Pediatrics852 IMMUNOLOGIC DISEASE which react with their own erythrocytes only in the cold. Upon rewarming comple-ment takes part in the reaction, and bysis Of the erythrocytes occurs,

AMERICAN ACADEMY OF PEDIATRICS

PROCEEDINGS

IMMUNOLOGIC DISEASE

By Sidney Raffel, Sc.D., M.D.Department of Medical Microbiology, Stanford University School of Medicine

PEDIATRICS, May 1958

849

PediatricsVOLUME 21 MAY 1958 NUMBER 5

I MMUNOLOGIC diseases are those in which

some kind of immunologic sequence of

events in the body is of prime importance

in initiation and progression. Underlying

this there may be an infectious or toxic

process, or simply exposure to an antigenic

substance or cell. The list of such diseases

is fairly lengthy, and they are often all

spoken of as diseases of allergy or hyper-

sensitivity. The main purpose of this paper

is to categorize these diseases, as well as

facts and speculation permit, on the basis

of underlying immunologic mechanisms;

the intention is to dispel the notion that

these are all necessarily products of those

changes which the term “hypersensitivity”

denotes.

It is worth while to bring precision to

our semantics because otherwise we may

easily be trapped into an assumption of

knowledge which we do not have, and

into a corollary tendency to stop delving

into that which we think we already know.

The term “hypersensitivity” implies certain

fairly well-understood immunologic proc-

esses which account for some of the dis-

eases to be mentioned, but from the mecha-

nistic standpoint these processes do not

Presented at the Annual Meeting, October 9, 1957.

ADDRESS: Stanford, California.

explain other disorders which may nonethe-

less be of immunologic origin.

The roster of these diseases includes such

unequivocally allergic conditions as asthma,

hay fever, serum sickness, and anaphybaxis,

as well as the so-called delayed allergic re-

activities which accompany infection or

follow contact with various plant and chem-

ical substances. To this list are added the

so-called “collagen” diseases : periarteritis

nodosa, disseminated lupus erythematosus,

rheumatic fever, rheumatoid arthritis and

dermatomyositis; glomerubonephritis, de-

myehinating encephalomyelitis, and sympa-

thetic ophthalmia; the disorders in which

two individuals are concerned, including

tissue grafting and transplantation, trans-

fusion reactions, erythroblastosis fetalis and

possibly reactions occasioned by platelet

and beukocyte group factors; and finally

those hematobogic disorders, including ane-

mia, thrombocytopenic purpura and agranu-

locytosis, in which a transfer of cellular or

tissue elements between two individuals

is not involved. There are other more re-

cent potential additions to this list; for ex-

ample, some kinds of thyroiditis’ may have

an immunologic basis.

by guest on February 26, 2021www.aappublications.org/newsDownloaded from

POSSI fiLE ME(Il ANISMS OF “IMMINOIA)GI( I)ISEASE’

IIy/)ersensitim’ity

. . . . CylotoxicitmjReaction Foreign A ntzgen+A ntibody

( humoral or cellular) I�()T17l5 Products Direct or Indirect Action of .4ntibodies on Tissues and (‘el/s

Which Injure Tissues

I 2 3 4

a. Ammaphylaxis

1�. Arthus

Periartitis mIo(IOSR

Serum sickness

Rheumatic fever?

Gloinerulomiephritis?

Demyelinating encephalomyelitis?

I)isseminated lupus erythemnatosus?

Rheumnatoid arthritis?

C. Atopic

Inhalants

Ingestants-foods

drugs

(Agranulocytosis?)

d. Infectious and contact (delayed)

Isoamltil)ody (vs. spe-(#{149}ft�antigens, or

cross-reactimmg for-

eign antigen)

II. RBC groups

Iraiisfusioii reac-

tions

Erytllroi)lastosis

fetalis

b. Platelet groups

C. Leukocyte groups?

d. Tissues generally

(grafting)

e. Experimental (Ma-

sugi) nephnitis

Antibody vs. foreignamitigen (drug, vi-

rus) acting tipoti

cells

a. RBC

I)rug-imiduced amie-

mnia

Virus (atyjical

pneumnonia)

1). I’lateletspurpura

(QuiriidineQuinine

Barbiturates

Benadryl#{174}

Sedormid#{174})

c. Leukocytes-agra ii-

ulocytosis

(Amidopyriiie, etc.)

(I. Other tissues, col-

lagemi?

Autoamitil)ody (vs. own

altered or cross-re-

acting foreign amiti-

gemi)

a. RBC

ileniolytic amiernia

Paroxysmal he-

moglobimiuria

Atypical pneun�omiia

(cold agglutimiins)

1). Platelets

Idiopathic thromu-bocytopenic pur-

pura

C. Leukocytes

Agranulocytosis?

d. Other

Thyroiditis

Sympathetic oph-

thalmia?

Disseminated lupus

erythematosus

Rheumnatic fever?Glommierimlomieplirit is?

l)emnyelimiatimig cmi-

(ephalomilyel itis?

I)ermnatomyositis?

Scleroderma?

850 IMMUNOLOGIC DISEASE

A great deal could be said about im-

munologic evidence concerning some of

these individual diseases, not much about

others. In this presentation little will be

said about any of them individually but

rather it is intended to essay a discussion

of two points : First, to set up a framework

of categories on the basis of how they might

come about immunologically; and second, to

say something about the general scope of

the evidence required to establish whether

or not these various diseases do indeed

originate from immunologic events.

Table I deals with the first point, the

organization of mechanisms of disease pro-

duction. This includes only pathways of an

immunologic nature; we cannot lose sight

of the fact that some of these diseases may

in the long run prove to have some other

origin. The immunologic mechanisms fall

into two general groups : hypersensitivity

and cytotoxicity.

Diseases of hypersensitivity (Table I,

column 1) depend in general upon the re-

action between an antibody and a foreign

antigenic substance. In the case of the

TABLE I


AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 851

ilnnze(liate reactions, this combination ap-

pears to release histamine among other puS-

sihie intermediary products, and this af-

fects various end organs-mainly 5ITh)Oth

muscle and vascular walls-to call forth

signs and symptoms which may be quite

variable in their manifestations. Such re-

actions account for anaphylactic shock, for

atopic hypersensitivities caused by inhaled

and ingested antigens, and for serum sick-

ness and peniartenitis nodosa. It may be that

collagen is also responsive as a “shock or-

gan” to such immunologic unions, and there

is some question as to whether rheumatic

fever, disseminated lupus erythematosus,

rheumatoid arthritis, gbomerulonephritis and

demyebinating encephabomyelitis should not

also be included here; this question will be

elaborated upon later.

Infectious and contact, delayed, hyper-

sensitive states fall into this column too,

and although one could readily organize a

debate within a debate regarding the rela-

tionship of this kind of hypersensitivity to

those already mentioned, we will for the

present accept on faith the fact that there

is such a relationship within the meaning

of the term hypersensitivity.

The second main category, cytotoxicity,

is subdivided into three kinds of mecha-

nisms. In these categories the damage done

to tissues comes about in a way which is

different from that occurring within the

understanding of hypersensitivity. Here,

there are direct actions of antibodies upon

cells or tissues, either because the anti-

bodies are directed against them (Table I,

columns 2 and 3) or against a substance

which is adsorbed to them (column 4).

In the first category under cytotoxicity

(column 2) two individuals of the same

species are involved, one supplying antigen,

the other antibody. The resulting reaction

occurs in one of these individuals where

the two entities have come together and is

called an iso-immunologic reaction. In the

transfusion reaction the individual supply-

ing the antibodies is usually the injured

member, while in erythroblastosis fetalis it

is the antigen possessor who fares badly.

The principle underlying both cases is of

co�irs’ the same; afltil)O(lies react with cry-

throcytes to cm-np them and eventually to

bead to their destruction. It seems doubtful

that intra-species antigens which are known

to exist in blood 2� and in leuko-

cytes4 bead to equally important untoward

results because their relative masses in the

blood stream are small.

In column 2 also falls the fascinating sub-

ject of tissue and organ grafting. It has

been surmised since Paul Ehrlich’s time’

that the rejection of homologous tissue

grafts might be an immunologic one, but

something more than suggestive evidence

for this hypothesis has appeared mainly in

recent years. To mention several high points

of this evidence: Irradiated or cortisone-

treated animals are able to accept grafts

during the time when their immunologic

processes are interfered � subjects

with hypogammagbobulinemia can accept

grafts at least for long periods of time;8’

and acquired postnatal tolerance to tissue

grafting can be induced by exposure of ani-

mals to the tissuesin utero.’#{176} The nature of

this immunologic reactivity to tissues is still

not clear. Certain evidence suggests that a

humoral antibody is involved while other

observations implicate lymphocytes as the

instrument of rejection.1’

The next category under cellular toxicity

(Table I, column 3) encompasses a more

subtle situation in which two subjects are

not involved. Here in some peculiar way

an individual becomes reactive to his own

tissues. Ehrlich speculated about this possi-

bility, to which he gave the name “horror

autotoxicus,” much as we speculate about

the potential consequences of radioactive

fallout. But this is not a speculative situ-

ation; it has been brought to pass expeni-

mentally on many 12 and you are

all aware of at least one classical spon-

taneous example of this in the human being

-paroxysmal hemogbobinunia. The mecha-

nism of this defect was described by Donath

and Landsteiner’3 years ago. Occasional in-

dividuals, formerly thought to have syphilis

but probably not,14 possess antibodies



which react with their own erythrocytes

only in the cold. Upon rewarming comple-

ment takes part in the reaction, and bysis

Of the erythrocytes occurs, just as in the

well-known hemolytic reaction in the test

tube. In addition to this special case, a

variety of acquired hemolytic anemias have

in the past 10 years been shown quite con-

elusively to depend upon an autoantibody,

and although all facets of correlation be-

tween presence or titer of antibody and

clinical status have not been adequately

explained, the broad truth that these are

diseases of autoantibody activity seems to

be ed516 The revelation thatmany cases of idiopathic thrombocytopenic

purpura depend upon a similar process is

well known.17 A similar rationale to explain

instances of agranulocytosis is, surpris-

ingly, very sparsely documented. Anti-

bodies against leukocytes in such patients

have so far been demonstrated in only a

few of the total cases 19

These hematobogic instances whet our

expectations that a similar kind of process

may explain the pathogenesis of other dis-

eases as well. Autoantibodies may be pro-

duced against other, less readily manipu-

lated cells, as exemplified by Stefanini and

Mednicoff’s20 report of antibodies for endo-

thelial cells in the sera of some patientswith thrombocytopenic purpura and pen-

arteritis nodosa. As already mentioned,

rheumatic fever, glomerulonephnitis, dis-

seminated lupus erythematosus, rheumatoid

arthritis and demyelinating encephabomye-

litis may represent diseases of hypersensi-

tivity, but also might fall into this category

instead. To take rheumatic fever and gb-

merubonephnitis as examples, both are

known to follow streptococcal infection.

Does the patient become hypersensitized to

some component on product of the strepto-

coccus so that, upon subsequent reaction of

the antibody with a coccal constituent, le-

sions occur in the gbomerubus on in the myo-

cardium and heart valves? On does the

streptococcus in some way induce the for-

mation of antibodies against kidney and

heart components? There is some experi-

mental evidence for both possibilities, and

it is too early to make a choice.’�24 There

are also alternative possibilities, such as a

direct action of a streptococcal toxin upon

affected tissues” or the occurrence of a

Shwartzman reaction.21’

The final category under cytotoxicity

(Table I, column 4) has to do with another

mechanism by which antibody may destroy

cells. In this case the antibody is not di-

rected against the cell itself, but rather

against an extraneous substance adherent

to it. It is a webb-known serologic technique

to dip erythrocytes into antigen which may

become adsorbed to the cell surface. Ex-

posure of such cells to an antibody against

the adsorbed antigen results in agglutina-

tion, and beyond this, the addition of com-

plement can induce lysis of the red cell.

The latter is a rather surprising fact if one

conceives of the cytolytic activity of anti-

body as a performance involving structures

of the membrane vital to the cell’s integrity.

But it is obvious from repeated test-tube

demonstrations that antibody need not be

directed against a portion of the cell itself

for lysis to eventuate, but only against some-

thing stuck onto it.

Some instances of hematobogic disease

seem to depend upon this kind of mocha-

nism in the body. Thus, there are anemias,

leukopenias and purpuras which are oh-

viousby related to the administration of

certain drugs, and which depend upon an

acquired factor in the serum of the pa-

tient.15’ 27-81

An interesting facet of this kind of ac-

tivity is that concerned with viruses. Cer-

tam of these agents have a predilection for

adsorption to erythrocyte surfaces. Aside

from the fact that the viruses themselves

can cause hemaggbutination, it is interesting

to consider that the antibodies directed by

the patient against the virus may in the

long run affect his own erythrocytes by

acting upon the virus in that locale. There is

some evidence for this in Newcastle virus

disease and possibly also in mumps and

measles.’4’ 32, 33 It is entirely possible alsothat other tissues aside from the easily cx-



amined blood elements may become in-

volved in activities of this kind. For cx-

ample, the fibnils of collagen may perhaps

adsorb drugs or viruses or other foreign

agents and be destroyed by antibody di-

rected against these.

We turn now from possible immunologic

pathways of disease production to the see-

ond point to be considered-the question of

the nature of evidence required to establish

a disease of the human being as one of

immunologic origin. Such evidence can

come from two sources: 1) clinical obs�rva-

tion and experimentation, and 2) expeni-

ments, mainly of inductive type, in lower

animals. An analysis of these kinds of cvi-

dence for each individual disease in the

roster would be outside the scope of this

discussion, but certain generalities can be

undertaken.

So far as evidence from the human being

is concerned, crucial information would in-

elude identification of the antigen con-

cerned, whether intrinsic or extrinsic, identi-

fication of the immunologic response di-

rected against this, and demonstration that

this immunologic response can cause dam-

age. In diseases of ordinary hypersensitivity

(Table I, column 1) these demonstrations

can often be accomplished, and they are to

some extent a part of routine clinical prac-

tice. The same may be said of periarteritis

nodosa, where a close relationship between

administration of an antigen and the oc-

currence of hypersensitivity and the patho-

logic process has been established.’4 In the

isoimmunologic diseases (column 2) these

postulates have also generally been met.

In the instances of the autoimmunobogic

diseases of the blood (column 3) antibodies

can be demonstrated either in the serum

on on cells or both,’5 and the antigens can

be at least located in cells even though they

cannot usually be identified. This is more

or less true also of the drug-induced hema-

tologic disorders (column 4) in which there

is a fair amount of evidence that the re-

sponse is directed against drug or perhaps

in some cases, virus, as already discussed.

There remain a number of other impor-

tant instances in which such information

has not been clearly established; these are

the diseases which in the preceding dis-

cussion could not be assigned to a definite

category in the Table. These include gbom-

erubonephritis, rheumatic fever, demyehina-

ting encephalomyelitis (with multiple scie-

rosis as the outstanding example), dissemi-

nated lupus erythematosus, rheumatoid

arthritis, dermatomyositis and scberoderma.

Of these, most information is available for

the first two, but there is little as yet upon

which investigators can agree. Antibodies

against kidney tissue have been reported

as occurring in the sera of patients with

glomerulonephritis by a number of investi-

gators, but not by 223, 36 In addition,recent work of Melbors and Ortega37 and

of Vazquez and Dixon38 has beautifully

shown, using Coons’s technic of fluorescent-

antibody staining, that gamma-globulin is

present in high concentration in the gbom-

erular lesion in nephritis. This is only pre-

sumptive evidence of antibody, but it is

suggestive. In rheumatic fever there have

been positive and negative reports of anti-

bodies against heart tissue,22’3941 and here

again the fluorescent-antibody technic has

demonstrated gamma-globulin in the cen-

tral lesion, the Aschoff body.38 Also, pa-

tients with this disease may be more sensi-

tive responders to various immunologic

stimuli than are other members of the

population.4245

In multiple sclerosis there is virtually no

direct evidence of an immunologic re-

sponse; most of the search for such a basis

for this disease stems from its similarity

to the demyelinization which can be readily

established in lower animals by apparently

immunologic 46 and from the fact

that some patients vaccinated against rabies

produce antibodies for nerve tissue,47 and

occasionally develop a demyelinating dis-

49 This is as yet a very roundabout

suggestion that “autoantibodies” may be

of some importance in the etiology of

multiple sclerosis.50

Various pieces of evidence suggesting

implication of immunologic mechanisms



cotild 11S() be cited, in diniinishing volume,

for disseminated luptis erythematosus and

the other diseases about which theme is

question. But in none of these cases has

the evidence-the demonstration of anti-

body, of antigen and of the injurious na-

ture of the reaction between them-come

full circle in satisfying fashion.

Experimental animals have been used

extensively in efforts to further understand-

ing of many of the diseases in question. The

reproduction in the lower animal by im-

munologic procedures of a condition which

occurs spontaneously in the human suffers

the disadvantage that the similarities may

be merely coincidental. Thus, one of the

easiest of the pathologic situations to pro-

duce in animals is demyehinating encephalo-

246 and furthermore this can be

accomplished employing brain tissue of the

experimental subject itself.” Yet there is

absolutely no factual basis at the present

time which will permit us to equate this

experimental feat with multiple sclerosis.

Again, if we take the single question as

to whether antibodies against kidney can

actually cause a glomerular lesion the an-

swer from experiments is emphatically, yes.

Experiments of the Masugi type (in which

antibodies produced in one experimental

animal against the kidney of another are

subsequently injected into the donor ani-

mal) cause lesions which most pathologists

consider to be those of glomerulonephritis.12

Yet for reasons already discussed there is

so far no satisfying equation of the experi-

mental with the clinical situation.

Indeed, it is an interesting fact that, at

the present time, those instances in which

clinically derived evidence is best in im-

plicating immunologic processes in the

causation of a disease are those in which

experimental evidence in lower animals is

poorest, and vice versa. Certain individual

instances of this kind are worth noting. In

the human being the most fully rounded

evidence for an autoimmunologic process

occurs in the hematologic disorders in-

volving erythrocytes and platelets, as men-

tioned before, yet no one bias succeeded in

reproducing an autoimniune anemia or

thirombocvtopenia in an anitnal. Certain

investigators� � have goiie so far as to

show the presetice of autoantibodies in ani-

mals given repeated injections of their own

erythrocytes under various conditions, but

they have established no anemia on this

basis. In comparison, the very good experi-

mental model which exists for the demye-

linating diseases and the Masugi nephrito-

genie model described before have failed

to clarify the pathogenesis of related hu-

man diseases.

Plainly, the immunologic evidence avail-

able in respect to the puzzling diseases ap-

pearing in Table I is very piecemeal but

suggestive. It is for this reason that in this

essay an attempt has been made to organ-

ize mechanistic pathways and to offer some

perspective of the nature of the questions

which require answers. If thinking in the

past had been confined to “hypersensitivity”

in its true immunologic sense, no one would

have sought for antibodies directed against

the patient’s own blood cells in cases of

hemolytic anemia or in idiopathic thrombo-

cytopenic purpura-hypersensitivity pre-

supposes a reaction of antibodies or tissue

cells with extrinsic antigens followed by the

action of intermediary substances upon cer-

tam body structures, of which the red blood

cell and the platelet do not appear to be

representatives. Tables of organization may

be restrictive, but if properly viewed they

can also provide impetus to the imagina-

tion.

ACKNOWLEDGM ENT

The author takes this opportunity to pay

tribute to one who has contributed to our

knowledge of the subject. This paper is

dedicated to the honor of Dr. Josef Tomcsik,

Director of the Institute for Hygiene and

Bacteriology at the University of Basel

School of Medicine on the occasion of his

sixtieth birthday.

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Pediatrics852 IMMUNOLOGIC DISEASE which react with their own erythrocytes only in the cold. Upon rewarming comple-ment takes part in the reaction, and bysis Of the erythrocytes occurs,