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Immunologic deficiency autoimmune disease and lymphomaObservations implications and speculations.

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Immunologic Deficiency, Autoimmune Disease, and
Lymphoma : Observations, Implications,
and Speculations
By H. HUGHFUDENBERG
R
PROGRESS IN ANY FIELD tends
temporarily to create confusion and
eben chaos. Recent advances in immunologic aspects of disease have been no exception. In the past decade, we have acquired more new knowledge than our intellectual capacities and organizational
talents have been able to absorb and integrate. Clinically, information has accumulated most rapidly in three broad areas of
immimology, the areas where clinical immunology, rheumatology, and hematology
overlap: ( I ) the immunologic deficiency
\tates: ( 2 \ diseases of immunologic aberration;’ and ( 3 ) neoplastic diseases of
immunologically competent cells-i.e,,
lymphoreticiilar malignancies. The failure
to integrate this newly acquired information is evidenced by the marked controver\ > over the etiology and pathogenesis of
these three groups of diseases. This failure
i<
especially siirprising since the association
of diseases of immunologic aberration
( D I 4 ) and lymphoma within the same
tamilv, and indeed in the same patient, has
heen noted with increasing frequency in
the past decade.l:{ Similar associations
have been noted between DIA and immunologic deficiencie~’*~-~
and between immunologic deficiencies and lymphomatous
malignancies.1s7,h The simultaneous presence of immunologic deficiencies, DIA, and
lymphomatous malignancies, then, would
not be unexpected, as commented on previously.l The DIA most commonly seen
with lymphoma is antibody hemolytic
anemia. What is the significance of this
finding?
Our previous concepts of the mechanism
responsible for this association were based
on the assumption that somatic mutation of
lymphoid cells often takes place but that
the mutant cells are usually destroyed by
the normal immunologic apparatus. Thus,
in a normal person mutations giving rise to
cells containing antigens not present in the
iinaltered host cells wonld be destroved. In
contrast, mutations resulting in antigenic
deletion-i.e., in cells antigenicallv deficient
compared with the host cells-could
remain and proliferate. in effect constituting
a “graft” within the host. For instance. the
mutant lymphoid cells of a lymphoma
would constitute such a graft. In this in-
Prcserited as a Special Clinical Science Lecture
ut Johns Hopkins University School of Medicine,
Baltimore, Md., December 9, 1965.
The original work cited in this article was supported in part by Cancer Research Funds of the
linzzjei,\,ity of Califoi nia (Webster and Schutz
birnds), Grant #T-386 from the American Cancer
5 ociety, and Contract Nonr-2656(12) ( N R 105708) hctween the Office of Naval Research, Depaitnierit of thil Nacy, and the University of Califort~aaMedical Centei, Sun Francisco, Calif.
H. HUGH F v r ) E w m & , M.D.: Plofesror of Medzcine arid Director, Hematology Unit, Department
of Medicine, University of California School of
APID
Medicine, Sun Francisco; and Professor of Bacteriology and Immunology, UnicersiFU of Californab,Berkeley, Calif.
*The so-called “autoimmune” diseases. Our
group prefers the term “diseases of immunologic
aberration” since it does not imply a cause-andeffect relationship between the various disease
processes and the serologic factors characteristic
of each. The evidence that these “autoantibodies”
play an etiologic role in most of the disease entities
termed “autoimmune” is, at best, sparse,
464
ARTHRITIS AND
RHEUMATISM,VOL. 9. NO. 3
(JUNE),
1966
I\T\71’\01.OGI(
DEFICIENCY, AUTOIMM‘IJNE DISEASE, AND LYMPHOhlA
5tmce the normal tissues of the host contain antigens not present in, and hence
toreign to, the “graft.” Such antigens conc-civabl) might induce the production of
mtibodies lw the graft directed against
t h c ~normal host tissue. Since, hypothetical1). the aberrant tissues are perfused by host
blood, mutant lymphoid cells might protliicc1 anti-erythrocyte antibodies against
antigens present in the host but not in the
graft. thus providing a conceptual basis for
the frequent occurrence of Coombs’ positi\ o hemolytic anemia in lymphoma and
Ivmphatic leukemia.9 ( Other autoimmune
manifestations are also found frequently
in association with lymphoreticular malignancie\ in man.l”)
Hrwlts obtained in studies with animal
oxprrimental models lend credence to this
concept. Graft-versus-host phenomena can
hc induced \?,hen immunologically competent cell, are injected into hosts incapable
of rejwting them because of genetic toleranc-r t o all donor antigen. For example,
\ i i c * l i immunologic di
ise can be produced
experimentah by injecting a F1 hybrid
rnoiisc. ohtaincd ln crossing two inbred
\train\, with lvmphoid tiswe from a donor
of d h e i - parental strain.“ The lymphoid
cell\ are not rejected because the F1 off\pring i \ geneticall!l incapable of recognizing thv injected parental cells as forctign-i.e., the recipient is “tolerant” to all
donor antigens. Furthermore, the injected
parental lymphoid cells, lacking antigens
present in the F, hybrid, direct a specific
immunologic reaction against “foreign”
antigens present in the offspring’s immunologic and hematopoietic tissues,* resulting
in the characteristic wasting syndrome,
runt disease.f An almost constant feature
of the graft-versus-host syndrome is
Coomhs’ positive hemolytic anemia. Polyarthritis. dermatitis, m d nephritis may also
occur.‘5
In ag~~mniaglobulinemia,
where immuno-
465
logic defense against mutant tissues is impaired, an increased incidence of lymphoma might be anticipated’” and has been
confirmed statistically.’ Lymphoreticular
malignancy occurs frequently not only in
typical agammaglobulinemia, in which all
three serum immune globulins are missing,
but also in “atypical” agammaglobulinemia,
in which only one or two of the three immune globulins are markedly diminished.
For example, lymphoreticular malignancy
is often found in patients with ataxia telangiectasia,17”s a syndrome characterized
by marked deficiency of gamma globulin.
Similarly, the patient described in a clinicopathologic conference in 1962,19 who had
what appeared to be dysgammaglobulinemia type 11. developed a lymphoma ten
years after the first of a series of multiple
infections.
Diseases of immunologic aberration, immunologic deficiencies, and lymphoreticular cell malignancies thus have many overlapping features. They often occur simultaneously in a patient or, as discussed subsequently, in an experimental animal. Especially provocative is the occurrence of
all three entities in greater than anticipated
frequency in certain fa mi lie^.^,^ Preliminary
data on the pathogenesis of the clinical
condition in man and in animal models
suggest that disturbances of the thymus
and other lymphoid tissues may underlie
all three phenomena. Five lines of evidence
support this concept. First, neonatally
thymectomized animals are immunologicaluImmunologic attack on lymphoid and hematopoietic tissues in the absence of attack against
other tissues appears sufficient to cause graftversus-host disease.12
{Runt disease may also be produced by injection
of immunologically competent foreign cells into
lethally irradiated adult mice13 and by treatment
of newborn mice with cortisol acetate.14 Presumably both of these maneuvers result directly or
indirectly in a diminution of host lymphoid celb
and immunologic competence.
466
ly deficient. (Thymectomy at or near birth
generally impairs ability to reject skin or
tumor homografts,20z21impedes or prevents
tlie development of delayed skin reactivity
to serum protein antigens and to tuberculin,
and impairs the capacity to form antibodies
upon subsequent challenge injection of
either particulate or soluble antigens.21,22
Such animals also develop wasting disease,
liyperplasia of the reticuloendothelial system, and terminal lymphoid aplasia closelj,
\imilar to that seen in graft-versus-host disNeonatally thymectomized mice also
have a high incidence of autoimmune phenomena, including Coombs’ positive hemolytic anemia.24 Similarly, Coombs’ positive
hemolytic anemia occurs in neonatally
thymectomized rabbits,25 as well as in rabbit radiation chimeras with graft-versushost disease.26 Mice treated with irradiation and thymectomy develop renal lesions
of the so-called autoimmune variety, i.e.,
containing bound yG-globulin and complement as demonstrable by immunofluorescence and by immuno-electron microsThese renal lesions are indistinguishable from those seen in the spontaneous glomerulonephritis of the NZB/BL
strain of mice.28 Second, the thymus is
abnormal in NZB mice,”2Bwhich invariably
develop Coombs’ positive hemolytic anemia
at 6 to 9 months of age.3o An abnormal
thymus has also been found in the few
cases of lupus erythematosus and similar
diseases in which this organ has been
studied.“’ Third, about 20 per cent of the
NZB mice surviving the hemolytic anemia
develop lymphoma.32 As stated earlier,
there is a high incidence of lymphatic leuOThe previously cited observation in the
thymectomized animals243 suggests that the apparently genetically determined Coombs’ positive
hemolytic anemia that develops in the NZB mice
may result from thymic deficiency, rather than
fiom aherrant or excessive thymic function, as
postdated hv Biirnet and Holmes.29
H. HUGH FUDENBERG
kemia and lymphoma in patients with
agammaglobulinemia. Fourth, about onethird of the F, hybrid mice which survive
the graft-versus-host reaction produced by
transplantation of parental lymphoid cells
develop lymphoma.33 Fifth, a recent report
suggestive of thymic deficiency, graftversus-host disease, and leukemia in man3*
provides additional support for the concept
that thymic deficiency is the primary event
in the immunologic deficiency-DIA-hematologic malignancy syndrome. A phenotypically male Negro infant, seemingly normal
at birth, ceased to grow after the third
month and developed generalized eczema,
recurrent pulmonary infection, and diarrhea, features commonly seen in mice with
“runt disease.” Gamma globulin levels were
consistently below normal values for the
patient’s age. Cytogenetic studies of peripheral blood lymphocytes revealed not only
XY cells but also XX cells (approximately
one-third of the total). In repeated studies
of bone marrow and skin cultures only XY
cells were found. No erythrocyte mosaicism
was demonstrable, and the percentages of
leukocyte drumsticks and buccal mucosa
Barr bodies were in the normal range for
males. Consecutive bone marrow specimens
showed the development of a hypodiploid
stem line and morphologic abnormalities
of the metaphase chromosomes reminiscent
of acute leukemia. At postmortem, only a
thymic remnant was found. Since XX
chromosomes were found in peripheral
blood lymphocytes but in no other cells,
the XX lymphocytes presumably resulted
from a “graft” of maternal (XX) lymphocytes into the infant in utero, analogous to
the experimental transfer of parental cells
into the Fl hybrid. The clinical and pathologic similarities to experimental runt disease are striking. It seems likely that such
maternal-fetal leukocyte transfer occurs
frequently or always in normal pregnancy,
but that the transferred cells are rejected
TMMUNOLOGIC DEFICIENCY, AUTOIMMUNE DISEASE, AND LYMPHOMA
bv normal fetuses. Presumably in the cited
case, the infant, immunologically deficient
because of thymic absence, was unable to
reject them, i t , , in effect was “tolerant” to
them.
Extrapolation of these observations to
agammaglobulinemia may provide an explanation for the interrelationship of immunologic deficiency, DIA, and lymphoreticular malignancy. Fragmentary data suggest that autoantibody formation continually occurs in normal persons.35 In the
normal individual, however, any “excess”
antibody-forming cells directed against selfconstituents presumably are destroyed or
inactivated by a normal immune apparatus.
Perhaps in agammaglobulinemia the cells
responsible for these defense mechanisms
are “tolerant” to abnormal cells, and possibly to all cellular and soluble antigens.
Recent, although still controversial, data
suggest that the tissue lesions of autoimmune diseases are mediated by delayed
hypersensitivity mechanism^^^,^^ in which
the immune globulins are not involved but
that transplantation rejection is mediated
by gamma globulin of the microsomal fraction of lymphoid cell^.^*^^* If so, the tolerance hypothesis can be invoked to explain
the interrelationships between DIA, immunologic deficiency disease, and lymphoma. Whereas lymphocytes of normal individuals are able by “transplantation rejection” to destroy the “abnormal” lymphocytes responsible for inappropriate or
excessive auto-antibody formation, the
lymphocytes of agammaglobulinemic subjects are “tolerant” to these abnormal cells
and unable to destroy them. In effect, the
abnormal cells constitute a graft, destroying
normal host tissues (red cells, thyroid, and
other tissue) by the delayed hypersensitivity mechanism (lymphocytic infiltration)
shown, both experimentally and pathologically, to be involved in autoimmune disease.
Serum factors, i.e., circulating “autoanti-
467
bodies,” not only appear unnecessary for
such destruction but may even be protecWhat evidence exists for “universal tolerance” in the lymphocytes of agammaglobulinemic subjects? Previous concepts of the
defect in agammaglobulinemia attributed
the absence of plasma cells and of antibody
formation to the inability of agammagIobulinemic lymphocytes to undergo normal
differentiati~n.~Z
Lymphocytes from patients
with agammaglobulinemia, however, are
capable of morphologic transformation in
in vitro culture in response to certain stimuli
to the same extent as are lymphocytes from
normal subjects; such stimuli include lymphocyte antiserum44and certain nonspecific
substances such as streptolysin S (SLS)
and phytohemagglutinin (PHA ) .44,45 ( W e
envision SLS and PHA not as antigens but
rather as antibodies directed to lymphocyte
constituents, perhaps membrane antigens. )
In contrast, addition of known antigen to
the culture medium elicits morphologic
transformation of lymphocytes of normal
donors but not of agammaglobulinemic
donors previously injected with the antigen.44s45Presumably, agammaglobulinemic
lymphocytes lack the small amount of immune globulin, present within normal
lymphocytes, required to capture added
antigen and initiate, presumably by aggregation at the cell surface, the cellular events
leading to morphologic transformation. Presumably, in cells possessing the appropriate
cellular machinery, the initial reaction at
the cellular surface triggers a sequence of
events culminating in the synthesis of gamma globulin and specific antibcdy. Hence,
the lack of transformation of agammaglobulinemic lymphocytes may be envisioned
merely as the morphologic concomitant of
the primary genetic defect, a defect which
leads to abnormal transcription of DNA
coding for one or both of the polypeptide
chains of immune globulin and resultant
468
production of a quantitatively or qualitatively abnormal m e ~ s e n g e r - R N A46. ~Mea~
surements of incorporation of tritiated uridine into RNA in the presence of antigen
of lvmphocytes of normal and agammaglobulinemic individuals provided preliminary results compatible with this concept.40
Lymphccytes from normal individuals immunized with tetanus toxoid demonstrated
increased incorporation of uridine into RNA
attrr 72 holm of exposure to the same
touoid, as compared with control cultures
to which no antigen was added. In contrast,
the lymphocytes of agammaglobulinemic
i~idivitiualspreviously injected with tetanus
toxoid showed a consistent and significant
decrement in total labeled RNA 72 hours
J t e r exposure to antigen. The absolute decrease in labeled KNA in antigen-stimulated
criltures, a, compared with control cultures,
suggests more than merely an absence of
one subpopulation of lymphocytes responsible tor antibody formation. I t should be
empliasizcd that ;he distribution of labeled
1:henol-extractable RNA was identical in
unstimulated normal lymphocytes and
~igaininaglobiilinemiacells. The finding that
production of RNA (presumably messengerRNA) was decreased is compatible with
the concept that agammaglobulinemia
probably does represent tolerance, provided
that tolerance is defined as a “positive” state
rather than a mere absence of antibodyforming cells.47 Subsequent experiments indicated that neither normal granulocytes nor
normal RNA corrects the defective labeling in response to tetanus t o ~ o i d , ~
localiz*
ing the defect directly to the lymphocyte.
Hence, a quantitative defect in the synthesis or stability of lymphocyte RNA appears to be present in patients with agammaglobulinemia. This defect may result in
impaired formation of one or another of the
polypeptide chains of the immune globulins, the consequent lack of intralymphocyte antibody results in an inability to
H. HUGH I’lJDBKBl?RC
capture antigen and respond, i.e., in “tolerance” to soluble antigens. Similar tolerance
of agammaglobulinemic lymphocytes to
cellular antigens in “mutant” cells would
permit survival of these cells, proliferation
and immunologic attack against the host,
and the clinical concomitants-lymphcreticular malignancy and autoimmune disease.
Experiments designed to test these admittedly wholly speculative concepts are now
in progress.
Since loss of,4Urather than the presence
of, tolerance to “self-antigens’’ is one explanation often invoked to explain autoimmune disease, the concept of “tolerance”
as a prerequisite for autoimmune disease
at first glance appears untenable. Tolerance
to viruses, however, especially “slow” viruses,3o such as lymphocytic choriomeningitis virus ( LCM) , appears to be associated
with dramatic increases in the incidence of
both “autoimmune” manifestations and
hematologic malignancies.
A direct relationship between tolerance
and “autoimmune” disease is indicated by
the data of Hotchin.51 His study showed
that mice of appropriate genetic constitution, and tolerant to chronic asymptomatic
carriers of LCM virus, develop features
characteristic of runt disease, whereas nontolerant mice exposed to the virus do not.*
Further, animals whose immunologic capacity is impaired, whether by specific tolerance, neonatal thymectomy, irradiation, or
antimetabolic agents, are more susceptible
to viral agents.535.T Neonatally thymectomized germ-free mice develop neither the
wasting disease nor the proliferative lesions
seen in neonatally thymectomized conventional animals of the same inbred strain,56v5T
Similarly, germ-free mice treated neonatally
with cortisol acetate fail to develop the
wasting syndrome seen in conventionally
“Similarly, the incidence of leukemic tumors
in tolerant chick carriers of avian leukosis virus
is six times that in control birds.52
reared animals similarly treated.58 Hence
the possibility that the so-called autoimmune lesions and the proliferative, malignant lesions are merely direct manifestatioiis of virusesj9 or of normal bacterial
Hora, tionpathogenic in animals with normal
immunologic responses,58 clearly warrants
conbideration. In addition, since antibody
response to tissue constituents altered in
vivo is now well documented,6o an autoimmime process, if such exists, might b e
secondary to tissue destruction initiated by
“\low’” viruses in a host of appropriate
qeiietic constitution.61
These and related problems are currently
iiiider active investigation in many laboratories.”2 ti4 Although existing data and concepts are highly controversial, they are perhdp5 less XI thdn the use of lyniphocytotoxic
agents (6-mercaptopurine and its analogues ) currently advocated for the therapy
of these diseases in many institutions. T h e
current investigations, it is hoped, will provide definitive information on the etiology
and pathogenesis of DIA, immunologic
deficiency states, and lymphoreticular malignancies rather than proving to b e additional examples of the “wasting syndrome.”
ADDENDUM
Since submission of this article, a paper has
appeared describing the experimental testing of
some of these concepts (Walford, R. L.: Science
.152:78-80, 1966). The results indicate that inimunologic mechanisms probably do play a part in
the genesis of lymphomas. Theoretical considerations similar to those cited herein have recently
been set forth in a paper by Schwartz and Costea
(Seminars Hemat. 2( 1):2-27, 1966).
SUMMARY
r 1
I lie associatioii of‘ inmiinologic deficiency, autoimmune disease, and malignancy of
the Iymphoid cells is discussed. The association of these diseases both in a given individual and in families is higher than would be anticipated on the basis of chance alone.
I t seems likely that immunologic deficiency predisposes to lymphomatous malignancy.
Other diseases may also arise as a consequence of immunologic deficiency. Experi-
iiieiital data compatible with these concepts are reviewed and criticized. Work currently
i i i progress in many laboratories should soon provide an answer to the significance of
these provocative associations.
SUMMARIOIN INTERLINGUA
Es commentate le association de carentia immunologic, morbo autoimmun, e malignitate de cellulas lfmphoide. Le association de iste morbos-tanto
in individuos
particular como etiam in familias-es plus alte que lo que pote esser expectate a base
de coincidentia per se. I1 pare probabile que carentia immunologic predispone pro
malignitate lymphomatose. Multe morbos pote occurrer in consequentia de carentia
immunologic. Datos experimental supportante iste conception es revistate criticamente.
Labores currentemente in progresso in numerose laboratorios va tosto-on pote sperar
lo-provider un responsa a1 question del signification de iste interessante associationes.
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