
is
more
accessible
than
under
normal
conditions.
In
many
of
the
miscellaneous
diseases
and
in
the
rheumatic
heart
disease
cases,
the
incidence
of
germinal
centres
could
also
be
explained
on
this
basis.
However
the
increased
number
of
these
structures
in
the
biopsies
obtained
from
RHD
patients,
considered
in
conjunction
with
the
high
incidence
of
other
thymic
abnormalities,
suggests
that
at
least
in
this
disease,
other
mechanisms
are
operating.
For
whereas
lesser
degrees
of
change
in
the
epithelial
cell
component
are
only
slightly
higher
in
RHD
than
in
the
other
two
groups
(Table
4)
and
could
perhaps
be
explained
on
the
basis
of
stress,
the
high
incidence
of
pro-
minent
epithelial
abnormalities
associated
with
evidence
of
chronic
inflammation
is
seen
only
in
RHD.
This
latter
finding
cannot
be
attributed
to
the
effects
of
continued
stress,
for
some
of
the
most
severe
and
long-standing
cases
of
heart
failure
were
patients
with
CHD,
who
did
not
show
this
change.
In
some
respects
the
abnormalities
present
in
the
thymuses
of
RHD
patients
resemble
those
found
in
the
non-neoplastic
thymuses
of
patients
suffering
from
myasthenia
gravis
and
SLE,
abnormalities
which
are
variously
referred
to
by
different
authors.
Mackay
(1966)
considers
the
structural
changes
present
as
being
of
a
dysplastic
nature,
whereas
Goldstein
(1966)
feels
that
the
germinal
centre
formation
and
increased
numbers
of
plasma
cells
seen
in
myasthenic
thymuses
represents
a
chronic
inflammatory
process,
and
that
the
term
'thymitis'
is
more
appropriate.
In
RHD
also
it
would
seem
pre-
ferable
to
apply
the
term
'thymitis'
to
describe
the
changes
present
in
the
gland.
The
process
of
chronic
inflammation
is
visualized
in
the
following
way.
Initially,
within
the
medulla,
there
is
active
germinal
centre
formation,
hyperplasia
of
epithelial
cells
and
Hassall's
corpuscles
secreting
increased
amounts
of
mucinous
material,
and
infiltration
with
increased
numbers
of
plasma
cells
and
lymphocytes.
If
the
stimulus
producing
these
effects
continues,
then
eventually
the
thymus
may
be
converted
into
the
chronically
inflamed
lymphocyte
depleted
epithelialized
gland
with
disruption
of
normal
architecture
in
which
the
epithelium
is
often
strikingly
epidermoid
in
character
and
may
show
infiltration
with
chronic
inflam-
matory
cells.
Cystic
spaces
and
clefts
are
formed,
but
mucin
secretion
is
markedly
reduced,
and
in
extreme
cases
the
thymus
shows
the
appearance
of
a
fibrosing
granulomatous
process.
The
structural
changes
present
resemble
in
many
ways
those
characteristic
of
the
thyroid
in
Hashimoto's
disease
or
the
salivary
glands
in
Sjogren's
syndrome,
diseases
in
which
autoimmune
phenomena
are
implicated
(Roitt
&
Doniach,
1965).
This
suggests
that
the
chronic
inflammatory
process
occurring
in
the
thymus
in
chronic
RHD
may
have
an
autoimmune
component.
The
question
as
to
why
the
thymus
should
be
involved
in
a
chronic
inflammatory
process
in
chronic
RHD
remains
to
be
answered.
Possible
explanations
in
line
with
current
concepts
of
autoimmune
processes
are
that
normally
sequestered
thymic
tissue
antigens
in
some
way
become
accessible
to
antibody
forming
cells,
or
undergo
some
alteration
so
that
normal
immunologically
competent
cells
produce
antibody
against
them.
Another
possibility
522
Kristin
Henry
however,
at
present
under
investigation,
is
that
the
heart
reactive
antibody
present
in
some
cases
of
RHD
might
also
react
with
thymic
epithelial
cells.
In
other
words,
the
common
antigenic
determinant
shared
by
cardiac
and
skeletal
muscle
and
by
some
groups
of
strepto-
cocci,
notably
the
group
A
fi
haemolytic
streptococci
(Kaplan
&
Meyerserian,
1962;
Nakahla
&
Glynn,
1967)
may
also
be
present
in
thymic
epithelial
cells,
in
the
same
way
that
certain
antigenic
determinants
are
common
to
cardiac
and
skeletal
muscle
and
to
thymic
epithelial
cells
in
myasthenia
gravis
(Strauss
et
al.,
1965;
Van
der
Geld
&
Strauss,
1966).
Thus
the
thymus
in
susceptible
individuals
might
be
the
site
of
an
antigen-antibody
reaction
resulting
from
a
streptococcal
infection
with
subsequent
formation
of
an
autoantibody
reactive
against
thymus
constituents.
It
would
not
appear
justifiable
however
to
suggest
that
the
perpetuation
or
initiation
of
chronic
rheumatic
heart
disease
is
primarily
induced
by
changes
arising
in
the
thymus
gland.
ACKNOWLEDG
MENTS
I
should
like
to
thank
the
surgeons
of
the
Brompton
Hospital,
London,
in
particular
Mr
0.
S.
Tubbs
for
supplying
the
surgical
specimens,
and
Dr
K.
F.
W.
Hinson
of
the
Brompton
Hospital,
and
Dr
M.
A.
Epstein
and
Dr
I.
M.
Roitt
of
the
Middlesex
Hospital
for
their
helpful
advice.
I
acknowledge
the
technical
assistance
of
Mr
G.
Ball
and
Miss
Valerie
Petts
for
their
help
in
the
preparation
of
the
photomicrographs,
and
I
am
grateful
to
Mrs
G.
Stead
for
typing
the
manuscript.
The
work
was
supported
by
grants
from
the
Board
of
Governors
of
the
Hospitals
for
Diseases
of
the
Chest,
and
the
Medical
Research
Council.
REFERENCES
BHATHAL,
P.S.
&
CAMPBELL,
P.E.
(1965)
Eosinophil
leucocytes
in
the
child's
thymus.
Aust.
Ann.
Med.
14,210.
BURNET,
M.F.
&
MACKAY,
I.R.
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