THE WWW-D! DEE‘E‘EW‘” SHEEGWES

Thesis (or the Degree 0‘? W S.
W! TE-‘EEG‘W‘! 5 WE UW‘ EH33! 2‘!
HOWARD MRG!’ 3-H !Cl!<
1969

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University J

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THE ANTIBODY DEFICIENCY SYNDROMES

By

Howard Aaron Click

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements

for the degree of

MASTER OF SCIENCE

Department of Microbiology and Public Health

1969

DEDICATION

To my parents without whom I could not have started;

and to Beth without whom I could not have finished.

11

 

 

ACKNOWLEDGMENTS

I wish to thank Dr. David Bing for his aid in the

preparation of this manuscript.

iii

 

II
III
IV

VI
VII
VIII

TABLE OF CONTENTS

Introduction ............................... 1
The Agammaglobulinemias .................... S
Delayed Hypersensitivity .................. . 13
Fate of Homografts ......................... 14
Pathology .................................. 18
The Immune Systems ......................... 21
Hypotheses for the Defect .................. 24
Summary and Conclusions .................... 28
List of References ......................... 33

Appendix OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO... 39

iv

 

I

Introduction*

When a foreign substance, called an antigen, invades a
vertebrate organism certain substances called antibodies are
formed in response to the antigen and in one way or another
eliminate the potentiality of the antigen doing harm to the
organism. This is called the immune response. This process
is characterized by (1) its inducibility, being capable of
reaction only when activated, (11) specificity, acting only
on those molecules which activate it, and (iii) memory, re-
acting much more quickly, to a greater degree and for a lon-
ger time the second or more times it is stimulated by any
specific antigen; the last phenomenon is termed the anamnes-
tic response. In addition to the humoral response, which
is mediated by circulating antibodies, there is also a cel-
lular, or hypersensitive response which is characterized

and mediated by specific kinds of cells whose origin is in

 

* In preparing this introductory discussion many texts and
reviews were perused by the author. It was decided that the
source most relevant and applicable to the main topic was
The Gamma Globulins by C. A. Janeway et. 21' (36). Unless
otherwise Indicated all material in cars section was drawn
from that source. Other good discussions can be found in
such texts as Fundamentals of Immunology by W; C. Boyd and
Microbiolo by—B. D. DEVis, R. DuIbecco, H. Eisen, H. Gins-
berg, an . Wbod.

 

 

 

2
the lymphoid organs. Hypersensitive immunity includes
allergies, atopic (skin) reactions, and delayed-type hyper-
sensitivity.

Antibodies are globular proteins and are contained in
the gamma globulin portion of the blood serum when its pro-
teins are separated in an electrophoretic field. The gamma
globulins move most slowly toward the anode in a field at
pH 8.6 and exhibit a mobility of 10-Scm2volt-lsec-1; they
are immediately preceded by the beta globulins, which follow
the alpha globulins, which follow the leading fraction, the
serum albumen. The alpha, beta, and gamma globulins together
are termed the immunoglobulins. These proteins are not, how-
ever, found only in the blood; fifty-five per cent of the
total body gamma globulin is extravascular (23).

The antibody fraction of the immunoglobulins, abbre-
viated Ig, is comprised of three major types of molecules
designated IgG, IgM, and IgA. These molecules are physical-
ly and antigenically distinct. They are comprised of two
types of polypeptide chains, light or L-chains which are iden-
tical in all three antibodies, and heavy or H-chains which
carry the antigenic determinents Y,” , andot, which charac-
terize the molecules. The antibodies also carry two major
genetic markers called allotypes. The Gm allotype, of which
some twenty variations have been found, is located on the
H-chain of the IgG molecule and so is unique to this class of

antibody. The Inv locus appears on the L-chain and is found

in all antibodies.

 

3

The IgG molecule has a molecular weight of 145,000 to
160,000 and a Y-shape as seen in the electron microscope.
This molecule makes up eighty per cent of the serum antibody
in adults and is found in the normal adult serum in a concen-
tration of 700-1500 mg1.* The interstitial muscle IgG con-
centration is 200-250 ng. It is formed in response to pyro-
genic bacterial antigens, viruses and toxins. The IgM mole-
cule is the largest of the antibodies but is only five to ten
per cent of the total serum antibody with a normal concentra-
tion of 60-170 ng. It has a molecular weight of 900,000
and is comprised of five gM subunits of molecular weight
180,000 each. Each subunit has two L-chains and two H-chains.
This antibody comprises the heterophilic (Forssman) antibo-
dies, Wasserman antibodies, cold agglutinins, isohemagglu-
tinins, and is formed as antibody against the O-antigens of
gram-negative bacteria endotoxins. IgA is the hardest to
isolate. It has a molecular weight of 160,000 and is ten
per cent of the total serum antibody in a concentration of
150-250 ng. It has few proven specificities but may act as

an isohemagglutinin and as anti-Brucellar, anti-diphtherial,

 

and anti-insulin antibody. It is found in the largest con-
centration in parotid saliva, colostrum, tears, and in lesser

amounts in the bile, succus entericus, and prostatic fluid.

 

* The notation "ngZ" is equivalent to "mg/100 ml."

 

4
In the process of the immune response IgM is the first
to be present in detectable concentrations followed by IgA
and finally IgG. Small doses of antigen elicit only IgM;
however, there is then no anamnestic response to a second
challenge by the same antigen. The newborn infant starts
synthesis of IgM at birth and by the end of his first year
has seventy-five per cent normal IgM level. IgA synthesis

is usually begun by the third week and is seventy-five per

, 7......
-3351. "MLj

cent normal by the end of the second year. The IgG level ;
is initially high at birth because the infant is protected

 

by maternal IgG which unlike the other antibody molecules “'
can pass the placental barrier. One-half of this antibody
is catabolized by the end of the first week, three-fourths
by the second month, and so forth. The maturation of the
lymph tissue, the organization of follicles and the appear-
ance of plasma cells is complete during the third month of
life. At this time the infant starts producing his own IgG.
Antibody is produced by plasma cells in the red pulp
of the spleen, the medulla of lymph nodes, and the lamina
propria of the bowel. These cells are formed from plasma-
blasts which are reticular or other relatively undifferen-
tiated mesenchymal cells in the reticuloendothelial system.
Ig_gi££g small lymphocytes can be changed into large immuno-
globulin producing cells by stimulation with phytohemagglu-
tinin, a kidney bean extract. The antibody production occurs
in two phases, an afferent phase in which the antigen ini-

tiates a response in the cell and an efferent phase in which

5

the antibodies specific for the antigen are produced.
Usually one cell will produce antibody to one antigen and
possibly to different specificities of a single antigen;
also one cell will synthesize only one type of L- or H-
chain. Immunoglobulin synthesis can be inhibited by protein
synthesis inhibitors or by purine and pyrimidine analogues
which inhibit plasma cell multiplication.

There are two main hypotheses of antibody formation.
The template theory argues that the antigen acts as a form 5

on which the gamma globulin is molded into the configura-

 

tion of an antibody molecule specific for that antigen; the
instructional theory states that the antigen in some way
affects the plasma cell DNA directly thereby inducing it to
produce gamma globulin molecules specific as antibodies for
that antigen. Both hypotheses have their strong and weak

points, but neither has been proven to be the actual case.

II
The Agammaglobulinemias

In 1952, Colonel O. C. Bruton published the first re-
port of a case in which a child with a history of repeated
infections was shown to have no gamma globulin in his blood(5).
Bruton termed this disorder agammaglobulinemia. At first it
was thought that the absence of both gamma globulin and anti-

body from the blood were two separate and distinct signs of

 

6
the disease (31); it was not shown until later that the
gamma globulins were the antibodies. Since Bruton's obser-
vations were published several different kinds of agammaglob-
ulin disorders have been distinguished and studied. The
major types of this rare disease are transient hypogammaglob-
ulinemia; congenital and acquired agammaglobulinemia; dys-
gammaglobulinemia; and the even rarer hereditary thymic apla-
sia, also called alymphocytosis or "Swiss-type" agammaglobu-
linemia for the location of its first description. Fudenberg
also includes a "symptomatic" agammaglobulinemia in which the
disorder is not the primary disease but rather a secondary
phenomenon caused by the replacement of normal immunologically
competent plasma cells by foreign cells in diseases such as
myeloma or leukemia (15).

The hallmarks of the disease are an increased suscep-
tibility to bacterial infections as demonstrated by frequently
repeated infections over a period of time, an absence of anti-
body from the blood and tissues, the failure of antibody pro-
duction in response to antigenic stimuli, and the absence of
plasma cells from the tissues (25, 31). However, as assay
methods have improved it has been shown that all people with
gamma globulin deficiency disorders, even the congenital type,
have some small level of immunoglobulin in their body (20, 23,28).

Transient hypogammaglobulinemia is not actually a disease
but rather a physiological state brought about by an abnor-
mally prolonged delay in the onset of immunoglobulin synthesis

in the newborn infant after all the maternal IgG has been

catabolized (36, 53, 58). This condition can occur in both
sexes and recovery usually occurs between the ages of nine
and twenty-four months. During this period of deficiency
the infant shows an increased susceptibility to gram-posi-
tive bacterial infections, usually occurring in the skin,
lungs, meninges, and respiratory tract. The IgG reaches
adult level in two to three years (58).

Congenital agammaglobulinemia is a sex-linked disease

and as such occurs only in male children (21, 23). Its onset

it flax—1.4.1:.- A man‘s rm." --- “1.715;; ‘T!
I

is usually at about nine months when all of the remaining
maternal IgG has been catabolized; however, it may start as
late as the second or third year (23). The child is seen to
be subject to repeated infections by pyrogenic organisms such

as Staphylococcus aureus, beta-hemolytic Streptococcus, Mening-

 

ococcus, Hemophilus influenzae, and usually die of pulmonary
disease if left untreated (53). On the other hand, they show
no increased susceptibility to viral, protozoal, or fungal
diseases, or to infections by gram-negative organisms (23).
They can deve10p viral diseases expressing typical symptom-
610gy and clinical course including recovery and resistance

to reoccurrance indicating a normal capacity to produce inter-
feron in response to viral challenge (22).

There are certain collateral diseases which these child-
ren deve10p too often for pure chance (28, 46). They include
chronic lymphatic leukemia, an uncontrolled proliferation of
lymphocyte cell-types; collagen diseases, reflecting an

8
alteration of the connective tissue; and rheumatoid arthri-
tis-like inflammations, many times without a basis in direct
infection of the joints. Occurrence of these with agamma-
globulinemia questions the belief that they are due to ana-
phylactic-type hypersensitivity. But the demonstration that

agammaglobulinemic patients can develop bacterial allergies

 

even with the inability to form antibodies indicates that ‘rfln
they may have an allergic basis instead. :
In congenital agammaglobulinemia the IgG level is found S
to be anywhere from less than 10 mg% to as much as 80 ng f
(21, 23, 35, 36, 47, 54) but it is generally around 25 ng; E.“

the IgM and IgA levels are about one per cent of normal
though no demonstrable isohemagglutinins are present (53).
This is seen to be a total body deficit not just a blood
disorder (21, 23). IgG administered intravenously or intra-
muscularly is catabolized at a normal or slower-than-normal
rate (21, 22, 31, 45, 60) so that the deficit is due to de-
creased synthesis not increased destruction or loss. This

is likewise reflected by the almost total absence of plasma
cells, the antibody producing cells, from the lymph nodes,
spleen, intestine and bone marrow where they are usually

found (21, 23, 46). The lymphocyte count which is a standard
indication of the ability to respond to immune challenge is,
on the other hand, normal at approximately 2000 cells/mm (36).
The serum constituents involved in resistance to infection
such as complement, lysozyme, and properdin are in normal con-

centrations (36, 53). Atopic, allergic and delayed

9
hypersensitivity reactions, that is, cellular immunity, are
also seen to be normal; however, at the same time antibodies
are just not elicited by any antigenic stimulation including
those by such antigens as diphtheria, pertussis, typhoid,
and tetanus. It is interesting to note that certain animal
viruses and phage particles can cause very low titers indi-
cating that the small amount of antibody present in the
serum is not inert (53). These children cannot reject homo-
grafts (24, 27, 30, 31, 32, 43).

Finally, Tennenbaum observed a sporadic form of congeni-
tal agammaglobulinemia which seemed to represent an autosomal
rather than an x-linked recessive trait (58). The IgG con-
centration was reported as high as 400 mgl and low titers of
IgM, IgA and isohemagglutinins were seen. One-third showed
splenomegaly, and one-sixth lymphadenopathy.

An agammaglobulinemic condition occurring after four
years of age is usually considered an acquired agammaglobu-
linemia. This is an arbitrary cut-off point chosen due to
the overlapping at this early age between this and the con-
genital form of the disease. The acquired disease affects
both sexes equally and may be manifested as late in life as
the fifties (23, 54, 58, 61). These patients exhibit the same
signs and symptoms as do children with the congenital form,
namely, undue susceptibility to infection with pyrogenic
organisms, lack of plasma cells, and decreased antibody con-
centrations. The lack of plasma cells, in this case, is

due to the abiotrophy of the plasma cell containing follicles

Fam.mmzr mwm‘rmj
I

10
instead of a congenital defect in maturation (36, 53). The
IgG level varies greatly with a reported range of 10 ng to
500 ng (36), but it is usually between 50 and 100 ng (23).
A complication of this form but notthe congenital type is
a sprue-like syndrome (sore mouth, gastrointestinal mucous

membrane inflammations, loss of weight, weakness, and a per-

 

nicious anemia-like blood disorder) including malabsorption ir—fi
difficulties; however, biopsies of the bowel are usually

normal (36). There are frequent instances of noncaseating

granulomas of the lung, spleen, and liver (53). These pa-

tients reject homografts normally (27, 30, 31, 32, 54). One i——3

hypothesis for this disorder is that it may be due to the
failure of a homeostatic mechanism for the immune system (47).
The primary type of acquired agammaglobulinemia, just
described, is not associated with any underlying pathology
but has been genetically linked to family immunoglobulin
disorders and familial predisposition to collagen diseases.
The families of people with acquired agammaglobulinemia show
an unusually high rate of qualitative and quantitative gamma
globulin abnormalities, much more so than do families of
children with the congenital disease (13, 15, 56). Positive
reactions to Coombs‘ test for Rh antibodies have also been
found in unexpected frequency in first degree relatives (15).
It is most widely hypothesized that this familial disposition
is the reflection of a generalized hereditary disease of the
mesenchymal tissue rather than a defect restricted to the

gamma globulins (13, 15, 27, 62). Therefore, under different

ll
circumstances this genetic trait or group of traits may be
expressed as a collagen disease, agammaglobulinemia, bony
defects or some other congenital abnormality. One-third of
the peeple with acquired agammaglobulinemia have arthritis,
sometimes rheumatoid arthritis, others have collagen diseases
and widespread fibrinoid vascular diseases (62).

Secondary acquired agammaglobulinemia is due to diseases
nor primarily involving the immune system (58). Patients
with this type of disorder have either some blood dyscrasia
or diseases characterized by abnormil loses of serum proteins;
also seen connected with this syndrome are chronic lymphatic
leukemia, multiple myeloma (bone marrow tumors), Waldenstrom's
macroglobulinemia (elevated IgM, lymphocytosis of the bone
marrow), nephrosis, and protein losing enteropathies.

The dysgammaglobulinemias are disorders in which only
specific immunoglobulins are absent while the others are
normal or elevated. Janeway £5 21;, classified the dysgam-
maglobulinemias into three main types: Type I in which IgG
and IgA are absent and IgM is elevated; Type II in which IgA
and IgM are absent and IgG is normal or slightly depressed;
and Type III in which IgA is absent but IgM and IgG are nor-
mal (36). This disease affects both sexes and may be con-
genital or acquired. It is most likely a recessive autosomal
trait (58). Plasma cells may be anywhere from absent to pres-
ent in a normal number. However, a large per cent of sufferers

are unable to produce delayed hypersensitivity reactions (58).

12

Hereditary thymic aplasia, the so-called "Swiss-type“
agammaglobulinemia, results from the failure of the embry-
onic differentiation of the thymus gland (36). This type of
agammaglobulinemia is much more serious than the other types
because there is no immunologic competency at all in these
patients, cellular or humoral. They usually die within their
first eighteen months of life despite gamma globulin therapy
and/or thymus gland homografts (ll, 46). This is mainly an
autosomal inheritance and strikes both sexes though it occa-
sionally shows x-linked characteristics in some families
(36, 52). Children with this disorder show a sudden precip-
itous failure to thrive and grow. A distinct "runting"
syndrome is evidenced. They show susceptibility to both
gram-positive and gram-negative bacteria, delayed hypersensi-
tivity is uniformly absent and vaccination is disastrous
causing fatal progressive vaccinia (36). They cannot reject
homografts (ll, 46). A deficit of lymphocytes in the blood,
bone marrow, and lymphoid organs is evident (36). In one
case the peripheral lymphocytes were seen to be in a thirty
to sixty per cent normal concentration despite the thymic
aplasia (42). These cells, however, did not respond to phy-
tohemagglutinin. Rosen reported the successful transferrance
of hypersensitivity with maternal bone marrow cells and the
concomitant elevation of the peripheral blood lymphocyte
count to a normal level (52). unfortunately, the infant

died before its ability to produce antibody could be tested.

III
Delayed Hypersensitivity

The fact that agammaglobulinemic patients could exhi-
bit delayed-type hypersensitivity while apparently remaining
negative as to circulating antibody production proved to be
a great boon to immunologists. Here was a ready-made test
system provided by nature for the determination of whether
delayed hypersensitivity was due to circulating antibody or
a cellular mechanism.

IMany investigators have shown that agammaglobulinemic
patients can give positive Schick (3, 6, 31, 47) and Dick
(3, 31) tests even after injection with toxoid, and positive
tuberculin tests (23, 51), though in some cases only after
immunization with BCG (47, 48). In addition, positive skin
reactions to 2,4-dinitroflurobenzene (DNFB) (23, 33, 47, 48);
skin reactions to poison ivy (23, 36, 49), and drug reactions
to penicillin (23, 43, 45) and novobiocin (45) have been re-
ported. Also in the literature are positive monilia reac-
tions (7) and reactions to Ascaris extract (27). Many of
the investigators have been able to transfer the hypersen-
sitivity to normal persons via leukocytes but not via serum
(27, 32, 33, 47). This is the most direct evidence for a
purely cellular basis for hypersensitivity. One investiga-
tor was able to passively transfer hypersensitivity to an
agammaglobulinemic patient from a normal person; this state

endured for one and one-half years (31). In none of these

13

14
cases, however, were any antibody responses elicited, even
to bacterial antigens such as diphtheria, pertussis, typhoid,
and pneumococcus. No mouse protecting or complement-fixing
antibodies to viruses were elicited from these patients
though they did show normal symptoms and recovery from viral
infections (3, 6, 31, 49). Skin tests to alpha- and beta-

hemolytic Streptococcus, pneumococcus, Staphylococcus aureus,

 

 

ygcrococcug tetrogenes, streptokinase or streptodornase

 

proved negative (23). Reactions to vaccinations are erratic
(31). Of five patients vaccinated prior to admission, four
showed typical reactions while one failed to react to four
vaccinations. Two others showed accelerated responses to
repeated vaccinations.

Accumulation of evidence of this type led to the con-
clusion that hypersensitive reactions are mediated by some
mechanism other than one involving circulating antibodies.
It is believed that it is some sort of cellular response
probably mediated by the lymphocytes and macrophages.
Exactly how it works, however, is not known, only that it

works.

IV

Fate of Homografts

Just as the circumstances of agammaglobulinemia became

a proving ground for delayed skin reactions so too it became

15
the laboratory for the exploration of the graft rejection
phenomenon in humans. In this field of investigation the
results are nowhere near as clear as in the area of delayed
hypersensitivity. Most, if not all, investigators agree
that persons with transient (54) and acquired agammaglobu-
linemia (27, 30, 31, 32, 54) can and do reject skin homo-
grafts; persons with congenital agammaglobulinemia usually
accept them with more alacrity (24, 27, 30, 31, 32, 43)
though on occasion they can reject them normally (51, 54).
Investigators tried to utilize lymph node and thymus trans-
plants as therapy, hoping the grafts would take and provide
a population of cells with the ability to provide the recip-
ient with some protection or with some factor which would
help him become immunologically competent. The few experi-
ments along these lines were somewhat uniform in their re-
sults but erratic in their conclusions.

Using lymph node transplants Good got no gamma globulin
production in congenital agammaglobulinemia but did restore
a definite but minimal immune response to subjects with the
acquired form (30). Martin got full function in eight trans-
plants into patients with the congenital disease (41). The
nodes functioned normally for 100-110 days and then partially
for 50-60 days after that. There was still never any detect-
able rise in gamma globulin concentration, but the patients
did deve10p a specific delayed cutaneous hypersensitivity to
donor leukocytes though they produced no circulating antibody
to them. This was also noted by Gitlin (24). Martin's

16
subjects remained free of major infection for the life of
the transplant but suffered severe repeated infections once
again after their rejection. Working with congenital agamma-
globulinemia Gitlin,found that after implantation of unstim-
ulated lymph nodes, stimulation caused low titers of antibody
to appear for pertussis (23). These nodes were further seen
to hypertrOphy during periods of upper respiratory infection.
In patients with the acquired form, implantation of previously
stimulated lymph nodes gave an antibody titer for about two
months (23, 23).

Experiments with thymus implants have shown that the
graft can survive but has little or no effect on the recip-
ient (24, 34, 52). Gitlin 35, 31. found at autopsy that the
implant was compressed, the small thymocytes were gone though
the large thymocytes (reticular cells) remained, only remnants
of Hassall's corpuscles were visible, plus there had never
been any host tissue reaction (24). A lymph node draining
the area of the implant showed no histological change, it
was still devoid of lymphocytes. In addition, the number of
lymphocytes in the peripheral blood was unaffected by the
implant. In Harboe's experiment a fetal thymus was implanted
in the rectus abdominus of a patient with agammaglobulinemia
and severe lymphocytopenia (34). Prior to the transplant
no plasma cells were seen in the bone marrow, afterwards
small numbers amounting to one to two per cent of the leuko-
cyte population appeared. ~Cell migration to the graft was

negligible (in neonatally thymectomized mice,lymph cells

l7
repopulate a thymus graft after the donor cells are gone).
No delayed-type hypersensitivity was ever restored though
an increased concentration of donor type gamma globulin
appeared in the host's circulation. This did not affect
the wasting disease or the clinical course of the agamma-
globulinemia.

These studies were meant to help decide whether homo-
graft rejection is mediated by circulating antibodies or
a cellular-type immune mechanism. Stetson concluded that
delayed homograft rejection in patients with agammaglob-
ulinemia supported the participation of circulating anti-
bodies in this process (53). However, most other invest-
igators showed that the graft rejection process was not
associated with detectable antibody formation but rather
was probably a delayed hypersensitivity type reaction (10,
42, 51).

This prompts one to ask why children with congenital
agammaglobulinemia who can express delayed hypersensitivity
cannot readily reject homografts. It may be that the min-
imal amount of antibody present in acquired agammaglobulin-
emia is enough and/or necessary to mediate graft rejection
possibly acting as a cofactor with the cellular immune

process.

V

Pathology

The singularly distinguishable defect in the agammaglob-
ulinemias is the absence of plasma cells and plasma cell pre-
cursors from the lymphoid tissue, even after stimulation with
virulent antigens (10, 19, 23, 31, 51, 63). The lymphoid
tissues themselves are disorganized or atrophied, showing
little or no follicular development (23, 46, 53). In the
congenital form there is a striking absence of adenoid tissue
in lateral view x-ray photographs of the nasOpharynx (23, 36,
39, 53). This is, in fact, a diagnostic test for this form
of the disease. There is usually a hyperplasia of reticular
cells but the lymphocytes will be lowered in number (19, 53).
The tonsils and appendix show hypoplasia and disorganization
(36, 53, 58). There are more small lymphocytes seen in the
lamina prOpria and spleen than in the lymph nodes, but no
germinal or toxic centers are evident (19). The thymus is
usually of normal size and may even have a fairly well de-
veloped lobular structure (15, 19, 40, 58) but the Hassall's
corpuscles are absent or gone and so are the small thymo-
cytes (62).

Treatment of normal persons with cortisone can produce
the symptoms of agammaglobulinemia, but pituitary-adrenal
cortical function has been shown to be normal in agammaglob-
ulinemia (26, 31, 33) as has liver function (30, 51).

Hematological disorders are the rule (8, 15, 21).

18

19
There are defects in the maturation of neutrOphils, eosino-
phils, and lymphocytes expressed as neutr0penia and aleuko-
cytosis. Whether infections are the primary etiology and
hematological disorders are secondary to the toxic effects
of the infection, or whether the disturbances in the peri-
pheral blood represent an inherent cellular defect peculiar
to agammaglobulinemia is not clear (22). Also evident is
the absence of beta and beta globulins (8, 15, 21) and
the presence of thezfibnormal gigbulins betaZE, becaz , and
gamma1A (4).

The pathology is somewhat more striking in the ”Swiss-
type” (alymphoplashc) agammaglobulinemia. The thymus is
extremely small, weighing from a few milligrams to around
three grams, and sometimes even unrecognizable from sur-
rounding connective tissue. no Hassall's corpuscles are
visible, and the lobules, poorly defined if present at all,
are separated by large amounts of connective tissue (ll, 18,
36). Some autOpsies have shown that the gland did not des-
cend to its normal intrathoracic position but remained in
an embryonic location in the neck, thereby being a truly
vestigial organ (46). Lymphocytes as well as plasma cells
are completely absent from the lymph nodes, spleen, tonsils,
and lamina propria (19, 46). Gitlin found that despite the
thymic aplasia, there were significant numbers of small
lymphocytes in the peripheral blood, perhaps originating
from the appendix (19).

The complement system has been found to be subtly

20
affected in all types of agammaglobulinemia. This immun-
ologically important system consists of eleven proteins,
designated C'l through C39, C'l having three components.
It exists naturally in the blood and can combine with an
antigen-antibody complex causing lysis of the antigen if
the antigen is an intact cell. Though as a whole its level
is always found to be normal or slightly elevated (l, 52, 58)
this has been shown to be an artifact (22, 37). Jansen
and Kiss in 1957 showed that though the total complement
level was normal the C'l fraction was depressed. This
was seen to have been balanced by a cancomitant elevation
of the C'4 concentration. Gewurz in 1968 showed that it
was specifically the C'lq fraction of the C91 that was
diminished. Cqu is a gamma globulin and it directly
mediates the binding of the other proteins to sites on the
antibody molecule. It was found to be markedly more dimi-
nished in the "Swiss-type" (27% normal) than in any other
form of agammaglobulinemia (751 normal). At the same time,
C'lq titers were normal or elevated in other diseases asso-
ciated with repeated infections and malignancy (17). There-
fore, this deficiency was related to the type of agammaglob-
ulinemia not the extent of the immunological deficiency,
and seemed to be a part of the inborn defect. The child
does retain the ability to exert complement dependent
bacterial and immune adherence functions (unfortunately,
the complement-fixing antibodies are not produced).

Chromosome studies done by Fudenberg and Ahuya in both

21
congenital and acquired agammaglobulinemic cases showing no
underlying disease such as lymphoma or leukemia, were nega-

tive as to gross aberrations of the chromosomes (12).

VI
The Immune Systems

Immunological experiments involving the chicken led to
the first unequivocal demonstration of an animal with two
distinct and independent immune systems (3?, 17). One is
rendered competent by the thymus gland and is represented
by the small lymphocytes and the white pulp type of develop-
ment in tissues. It is responsible for the development of
immunologic competence reflected in the ability to initiate
a response to an antigen. The other system is directed by
the Bursa of Fabricius, an organ located near the cloaca,
and is represented morphologically by the large lymphocytes
and functionally by the ability to produce antibodies. This
separation is also seen in rabbits, where the thymus has
been shown to be necessary for the development of an immune
response but at the same time plays no part in the enhance-
ment or inhibition of antibody production (1, 38, 39). It
is thought that the gut lymphoid tissue (Peyer's patches and
the appendix) is the mammalian equivalent of the Bursa of

chickens. Studies showed that manipulation of these two

22
systems in the chicken could produce agammaglobulinemia
syndromes identical to those seen in humans. This was the
first time that agammaglobulinemia could be tied directly
to the workings of the immune response in an experimental
model.

Thymectomy and irradiation of chickens caused them to
lack a substantial papulation of small lymphocytes, to lose
the ability to develop allergic reactions and exhibit graft-
versus-host reactions, and to be unable to reject homografts.
They were also unable to form antibodies to certain antigens
even though there were normal amounts of IgG and IgM in the
blood (.9'). Bursectomy and irradiation did not influence
the normal development of a system of small lymphocytes in
the lymphoid tissue, the ability to reject homografts, or
the showing of normal graft-versus-host reactions. It did,
‘however, impair their ability to synthesize clearly definable
immunoglobulins, completely destroyed their ability to form
circulating antibodies even to strong antigens, and pre-
vented the formation of germinal follicles and plasma cells
(:9 , 44). These symptoms and manifestations are almost
identical with those seen in congenital agammaglobulinemia
in humans (46). In addition, chickens which were irradiated,
bursectomized and thymectomized were agammaglobulinemic,
leukopenic, and lacked both the humoral and cellular immune
responses (9:). This is identical with the ”Swiss-type“ of
agammaglobulinemia seen in man.

The discovery of two independent immune systems which

fl...

23
allow the production of conditions in fowl identical to
those manifested in human agammaglobulinemia has allowed
investigators to more clearly approach an explanation for
the pathology of the disease in man. It is this separation
of functions that would explain why agammaglobulinemic per-
sons can display cellular immunity while being devoid of
humoral antibody, why the lymphocyte count may be normal
while there is a virtual absence of plasma cells, and why
patients with certain agammaglobulinemias can reject homo-
grafts while others cannot. We are probably looking at
various degrees of impairment of one or both of the systems
rather than a defect in a single integrated response mechan-
ism.

Evidence for this is seen in that the thymus in man
too appears to have no clear effect on the germinal centers
or plasma cells (the immunoglobulin production center of
man) ('9 , 22). The tonsils and appendix are found to be
disorganized in congenital agammaglobulinemia and these
organs have been indicated by many as being the possible
human counterparts of the Bursa in chickens (2, "9., 32).
Recently, however, this has been seriously questioned and
Peyer's patches have been most strongly implicated along
with the appendix and other gut lymphoid tissue (Personal
Communication with R. Hong of R. A. Good's group at the

University of Minnesota).

VII
Hypotheses for the Defect

There are two main hypotheses for the defect which
causes the agammaglobulinemic condition in persons with the
typical forms of this disease. One group feels the fault
lies in the genetics of cell transformation (22, 50,359)
while the other cites the genetics of antibody polypeptide
chain synthesis (14, 15, 18). Both agree that the result
is the failure of the transformation of pre-plasma cells to

plasma cells; it is the process causing this that they dis-

 

agree on. (However, one cannot get around the virtual con-
genital absence of plasma cell precursors that underlies
the "Swiss" form of agammaglobulinemia.)

One argument is that since some gamma globulin, no
matter how slight, is produced in agammaglobulinemia it is
unlikely that the disorder can be attributed to the absence
of gamma globulin alleles (22). Furthermore, the mode of
inheritance of agammaglobulinemia, according to Rosen, is
different from that of the gamma globulin allotype making
it unlikely that these immunoglobulin disorders are directly
due to a genetically determined inability to synthesize all
or part of the antibody molecule (50). It is more likely
due to a genetic variation involving plasma cells either as
(i) an absence or suppression of genes necessary for the
synthesis of a substance essential to plasma cell formation,

or (ii) a genetic variation resulting in a substance inimical

24

25
to plasma cell formation. (The latter seems questionable
since Tormey st. 51. demonstrated that serum from agamma-
globulinemic patients did not inhibit plasma cell production
from normal precursors induced ig_!i££g with phytohemagglut-
inin (69).) Rosen goes on to state that since in the absence
of plasma cells, gene complexes for gamma globulin synthesis
lack the means of expression, the formation of plasma cells
could be dependent on activation of gamma globulin genes
and consequently these cells could not develop in the absence
of these genes. This would seem to be almost exactly what
Fudenberg is saying except that instead of the gamma globulin
genes being absent, Fudenberg sees them as being present but
defective (14-, 15); this would amount to the same thing if
the transcription was inhibited or in some way defective.

In experiments with phytohemagglutinin and streptolysin-S
Fudenberg showed that lymphocytes from agammaglobulinemic
patients showed the same mitotic potential as did normal
lymphocytes but no gamma globulin synthesis; he therefore
concluded that the problem was not in the genetics of cell
transformation but rather in its inducement. He feels that
it is the initial production of antibody that initiates the
transformation of plasmablasts to plasma cells rather then
vice versa as Nossal postulated (Sci. Am., Dec. 1964). The
primary defect is therefore the aberrant or lack of produc-
tion of the L- or H-chains resulting in defective antibodies,
and the lack of differentiation of lymphocytes to plasma cells

is the secondary morphological result of this genetic defect.

.f»

26

This conforms with Rosen's hypothesis that the defect is
the absence or suppression of genes necessary for the syn-
thesis of a substance required for plasma cell formation.
In this case, that substance is antibody itself.

The defect in antibody synthesis could possibly be
(i) a mutation at regulator gene loci controlling quanti-
tative aspects of immunoglobulin chain synthesis; (ii) the
loss or duplication of genetic material due to unequal
homologous crossing-over during mitosis or meiosis of
chromosomes bearing the structural genes for the H- and L-
chains (55); or (iii) a mutation at a structural gene (14).
The structural gene codes for a messenger RNA (mRNA) whose
sequence is read on the ribosomes and translated by transfer
RNA into an amino acid sequence thus creating a protein, in
this case, part of an antibody molecule. Cline 35,31.
showed quantitative abnormalities in net RNA labeling in
lymphocytes from agammaglobulinemic persons. However,
since the synthesis of ribosomal and transfer RNA was
grossly normal, it seemed apparent that the defect was
associated with either the afferent phase of the cell's
response or with the transcription of the DNA (.8). In
this case a mutation in a structural gene could possibly
result in (i) the formation of appropriate mRNA but in
insufficient quantities; (ii) the formation of altered
mRNA incapable of coding for normal immunoglobulin; or
(iii) the formation of faulty mRNA capable of binding to

and "blocking" ribosomes responsible for the synthesis of

27
immunoglobulin polypeptide chains (15). Any one of these
defects would cause aberrant production and, therefore,
aberrant plasmablast transformation.

As one can see, there are intrinsic contradictions in
each of these theories. When the antibody producing mechan—
ism is available in a normal cell, stimulation with phyto-
hemagglutinin will initiate antibody formation prior to mi-
tosis (15). So, if the genome for antibody production is
unimpaired but those for the cells that utilize them are,
why is it that precursor cell lines can be induced by non-
specific stimulants into transforming into unproductive anti-
body producing cells? On the other hand, if it is the anti-
body coding genes that are defective but not the transforma-
tion ones, why is some small level of antibody found in all
patients with agammaglobulinemia? The answer to the latter
question might be found in abnormalities at the Gm or Inv
loci. The Gm markers are found only on IgG molecules but
the Inv allotype is found in all antibody classes. Aberra-
tions at all Gm and the Inv locus would result in true
agammaglobulinemia, but abnormalities of only the Inv would
result in antibody molecules completely lacking or having
nonfunctional antibody combining sites. Patients so affected
would have measurable but physiologically inert immunoglob-
ulins (18). This could explain why there might be low levels
of perhaps "natural" antibodies present in the blood but none
produced by an immune response since the inducer molecules,

the antibodies themselves, are defective and unable to cause

28
a response to a challenge. This is assuming, of course, that
the change of a single amino acid in the allotypic marker
sequence would be enough to completely inhibit the effective-
ness of the molecule. It is obvious, though, that if the
condition were due solely to a defect in the antibody coding
genome, then the disease would have to appear as an autosomal
trait, In the case of the sex-linked varieties there may then
be a represser molecule being coded for on the x-chromosome.
This cannot be said for the transformation genome, however,

since it is not known how this is inherited.

VIII

Summary and Conclusions

The immune response of man protects him from invasion
by foreign and therefore potentially damaging organic mate-
rials. This response can take two forms, a humoral one med-
iated by proteins called antibodies, and a hypersensitive
one mediated by cells from the lymphoid organs. The anti-
bodies are gamma globulins and are synthesized by the plasma
cells in three major types, IgG, IgM, and IgA.

Recently, a condition has been discovered in man in
which the blood and tissues are devoid of the antibodies.
This has been termed agammaglobulinemia. The disorder can

take several forms including a nongenetic physiological

29
state occurring shortly after birth, and a genetically
determined defect which may be congenital or acquired. The
acquired form is so called because it occurs later in life
and was identified and named before it was known to have a
genetic basis. A third type of agammaglobulinemia, hered-
itary thymic aplasia, is a result of embryonic defects in
the differentiation of the thymus gland.

The agammaglobulinemic disorders are uniformly char-
acterized by the absence of plasma cells from and the general
disorganization of the lymphoid tissues. Since it is this
absence of plasma cells that is the singular gross defect
responsible for the lack of gamma globulin, the agammaglob-
ulinemia must be thought of as a secondary condition brought
about by the actual disease which this author believes could
more accurately be termed some sort of aplasmacytosis.

In the clinical course of the disease patients suffer
repeated virulent infections without the ability to produce
antibodies against the invading organisms. They can, on the
other hand, demonstrate allergic (cellular) reactions to
them. Children with hereditary thymic apiasia cannot ex-
hibit humoral or cellular immunity and, in addition, can-
not reject homografts. Patients with the congenital form
cannot reject homografts either, but those with the acquired
type can. PeOple with the acquired form also develop col-
lagen diseases too frequently for pure chance thereby sug-
gesting the possibility of some reciprocal or common causal

relationship.

30
The paradox of patients with typical agammaglobulinemia
being able to exhibit cellular but not humoral immunity
has been partially explained by the discovery of the exist-
ance of two independent immune systems. One system, depend-
ent on the thymus, is responsible for the cellular immunity,
the other dependent on the gut lymphoid tissue is respon-
sible for Ig competency. Experiments with these systems in
chickens has led to the creation of syndromes in fowl iden-
tical to those seen in human agammaglobulinemias. Destruc-
tion of only the Ig system resulted in typical agammaglob-
ulinemia with intact cellular immunity, while destruction
of both systems caused a syndrome identical with hereditary
thymic aplasia.

The circumstances of agammaglobulinemia and the syn-
dromes produced by it have been used as a model system for
the elucidation of the basis for hypersensitivity and homo-
graft rejection. It has been shown that hypersensitivity
is the result of cellular immunity since it can be trans-
ferred from agammaglobulinemic patients to normal persons
via leukocytes. The basis of homograft rejection, however,
is still not clear since children with congenital agamma-
globulinemia cannot reject them while pe0ple with the ac-
quired form can.

Even though this insight has been gained into the
nature of the normal immune response, the nature of the
disease itself is essentially as much a mystery now as it

was in 1952. The more that speculation is made in this area,

31

the more questions there are raised. For instance, if a
person with 100 ng gamma globulin can reject homografts
with the same alacrity as a person with 1200 ng who is to
say what a "minimal" amount of gamma globulin is? A "normal"
amount may be 700-1500 ng but is all this gamma globulin
really necessary or is it a supersaturation for the purpose
of being a totally unassailable defense? There are persons
with congenital agammaglobulinemia who lead perfectly normal
lives even without gamma globulin therapy. The only sign
of their deficiency is an abnormal electrophoretic pattern.

Hypotheses for the cause of the agammaglobulinemic con-
dition are based on explaining the fundamental defect, the
absence of plasma cells. There are two main hypotheses,
both are genetic in nature. One contends that the defect
lies in the genetics of plasma cell precursor differentiation
thereby eliminating the possibility of antibody synthesis.
The other states that plasmablast differentiation is actually
antibody induced and therefore the defect is in the genome
coding for antibody production thereby depriving the system
of its inducer molecule. Both these hypotheses have their
drawbacks and neither has been conclusively proven. The
problem with making genetic hypotheses at this time is that
not enough is known about the antibody producing and trans-
formation genomes themselves. With the possibility of re-
presser and inducer mechanisms, histone concentration var-
iables, and interacting autosomal and sex-linked genes, the

variety of theories that could be compounded is staggering.

32
Experiments in bone marrow replacement and general
lymphoid tissue transplantation has pointed to a possible
direction for finding a cure for the disorder. Currently,
the routine therapy is gamma globulin replacement. Inter-
estingly enough, though, the cure might be found before
the disease is discovered. This might have to wait until

DNA reading and genetic surgery are realities.

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tological Disorders. New Eng. J. Med. 266:473.

Zimmerman, H. H., and W. H. Hall. 1954. Acquired
Agammaglobulinemia: Report of Three Cases. JAMA.
. 156:1390.

APPENDIX

APPENDIX
The DiGeorge Syndrome

Another syndrome which lends evidence for the presence
of two independent immune systems in man was first described
by DiGeorge in 1965.1 It is caused by a congenital failure
in the development of the thymus gland from the third pharyn-
geal pouch. (The parathyroid glands also fail to deve10p
causing hypothyroidism, but this plays no known part in the
syndrome.) The symptomology resulting from this anomaly,
which ahould not be confused with Swiss-type agammaglobulin-
emia, is a mirror image of that manifested in congenital agam-
maglobulinemia, thereby demonstrating unequivocably the exist-
ance and independence of the two systems. The DiGeorge syn-
drome is characterized by the failure of the thymus and thymus
dependent lymphocyte system to develop. The presence of nor-
mal immunoglobulins and normal antibody formation is paralleled
by an absence of cellular immunity including impaired delayed
hypersensitivity, homograft rejection, and in 23552 lymphocyte

response to phytahemagglutinin. In congenital agammaglobulinemia

 

l. DiGeorge, A. M. Discussion of Paper by Cooper, M. D.
g£_gl. J. Pediat. 61:907, 1965.

39

40
the latter is normal and the former is grossly impaired. The
children described by Kretscher showed negative hypersensitive
reactions to monilia, streptodornase, streptokinase, diphtheria
toxoid, DNFB, and PPD while exhibiting prompt and extremely
high secondary humoral responses to diphtheria and tetanus
toxoids.2 However, patients with this syndrome die of re-
peated infections with bacteria, viruses, and fungi even with
normal immunoglobulin concentrations. (This would imply the
import of the cellular defense in combating disease.) They
have normal cortical germinal centers in the lymph nodes and
spleen with at least normal numbers of plasma cells present
there and in the medullar regions. The follicular develOpment
of the Peyer's Patches is normal. On the other hand, there
is a moderate to marked deficit of lymphocytes in the deep
cortical (thymus dependent) areas of the lymph nodes and the
venules and periarteriolar sheaths of the spleen.3 The cir-
culating blood lymphocyte count is normal or nearly so but
these cells show no response to PHA. The polymorphonuclear-
leukocyte function is normal as are the erythroid and myeloid
precursors in the bone marrow. This indicates no accompanying

disorders as is regularly seen in agammaglobulinemia.

 

2. Kretscher, R., B. Say, D. Brown, and F. S. Rosen. Con-
genital Aplasia of the Thymus Gland (DiGeorge's Syndrome).
New Eng. J. Med. gzg;1295, 1968.

3. Good, R. A., M. D. Cooper, R. D. A. Peterson, J. R. Hoyer,
and A. E. Gabrielsen. Immunological Deficiency Diseases
of Man-~Relationships to Disturbances of Germinal Center
Formation. In Cottier, N. Odertchenko, R. Schindler,
and C. C Confiden, (eds.). Germinal Centers in Immune
Responses. Springer Verlag New York Inc. 1967,
pp 0 393-395 a

41
Cleveland has reported total immunologic restoration of a
patient with the DiGeorge Syndrome by thymus transplantation
therapy.4
This syndrome in humans is equivalent to that which can
be induced in chickens by total body irradiation and removal

of the thymic masses while leaving the Bursa of Fabricius
intact.

 

4. Cleveland, W. W., B. J. Fogel, and H. E. Kay. Implant of
Foetal Thymus in Infant with III-IV Pharyngeal Pouch
Syndrome. J. Clin. Invest. 41:20a, 1968.

 

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