Future lines of research on rheumatoid arthritis

FUTURE

LINES

OF RESEARCH

ON RHEUMATOID

LEWIS THOMAS, M.D.

From the Department College of Medicine

NEW YORK,

(Received

I

N HIS

r\T.‘i’.

admirable

arthritis,

Dr.

for clinicians closely

and ulcerative may

have

that

although

colitis, these

importance

may be involved

in parts

large

area

theme

an eye

on

of experimental

run the risk of presenting

medicine

a rather

disjointed

laid side to side but not quite fitting What

I hope to show is that

rheumatoid verted

arthritis,

fever,

His implication

different

and I intend

situations

ritis as such.

the direct,

lecture,

is

anal-

to emphasize

the

fields in a

To do this,

I must

made up of odd-sized

to examine

quickly

parts

the pathogenesis

and sometimes

approaches

distance

In

di-

models in aniexperimental

and there are a great

to an uncomfortably

or precise

We can go only a certain

of

surprisingly

ones at first, and then quite unrelated

we are limited frontal,

diseases,

in neighboring

and pathology.

as we shall see, one thing leads to another,

only

in

psoriasis,

of them.

when we begin

to the study of other diseases-related

we attempt

gout,

together.

we find ourselves

inviting garden paths. My point will be that

important

to new developments

ones-or to the investigation of what we hope to be experimental mals, which lead out in what soon appears to be all directions. pathology,

of rheumatoid

it is most

arthritis.

as quite

of my paper,

analogous

University

that any news from these quarters

recognizable

of keeping

alive

of rheumatoid

are clinically

is to be the central

York

aspects

that

of rheumatic

in view of the possibility

New

June 10, 1959)

times

to remain

such as those

on the problem

ogous mechanisms

rather

fields,

Medicine,

and clinical

out several

in this disease

clinical

bearing

for publication

of the historical

has pointed

interested

adjacent

This

survey

Short

of

ARTHRITIS

before

narrow

to rheumatoid

our information

many area

if

arthand in-

struments become inadequate for the task, and we are then required to look for new clues or openings in adjacent areas, and then, having studied these analogous The problems raised by rheumatoid situations, to move still further afield. arthritis extend across interdisciplinary lines into an extraordinarily broad field questions about this disease are less of biology, and answers to the important likely to be obtained locally than they are somewhere at the far periphery. I shall begin with the local dilemma of the joint, in rheumatoid arthritis proper, and finish with a consideration of the normal human placenta, which, in my opinion, shares certain problems with the arthritic joint, and in between, more or less connected together, I shall deal with certain immunologic phenomena that

form

the links

between

these

distant 42x

topics.

Volume 10 1Xumher5

RESEARCH

RHEL’MATOID

ON RHEl’MATOID

429

ARTHRITIS

ARTHRITIS

As Dr. Short has indicated, there is a fair degree of agreement among authorities as to what rheumatoid arthritis is, or how it is defined-apart a certain the

amount

propriety

patients

with

nature

of doctrinal

of including ulcerative

colitis

someone

understood,

should

present oratories

originally

Dr. Kulka entitlr,

has convinced blood

to some

hemolytic

streptococci,

the

between

tendenc),

seems

Dr. Kunkel event

grow

universally

determinants

it seems

nothing Dr.

could

or some virus arthritis.

mechanism

has presented

the evidence

probably

necessarily

underlies

the

the recent

evi-

or other-could with

after

rules

possible

agent-L-forms,

I agree

as generation

approach

approach

to the arthritis

there

from

the

be more

from the involved Kunkel

as a pathologic in the reactivit).

the initiating

to me quite

distributed

out

that

a11

or

generation

that

in

non-

as well be inherited however,

in-

a defect

for example,

him,

doubts

efforts joint

direct

of

as is

infection

of bacteriologists

are being

fluid

rise

in certain

of arthritic

than

and perhaps

to one side,

laboratories

joints.

the isolation

something Suppose

to

Certainly.

of a pathogenic But of this.

will come

it, and so do I, and in this circumstance

Here is where we must begin to move afield.

agent

we have abandoned almost Many investigators are loath

made

or tissues

or convincing

tissues,

infectious

an

problem,

is to the problem.

and commendable

something

agent

Dorfman’s.

and disseminated lupus, and further, I am not as sure as Dr. Kunkel

It seems to me that if we set the possibility

to do this,

from lab-

Dr.

and fall again.

as an unpromising the only direct

like arthritis

which

is begin-

we owe for our

an abnormality

to do with

this disease

since

less and less likely,

to the problem

debt

He has also summarized

of genetic

to develop

in the disease

us, and parenthetically

of both conditions.

in arthritis,

resistance

much

of

biochemical

to work coming

of rheumatoid

about

or the arthritis The

diseases,

that

determining

determination

agent

have

arthritis.

the demonstration

fectious

rheumatic

Finally,

as the

dence for a relationship is that

may

involved has shown

chemistry

good grounds,

of rheumatoid

for the genetic

with

in the joints.

hypersensitivity

not to enter,

arthritis

the considerable

us of the existence on

vessels

of tissue damage pathogenesis

sometime, polysaccharide

concerned

and he suggests,

of terminal

tissue elements

as Dr. Dorfman

of tissue

I propose

as psoriatic

or with agammaglobulinemia.

acknowledge,

knowledge

into which

things

of some of the connective

ning to be better

for

dispute,

such

clinical from

what

comes

we consider,

next!

for opera-

tional purposes, that the rheumatoid factor has something to do with the patho. genesis of arthritis. This is an antibody against gamma-globulin, or, if you will, an anti-antibody,

and it exists

I am

how one could

not

certain

in the circulating possibly

blood

go about

antibody complex of this kind can be damaging rheumatoid arthritis, but an elegant experimental sort of thing.

attached

showing

to its antigen. that

to the joints model exists

an antigen-

in patients with for studying this

SERUM SICKNESS

Serum

sickness

glomerulonephritis

is a syndrome occur

as systemic

in which reactions

acute

polyarthritis,

to a foreign

angiitis, protein

and

antigen.

430

.I. Chron. Dis. November, 1959

THOMAS

There

are differences

vessel

lesions

in intensity

of rheumatoid

and pathologic

arthritis,

side by side as manifestations be related arthritis

to each

of preciseI>-

At any

other.

for us to know as much

serum sickness. Thanks to the recent it is now known

that

the local deposition, complex.

It

vascular

tissue;

released

as possible

work of Dixon

understood

about

or activated

such

Good

seem

been

evidence

Germuth,”

sickness

blood vessels,

of

involved

~II

and others, with

be irritating

proteoI\$c

the notion

ma>

of antigell-autibod\-

should

that

they interests

are associated

and that proteolysis

for or against

still

in the best

complexes

at the site of deposition

of the tissue.

but

and blood to set them

the mechanisms

of serum

has been suggested

unwise

thing,

seem

and co-workers,4

lesions why

the possibility

from the joint

be most

the same

it would

in the walls of the involved

is not

to have

rate,

the vascular

detail

and it would

enzymes

to ::re

leads to damage

is Ilot available,

but we

presented with an excellent model with which to explore One of the cardinal lesions of serum sickness is acute more deeply.

the matter

glomerulonephritis,

and

McCluskey,

Benacerraf,

and

PotteP

have

recentI!.

shown that this lesion can be reproduced in mice within 36 hours or less after an intravenous injection of soluble antigen-~~ntihod~ coml,lex. In a sense, then, this model for the experimental production of glomerulonephritis in mice can be regarded as one of the currently matoid arthritis. It is now known blood

stream

of uptake

that

in a curious

depending

of foreign

gamma-globulin--the

complex,

culating joints

arteries

they

that synovial

particulate

material.

be that

have been selectively of speculation

complexes

is quite

the nature

aild

the trouble

of rheumatoid

up b). local vessels,

fruitless

injection

and the

glo-

1II addition of antigen1t so.

bs. doing

circumstances, the

the

of the antigen.

large amounts

to be damaged

undertake

from

in the site

by a massive

and stomach

cells engulf

of rheu-

removed

variatioils

and the most damage.

do not seem

(‘onceivably,

the complex picked

and

of the heart

uptake

cells

are

are probabl?.

cells can, under certain

of reticuloendothelial

might

to the problem

the type produced

the reticuloendothelial although

has been claimed properties

example,

show the greatest

to the blood vessels, antibody

and there

on the size of the complex

serum disease-for

capillaries

approaches

~~ntigen-atltibod?, fashion,

In classical merular

available

assume

phagocq.tosis

in rheumatoid

the

of cirarthritis

factor

and its globulin antigel But this sort or s?,novial cells.

and can lead nowhere

until we know much

more

than me do about the mechanisms of tissue damage ill serum sickness, and the factors which influence the uptake in various tissues of antigen-antibody complexes. Also, it should be added, an>’ such explanation for the joint lesions of rheumatoid

arthritis

of children

with

will create

real discomfort

agammaglobulinemia

in pediatric

circles

where

numbers

and a syndrome indistinguishable from To the pediatricians concerned, anything

rheumatoid arthritis are being stuclied.g remotely resembling serum sickness would be an impossibility in these children, If the rheumatoid factor is involved in since they can’t make antibody- at all. the pathogenesis of classical rheumatoid arthritis, it is difficult to see how the same mechanism can account for the arthritis of agammaglobulinemia, unless the

volume Number

10 5

RESEARCH

children

with this disease

analogous type

to whatever

reactions

ON RHEUMATOID

possess

a more subtle,

the mechanism

of bacterial

431

ARTHRITIS

cellular

form of the same factor,

is which permits

them to have the delayed-

allergy.

AI’TOANTIBODIES

Apart

from the rheumatoid

ing something is another the

factor,

other

factor

to serum

immunologic

L.E.

with

analogous

abnormality

au antibody

nuclear

As Dr.

for a close

lupus erythematosus. The L.E. factor actually

responsible

of replaceable

form complexes some

with

clarification

autoimmune death. The which turn

may

This

are

The

was discovered

some

and specific

own antibody. the same condition ing brain

antigen

The and

disease

other

patchy

25 years

as significant

humans

Freund’s

Waksman31

adjuvant

animals.16~17

and inflammatory appear

with facility

has been produced

of demyelination

in and around which

with

by Kabat

the vessel

involvement

has suggested

as allergic

in which

Kivers,lg

a contribution

animals’ and ma)

to the arthritis

unequivocal demonstration within an animal, leading and Wolf’”

and

encephalitis,

own or other

ago by Dr.

to and

destruction

own tissue and

of a to the by his

Morgan15

and reproducibilit), rabbits,

dogs,

lesions

that

by combin-

of the lesions masses

cats,

in the

of multiple

of the veins and venules,

walls bq- dense

to be plasma

circumstances

their

microscopic

reminiscent

factor

unsettled,

mixture.

in monkeys, The

to

in the normal LE.

remains

of one kind of the animal’s

it was found

can be produced

laboratory

areas

destruction

Later,

According

for the

in tissue

known

against

or not it is

only in sites inaccessible

other

disease

animals

problem as anything else. ‘This was the first disease state produced by an immune response selective

Whether

point

to be involved

part

and disseminated

is not clear.

is present

by considering

known

been

disease

the lymphocytes,

is the experimental

to have

is demonstrable

and it constitutes

there are ample opportunities

by immunizing

out eventually

this

of lupus

or antigens.

be gained

us, this

there

This is of DNA

or combinations

an autoantibody.

lesions

of invok-

for arthritis, implications.

arthritis,

between

notably

its antigen

best of these

tissue.

DNA

since DNA

to others, cells,

mechanisms

is produced

brain

unlikely,

larger

showed

with rheumatoid

for the various

but, according

breakdown

rather

against

relationship

it has raised

in accounting

Kunkel

is, par excellence,

some, this is theoretically to antibody;

with

directed

materials.

in over 20 per cent of patients of the evidence

and the possibility

sickness

of mononuclear

rats,

mice,

brain

show

sclerosis

in

with infiltration cells,

many

of

cells. that

the t)-pe of circulation

of blood

through

the

venules and small veins may be important in determining where lesions occur. If the flow of blood is sufficiently slow, and the arrangement of venules sufficientI> elaborate, mononuclear cells in the blood can become attached to the vessel walls, migrate through, and form the granulomatous vascular lesions which characterize allergic encephalitis. He suggests that the surface charge of the leukocytes and that of the vessel walls may be of importance in determining the particular areas into which cells penetrate. But it also seems possible that the force that attracts

432

J. Chron. Dis. November, 1959

THOMAS

the mononuclear

cells to these

the wall, in the white matter they

are already

analogous

forming

to that

munized

against

organisms,

certain

veins

may

be the antigen,

just

and the cells may be attracted The situation against brain antigen.

antibody

shown

the surface

particular

of the brain,

earlier

with isolated

bacteria;

lymph

node cells from animals

when placed in a suspension

of the cells become

coated

across because may be im-

of the same micro-

with agglutinated

masses

of bac-

teria. ~8 Here, in the brain, the same thing may be going on in reverse, with masses of antibody-forming cells sticking to the surface of a very large antigenic mass. It should

be said at once that,

the immunologic white

matter

basis

although

of this disease,

of the brain,

very little

there

is

nor as to it is known

110

reasonable

exquisite

about

doubt

specificity

the nature

as to for the

of the autoanti-

and nothing is known about how the tissue is damaged. A body involved, complement-fixing antibody occurs in the serum of rabbits, dogs, and several other

species

has yet injecting

not with

that

animals

type

when injected Other the

adjuvant

disease

from

disease

organs

or tuberculin, serum).

of testicular

cells

occurs

combined

to lupus

to acute ill

that

striking

immunization

thyroiditis,

extremely

in guinea

with Freund’s

adjuvants.

examples,

with

with circulating

high titer.

Since

node

disease

can be transferred

inwith

by the way, have shown

after

7 The

to react

extract

antibodies

this work,

moto’s disease, a form of thyroiditis the presence of antithyroid antibodies

this

of the delayed destruction

Aspermatogenesis

pigs

thyroiditis.

thyroid

by

successful

of lymph

that

to autoimmune

immunization

adrenal

similarly,

and one which

is allergic

no one

extract.

encephalitis.

of the eye3z16 are reported

and arthritis,

(which

to be vulnerable

in allergic

reported

injection

possibility

but

to another

show skin reactions

with brain

have been shown

animal

PatersonI

and Morrison,30

encephalitis

used

tract

the

type of allergy

Waksman

allergic

intradermally

immunization. One of the most shown

suggesting

techniques

extract

and uveal

back

Recently,

mixtures,l6JJ one

in rats by the intravenous

animals,

developing

Sdme

destruction testis

brain

the

immunized

the delayed,

cells but

by

with

of paralytic

from

volves

immunization in transferring

serum, even in heroic amounts.

transfer cells

after

succeeded

gland, after

will direct

Witebsky and

Freund’s

which

react

and

and with

pancreas,

appropriate our attention Roses2 have

adjuvants

leads

with thyroglobulin

it has been demonstrated

that

Hashi-

in human beings, is also associated with Now it appears in the patient’s serum.*”

that this kind of autoantibody may represent, in some patients, a manifestation of lupus erythematosus. I have recently been shown, by other clinicians, material from 2 patients with Hashimoto’s disease, who also had positive L.E. reactions, antinuclear antibody in the serum of patients and Vazquez 29 has demonstrated originally presumed to have only Hashimoto’s disease. Thus, we now have quite good evidence for the existence of autoimmune disease involving several different organs in experimental animals, and quite good evidence for at1 autoimmune process in thyroiditis in the human. With all this, the position for regarding autoantibodies as important factors in lupus From here to a similar view of rheumatoid erythematosus seems a stronger one. arthritis, with its rheumatoid factor, or with some other antibody against some as yet undetected tissue antigen, would require no great leap of the imagination.

Volume Number

10 5

RESE.kRCH

HOMOTRANSPLANTATION

What anisms

433

ARTHRITIS

IMMUNITl

is needed,

at this point,

in autoimmune

is more

information

about

the actual

mech-

and, in particular, about the pathologic For this, it may be helpful to turn events involved in this kind of tissue damage. our attention to another experimental model in which the immunologic destruction

concerned

ON RHEL-MATOID

of a predictable

before

area of living tissue can be brought about, This is the phenomenon of homotransplantation

our very eyes.

best exemplified Consider another,

disease

by the rejection the situation

of a skin graft.

of a homograft

on the fifth day after healthy

in appearance,

the

rabbit’s

own

day,

there

would be little

of the same

rabbit

done

so, the homograft plasma

hemorrhages

and,

to choose

between

albino

rabbit

is at this stage

and purposes, histologically

to well

part on

of this

this piece of skin and an autograft However, within the next day or

time.

infiltrated

one

tissue

for all intents If examined

tissues.

at the same

will become

which

eventually

the homograft If now, after

from

living

from

The

by large numbers

of lymphocytes

and

cells, densely concentrated in the immediate vicinity of small blood Small thrombi will occur in capillaries and venules, followed by petechial

vessels. day,

of skin,

transplantation.

vascularized, recipient

so to speak, immunity,

the same

the third

rejection,

donor,

or fourth

This,

as

become

will undergo

confluent,

and,

on the eighth

or ninth

rejection.

the same

accelerated

animal

is grafted

rejection

occurs

a second

time

with skin

and the skin is destroyed

on

day.

Medawar,

Billingham,

and

their

colleagues

have

shown,

is

an

immunologic phenomenon, and it represents one of the most highly specific and selective forms of hypersensitivity.14 It can be transferred from one animal to another

by means

of leukocytes

delayed,

or tuberculin,

in detail

a kind of artificial

and incorporates foreign antigenic

type.

a living material,

and is associated

It provides autoimmune

tissue

into

and finally

with skin reactivity

an experimental state

in which

his own, rejects

then

of the

model

for studying

an animal

first accepts

recognizes

it by actively

it as containing

destroying

it in its

entirety. Several years ago, Medawar known as homograft “tolerance,” proaches

to the study

and his associates

cells from one mouse are injected into a newborn newborn animal is misled into regarding the injected fully

grown,

other

line, This

such

a mouse

and will accept observation,

discovered

the phenomenon

which has since opened up several new apof autoimmune reactions. They found that when living

can them

which

be grafted

with

permanently

seemed

to hold

mouse of another line, the cell line as his own. When

skin

or other

as though promise

they

tissues

from

the

were autografts.

for future

n&w ways

of

bringing about permanent retention of homografts, soon led to an ancillary finding with quite the opposite implications-the so-called “runting syndrome”“which has suggested an entirely new approach to the problem of autoimmunit) and tissue destruction. The

runting

syndrome

is brought

about

in the following

manner:

Spleen

or lymph node cells from inbred adult mice of one line, say Ajax, are injected in When this is done, large numbers into newborn mice of another line, say C57.

434

J. Chron. Dis. November, 1959

THOMAS

two things

begin

to the injected throughout cells,

to happen.

Ajax

cells,

his tissues,

having

come

newborn

anemic,

mouse,

develops

in this

and dies within

rejecting

a graft,

adult

animal.

with

the

when

injected

with

mice immunized

is that not

he becomes

birth.

Here,

and

profoundl) organs,

instead

that runting isologous

spleen cells, presumabl>-

indicating

temporarily

also prevented

at least,

runting

from

such

spleen

homologous

the injected tolerant,

in which they find themselves.

of adult,

litters

“tolerant” themselves

fails

of the host

the host.

an injection

homologous

against

event

themselves

survive;

in our laboratory

the Ilewborn, cells;

becomes distribute

in his liver and other

or so after

has rejected

receives

We have

hon~ologous

are

cannot

of necrosis

two weeks

same time as the homologous cells have converted

mice,

situation,

been learned

C57,

to proliferate,

Hut, the second

rijax

lesions

the graft

mouse

mouse,

them

to the (‘57 tissue antigens

to grow,

if the newborn

mature

extensive

It has recently

recipient

and survive.

from

begin to form antibodies The

The

and allows

into an immunologically do not

Furthermore,

cells will confer

cells at the

that the isologous

b\r immunizing

mothers

cells.

can be prevented spleen

pregnant undergo

serum

passive

mice

runting

from

protection

adult

against

runting.‘” This bilities

area

of immunology,

for the study

or immullop~ltholog~,

of diseases

presumed

If we can look far enough

along

about

foreign

the ways

individuals,

and

in which the ways

these

approaches,

the activit!.

without jeopardy to the host. Whether or not this experimental rheumatoid seems

factor,

to me almost

and runting

which

the L.E. beside

factor,

the point,

has been

of its implications

that

of us who are primarily

arthritis

my

of such has

in many

for other

disease

anything

interested

to do with

interest

in

be cancelled

autoimmune

laboratories states.

possi-

established

cells can

of the kilown

lvith

find out new things

become

in view of the intrinsic

developed

regardless those

situation

or

cells

alive

with autoantibodies.

we may

antibody-forming

in which

seems

to be associated

the

diseases, in tolerance

across

the world,

Nevertheless,

I suggest

in the pathogenesis

of rheumatoid

and lupus would do well to keep a sharp eye on anything new that tyrlls and particularI>. in the runting s)-nproblem,

up in the homotransplantatioll

drome. The runting syndrome contains, defect in the placenta which might to take

up residence

in the fetus

that by the wap, the implication permit maternal reticuloendothelial

might

lead to serious

immunologic

an? cells

dificulties

Apart from this, there are other reasons for us later in life, in a hybrid species. which I should like to introduce as the next digresto be interested in pregnancy, sion in this lecture. It is a famous fact that rheumatoid arthritis often seems to undergo remission during pregnancy, a state of affairs attributed in some quarters to cortisone. Another, less famous but equally interesting, fact about pregnancy is that various other inflammatory reactions involving hypersensitivity seem to come under some dampening influence. Skin reactions to bacterial antigens, such as tuberculin, are said to become milder, various allergies ameliorate, and it is even claimed

that

skin homografts

persist

for longer

than

survival

periods.

THE FETAL

The

PLACENTA

most

remarkable

instance

of immunologic

apathy

in pregnancy

seems

The fetal placenta, in any hybrid species such as to me to be the placenta itself. The great mass of the ourselves, is in the biologic position of a homograft. placenta, blast,

with its branching

is actually

a very

individual-the distinct

manages

to survive

as would

in general.

quite events

are,

that

we might

ways

of being

fetal

or later

at some

pregnancy,

cells become

tissues

antigenically

to explain

in general

cipients,

but

are recognizable

the fetal

It occurred

to us that

tizing the mother circulation.

placenta

against

perhaps

This was suggested,

of some premature

this dilemma.

the placenta

One is

ma)’ be the case,

among

fetal cells, since

parturition,

month

a11 other

of gestation

fetal

b!r adult

re-

in persisting.

has a way of continually

releasing

im-

This

and are rejected

somehow

initially,

phenomena

so immunologically

and before

as homografts

itself by steadill,

7 or 8

probabl!,

understanding

away

In the ninth

succeeds

after

we would

such as eclampsia.

is forever

pregnancy

mature.

rejected

abortion.

trophoblast

time during

of one

of an immutl-

of autoimmune

have a better

mature as to be anonymous throughout al1 of pregnancy. but if it is it would imply that the trophoblast is unique sooIler

blood

of homografts,

and even habitual several

the

tropho-

by the cells

If we knew how this sort of homograft

for our understanding

the fetal

by syncytial

lined

circulate

kinds

which interrupt

of course,

the stand

must

or so, instead other

Also, parentheticall!,, of the placenta,

There to take

useful

villi covered

compartment

mother.

for 9 months

be the case with

of the pathologic separation

which

individual-the

know something

of chorionic

vascular

fetus-through

ologically days

stalks

large

desensi-

its own cells into the maternal

by the frequent

reports

by pathologists,

fragments in the capillaries beginning with Schmorl, 22of the finding of trophoblast of the mother’s lung in deaths from various causes during pregnancy, and especially

in deaths

from

Billingham

and

Brent’

showed

in mice

could

be considerably

homografts graft

were injected

eclampsia.

by vein,

several

beforehand,

years

ago that

prolonged

the survival

if the

with large numbers

of skin

recipients

of viable

cells

of the from

the donor of the graft. perhaps ceils,

It is a reasonable guess that some kind of desensitization, due to flooding of the host with a vast excess of viable antigenic

simply

is responsible Recently,

of pregnancy.28

of graft

that an analogous

survival. process

is going on during

most

We have sampled the uterine vein blood at various stages of the twelfth week onward, and have consistently found that un-

pregnancy

from

mistakable

syncytial

These

for this prolongation

we have learned

trophoblasts

cells are obviously

are present

so large

that

in the maternal they

would

blood.

inevitably

be stopped

by the pulmonary capillary circulation and, in view of the fact that approximateI\, one such cell is contained in each cubic centimeter of blood returning from the placenta, some mechanism must exist for their destruction. Otherwise, it is evident that the lungs would be virtually replaced by trophoblast after a few weeks of pregnancy. A possible mechanism for the lysis of trophoblasts is suggested

by our finding

that

they are extremely

vulnerable

to the action

of trypsin

436

J. Chron. Dis. November, 1953

THOMAS

and also plasmin. trophoblasts

Within

centimeter,

the

disintegrate

completely.

cell,

cells

and appears

Perhaps, emboli ance

does

lungs,

occur

property,

membranes with

any

proteolytic

may

viable

syncytial

the case,

be implicated

and

known

the)

type

of

of the trophoblast.

blood

enzymes

per cubic

rupture, other

or vulnerability,

if this is indeed

and substrate

of intact,

as low as 1 mcg.

into the maternal

plasma

And perhaps,

their

not

cells are released

of protease

after exposure

in concentration

vacuolated,

This

to be a special

as these them.

trypsin,

become

in the mother’s

destroy

a few minutes

to crystalline

and lodge as micro-

become

activated

abnormalities

in some

aud

in the bal-

of the accidents

of

This remains to be determined, but the possibility exists that here, pregnancy. at the far periphery, we may be dealing with mechanisms involved in the regulation or suppression of autoimmune to those which occur in rheumatoid

reactions arthritis.

in general,

and with events

At any rate,

related

it seems worth

while

and perhaps of importance to keep an eye on this adjacent field. One attractive opening is the recently reported observation *I that pregnant women do seem to become

immunized

the frequent

to the cellular

occurrence

or 6 pregnancies.

Perhaps

alld the sharing

of common

is, in any event,

I should

worth

mention

antigens

of agglutinins

of other

this is due to repeated antigens

looking

one other

between

trophoblasts

large

fibrinoid

be due to interaction molecular

To explore

size,

with

this further,

in the blood by injecting

approach

deposits

between

to the arthritis

we found

of papain,u~‘*J7

5

with trophoblast, It

problem

Shwartzman

and an acidic

of fibrinogen

we tried to manipulate

which

turned

to learn something about the mentioned, we formed the view

as an insoluble

the amount

reaction

polysaccharide

of available

of

mass.25,*6 fibrinogen

a variety of proteolytic enzymes, and by good fortune Papain had no effect relevant to the fibrinogen problem, led us straight

down

a new

garden

from the Shwartzman reaction, and, I suspect, closer to problems arthritis than we would have predicted at the outset. In brief,

bq

after

and leukocytes.

in the generalized

fibrinogen

precipitation

happened on papain. but did something else which

jection

as judged

in women

into.

in our laboratory while we were attempting origin of fibrinoid. As Dr. Dorfman has already might

beings,

leukocytes

immunization

up

that the intravascular

human

for human

that

when

a normal

the ears collapse,

rabbit

partially

is given at 4 hours

path,

awa)’

of rheumatoid

an intravenous and completely

inat

12 hours. This curious cosmetic effect is due to the loss of cartilage matrix. The same change, with depletion of the basophilic component of cartilage, occurs in As depletion of the basoghilic other cartilaginous tissues in all parts of the body. component of cartilage occurs, chondroitin sulfate disappears from the cartilage Evidently, what papaill has done is to unand appears in the rabbit’s blood. couple chondroitin sulfate from whatever the protein is that binds it in cartilage, and when this happens the structural integrity and rigidity of cartilage are lost. The mobility of chondroitin sulfate away from cartilage is hardly less striking Within 2 or 3 da>-s the rabbit’s ears are up than its resynthesis, or redeposition. begins to resume its normal histologic appearance. again, and the cartilage

Volume 10 Number 5

RESEARCH

Cortisone

prevents

ears in a state

ON RHEUMATOID

the reconstitution

of permanent

of cartilage,

collapse,

presumably

and

therefore

maintains

by preventing,

to do, the synthesis of sulfated mucopolysaccharide. and cortisone offer unexpected approaches for study joint

437

ARTHRITIS

the

as it is supposed

These effects of papain of the pathophysiology of

tissues.

EFFECT

OF VITAMIN

In closing, tance

that

which

A

I should

like to present

can be spanned

different

biologic

within

one final illustration

the problem

phenomena

can

of arthritis,

be related

of the biologic

dis-

and the distance

to each

other.

from

Fell

and

Mellanby,5 some years ago, showed that the addition of vitamin A to embryonic bone cultures caused a depletion of basophilia, and of chondroitin sulfate, from the growing

cartilage.

of vitamin

A could

to the plasma we felt duty tube,

on which bound

in large

basophilia droitin

doses,

appeared

A in cartilage,

Miss

I6 discovered of crystalline

Fell

bones

the thing

to young

of papain,

and

by the addition

embryonic

to turn

were cultivated.

around,

rabbits.

and metachromasia

sulfate

the action

Recently,

be duplicated

in the

blood,

conceivably

Having

36 hours,

indicating

that

found

ears

this,

collapsed,

matrix,

something

of a tissue

action

protease

A by stomach

the

from the cartilage

the activation

this

papain

and we fed vitamin

Within

disappeared

that

and chon-

analogous

protease

to

by vitamin

had occurred.

CONCLUSION I

seem to have

suggested

that

clude not only such immediately erythematosus serum

and

sickness,

immunologic

tolerance,

and the maternal now make rheumatoid

rheumatic

allergic host,

it clear

that

arthritis

the problem

related fever,

but

the runting none

problem;

syndrome,

distant

represent

proposed illustrations

placenta

A.

as answers

I should to the

of the diversity to questions my colleagues

now on

construct

in this lecture. matoid arthritis

The point to be made is that the future lines of research in rheumust include areas which now appear to be at the remotest

tinent

for it is here that

and meaningful,

investigation

although

list of problems

as

the panel could

periphery,

larger

in-

lupus

rejection,

of the fetal

of vitamin

of fields in which questions can be asked which are comparable being raised concerning rheumatoid arthritis. I am sure that a much

may

phenomena

homograft

the relation

are seriously

rather,.they

more

and those

arthritis

as disseminated

thyroiditis,

of papain,

of these

problems

also such

encephalomyelitis, the effects

of rheumatoid

clinical

will eventually

at the moment

in fields not mentioned

lead to the most

unpredictable,

per-

questions.

REFERENCES 1.

2. 3.

Billingham, R. E., Brent, L., and Medawar! I?. B.: Enhancement in Normal Homografts, With a Note on Its Possible Mechamsm, Transplant. Bull. 3:84, 1956. Billingham, R. E., and Brent, L.: A Simple Method for Inducing Tolerance of Skin Homografts in Mice, Transplant. Bull. 4:67, 1957. Collins, R. C.: Experimental Studies on Sympathetic Ophthalmia, Am. J. Ophthalmol. 32:1687. 1949.

438 4.

5. 6.

7. 8. 9. 10. Il. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

2.5.

26. 27. 28. 29. 30. 31. 32.

THOMAS

J. Chron. November,

Dis. 1959

Dixon, F. J., Vazquez, J. J., Weigle, W. O., and Cochrane, C. G.: Immunology and Pathogenesis of Experimental Serum Sickness, in Lawrence, H. S., editor: Cellular and Humoral Aspects of the Hypersensitive States, New York, 1959, Paul B. Hoeber, Inc. Fell, H. B. and Mellanby, E.: Effect of Hypervitaminosis A on Embryonic Limb-Bones Cultivated in Vitro, J. Physiol. 116:320, 1952. Fell, H. B., and Thomas, L.: To be published. Freund, J., Lipton, M. M., and Thompson, J. E.: Xspermatogenesis in Guinea Pig Induced by Testicular Tissue and Adjuvants, J. Exper. Med. 97:711, 1953. Germuth, F.: Anaphylactic Shock Induced by Soluble Antigen--Antibody Complexes in Unsensitized Normal Guinea Pigs, Fed. Proc. 16:320, 1952. Gitlin, D., Janeway, C. A., Apt, L., and Craig, J. M.: Agammaglobulinemia, in Lawrence, H. S., editor: Cellular and Humoral Aspects of the Hypersensitive States, New York, 19.59, Paul B. Hoeber, Inc. Kabat. E. A.. Wolf. .A.. and Bezer. X. E.: Raoid Production of .\cute Dessiminated Encephalomyelit’is in Rhesus Monkeys by I’njection of Heterologous and Homologous Brain Tissue With Adjuvants, J. Exper. Med. 8.5:117, 1947. McCluskey, R., and Thomas, L.: The in Vivo Removal of Cartilage Matrix by Crystalline Papain Protease and the Prevention of Recovery by a Direct .‘2ction of Cortisone on Cartilage, Tr. A. Am. Physicians 71:297, 1958. McCluskev. R.. and Thomas. L.: The Removal of Cartilace Matrix. in Vivo. bv PaDain: Iden&ication of Crystalline Papain Protease as the%‘Cause of ‘the Phenomen