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On the mechanisms of transport and biological significance of antibodies in external secretions.

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CURRENT COMMENT
On the Mechanisms of Transport and Biological
Significance of Antibodies in External Secretions
By THOMAS
B. TOMASI,
JR., M.D., b . D .
Recent evidence suggests that the antibodies present in certain external secretions are produced locally, and that the
predominant immunoglobulin in these
secretions appears to be yA, which is
complexed to a nonimmunoglobulin glycoprotein referred to as the secretory
“piece” or T chain. The secretory im-
A
munoglobulin system may be of importance in determining local flora and the
resistance of mucous membranes to colonization by potentially pathogenic bacteria and viruses, and may be involved
in hypersensitivity reactions on mucous
surfaces as well as in certain so-called
autoimmune processes.
of observations in the older
literature indicate that under certain
circumstances susceptibility to infection
and resistance following immunization is
not directly related to the titer of serum
antibody. Studies, particularly those of
Burrows and Havens1 on experimental
cholera, suggest that the titers of antibodies
present in external secretions such as those
of the GI tract are better correlated with
resistance to infection than those of serum,
and moreover that secretory antibodies are
not derived from serum, at least by simple
transudation. Recently the characterization
and description of the secretory immunoglobulin system: the most outstanding
feature of which is the predominance of the
yA type of immunoglobulins, have helped
to clarify some of these older findings.
It has been found that nonvascular fluids
can, for the most part, be classified into
two groups. Internal secretions, such as the
aqueous fluid of the eye, cerebral spinal
fluid, and synovial fluid have a yG:yA
ratio which is similar to that of serum, i.e.,
5:1. External secretions, which bathe
mucous membranes which are in direct
continuity with the external environment,
show a predominance of yA. External
secretions include tears, nasal fluid, saliva,
respiratory and gastrointestinal tract secretions, and colostrum. It has been found that
the yA molecule of secretions has unique
chemical as well as antigenic properties
and that these characteristics are conferred
on the molecule by the presence of a nonimmunoglobulin glycoprotein termed the
secretory “piece” or T component.2 A similar type of system probably exists in many
species and has been most thoroughly investigated in the rabbit?
Evidence has been presented4 that the
11s secretory molecule, having a molecular
weight of 390,000,consists of a dimer of
7s yA plus the secretory “piece” (SP) of
molecular weight 58,000. Approximately 20
per cent of the SP is bound to the yA
portion of the molecule by noncovalent
forces and can be released by treatment
with agents such as urea or guanidine. The
From the Rheumatic Disease Unit, Department
of Medicine, State University of New York at
Buffalo, Buffalo,New York.
THOMAS
B. TOMASI,
JR., M.D., Ph.D.: Professor of Medicine, Rheumatic Disease Unit, De-
partment of Medicine, State University of N e w
York at Buffalo, Buffalo, New York 14214.
Reprint requests should be addressed to Dr.
Tomosi.
NUMBER
~~
ARTHRITISAND RHEUMATISM,VOL. 12, No. 1 (FEBRUARY
1969)
~~~~
45
46
remaining 80 per cent is bound firmly by
disulfide linkages and requires reductive
cleavage followed by treatment with hydrophobic bond-breaking agents. Whether the
noncovalently linked SP is present in those
y A molecules ( y A 2 class) which also have
noncovalently bonded L chains, as shown
by Grey et al.,5 has not as yet been determined. The SP isolated from the intact
molecule is identical immunologically to
that which occurs free or unattached in the
secretions of agammaglobulinemics, newborns, and certain adult secretions such as
urine and colostrum. The SP is responsible
for the unique chemical and antigenic
properties of the 11s secretory molecule,
the y A portion of the molecule apparently
being identical to serum yA, at least by
antigenic analysis. The significance of the
SP has not been clearly established although it appears to stabilize the yA molecule, rendering it more resistant to proteolysis with a variety of enzymes. There is
no evidence for or against its involvement
in the transport of y A from serum to secretions. Moreover, that SP binds nonspecifically to y A and has little or no biological
significance has not yet been completely
excluded.
The information presently available regarding the sites of synthesis of the secretory immunoglobulins is as follows:
1. There is no direct correlation between the
serum and salivary levels of yA in diseases associated with either increased or decreased levels
of yA in the serum. For example, in yA-type
myeloma the salivary levels are essentially norma12 and conversely several reports have appeared of patients with a normal secretory system
who apparently completely lack serum yA.6
2. There is a dissociation between the serum
and secretory levels in yA during development
following birth.? The secretory system appears to
mature more rapidly and reaches adult levels of
yA much more rapidly than does the serum. yA
can be detected in external secretions as early as
10 days of age, frequently at a time when
serum yA is demonstrated to be absent by sensitive technics.8
THOMAS B. TOMASI, JR.
3. Radio-labeled serum 7s yA given intravenously to normal individuals does not enter into
the saliva.2 Likewise, experiments with exchange
transfusions in newborns fail to show significant
transport of yA or other immunoglobu1ins.g However, one report has appeared indicating that
selective transport of yA into saliva may occur in
agammaglobulinemic subjects when high serum
levels are obtained by whole plasma infusions.10
In this situation the transport system is specific
for yA since yG, which is present in much higher
serum concentrations following infusion, does not
appear in the parotid fluid.
4. In tissue culture experiments, human parotid
and mammary glands incorporate 1%-labeled
amino acids specifically into yA.1 It is not known
in these studies whether the label is incorporated
in the yA portion of the molecule, SP, or both.
However, experiments with rabbit mammary gland
have suggested that the incorporation is primarily
into the SP portion of the secretory molecule.12
5. Fluorescent antibody studies in humans,2
and also in rabbits,l3 have shown an accumulation
of immunoglobulin containing plasma cells in the
lamina propria of the GI and respiratory tracts
and interstitially between the salivary gland acini.
yG and yM cells are present in varying proportions
but most tissues show a striking predominance of
the ybcontaining cells. Using SP specific antisera
no staining is seen in the interstitial or lamina
propria area and specific fluorescence is localized
to the epithelial cells.2
6. In patients with agammaglobulinemia and
dysgammaglobulinemia involving a deficiency of
serum yA, SP is synthesized in approximately
normal amounts.10 Moreover, the epithelial cells of
these patients stain with fluorescent SP antisera.
The above observations are most consistent with the following interpretation: In
the human salivary gland and probably the
GI tract and respiratory tract, a significant
fraction of the immunoglobulins present in
these secretions is synthesized locally in
lymphoid cells which are found in close
anatomical relationship to the glandular
and mucous membrane epithelia. The possibility of some transport from serum cannot
be excluded particularly if inflammation of
the mucous membrane occurs. The locally
produced y A is probably structurally identical with serum y A although this has not
been proved. yA traverses the basement
ANTIBODIES I N EXTERNAL SECRETIONS
membrane of the mucous membrane or
glandular acini and then by some as yet
unknown mechanism crosses the epithelial
membrane. Recent evidence obtained in our
laboratoryl4 suggests that transport is in
large part through intercellular channels.
In many epithelial tissues, such as those in
the GI tract and salivary gland, the apical
portion of the cell membranes of two adjacent cells are in direct apposition, forming a tight junction15 which presumably
would inhibit direct access via the intercellular channels of the secretory macromolecule to the lumen. Because of the
finding of a chain determinants along with
SP in the apical portion of the epithelial
cells, it is hypothesized that the secretory
molecule leaves the intercellular space at
its apical limit and migrates through the
cytoplasm and into the lumen perhaps by a
process of reversed pinocytosis. The SPYa
nonimmunoglobulin glycoprotein which is
intimately associated with cell mucins and
which has apparent specificity for the yA
molecule, is synthesized by the epithelial
cell. It complexes firmly with the (Y chain
of yA by both disulfide and noncovalent
forces to form the intact 11s secretory
molecule. Whether the yA is produced by
the plasma cell as an 11s molecule or
dimerizes on complexing with SP has not
been determined. Also, where the SP and
the yA portions unite, whether inside the
epithelial cells, on one of its surfaces, or in
the lumen, is unknown.
The hypothesis presented above concerning the morphological aspects of transport is at present highly speculative and
requires further experimental verification.
Although, as indicated, it seems likely that
in man the majority of yA in most normal
external secretions is synthesized locally,
there is evidence for individual variation
between secretions and in different species.
For example, in the case of the GI tract
and nasal fluid, a small fraction of yA may
47
be transported from serumlo and this may
increase if idammation is present. In the
mammary gland of certain species, such as
the cow and sheep, there is good evidence
that the secretory immunoglobulins are
derived from serum and that transport of
immunoglobulins is highly se1ective.l'
Whether the human mammary gland also
shows selective transport rather than local
synthesis has not as yet been determined.
Thus, although there appears to be
species variation and also differences between organs of the same species in regard
to sites of synthesis and mechanisms of
secretion of immunoglobulins, the common
characteristic in all species examined so far
is the presence of a specific immunoglobulin class in proportions quite different
from those found in serum. This, together
with the apparent independent regulation
of serum and secretory antibodies in certain
situations, appears to justify the separation
of the secretory system from that responsible for the production of circulating antibody.
The biological significance of the secretory system in terms of its role in normal
body defense mechanisms and in various
diseases is at present an area of active investigation in many laboratories. The secretions of normal subjects have been shown
to contain a number of "natural" antibodies,
and many of these have been identified as
secretory (11s YA) in type.lS It seems
likely that these immune globulins play an
important part in the regulation of normal
flora and the resistance of mucous surfaces
to colonization by potentially pathogenic
microorganisms and viruses, although this
has not been proved. Moreover, the mechanism by which yA-type antibodies exert
their protective action remains unknown,
since yA, both that isolated from serum
and that in secretions, does not fix complement. It is generally thought that antibodies inhibit the growth of bacteria only
48
THOMAS B. TOMASI, JR.
in the presence of complement causing termine whether local immunization is inlysis, or phagocytic cells leading to inges- deed the preferred route.
Of considerable interest is the possible
tion and killing by intracellular enzyme
systems. It has been suggested by Adinolfi participation of the secretory system in
et al.1° that secretory yA antibodies are able local allergic reactions of mucous memto lyse Escherichiu coli in the presence of branes. Evidence is available25 that indicomplement and lysozyme, all of these viduals allergic to ragweed have a secretory
components being required for lytic action. yA antibody in their nasal secretions which
However, these findings are yet to be veri- is capable of interacting specifically with
fied in other laboratories.
ragweed pollen antigens. Whether it is this
Evidence has been presented that re- antibody that is responsible for the clinical
covery from certain viral respiratory in- manifestations of ragweed allergy has not
fections is better correlated with the titers been shown. Likewise in the GI tract, parof viral-neutralizing antibodies in nasal ticularly in milk and food allergies, it is
secretions than with serum titemZ0Similar possible that locally formed secretory anticonclusions have been reached in regard to body is involved in these reactions.
respiratory infections with Francisella
The role of the secretory system in other
tularen.sis,21 in which the serum antibody human diseases has not been clearly deis primarily yM and the nasal secretion fined. It is possible, for example, that local
antibody entirely yA. In the GI tract it has antigen-antibody reactions involving the
long been known that recovery from ex- secretory system may participate in certain
perimental cholera is related to titers of of the so-called autoimmune diseases such
coproantibody rather than those in serum.l as Sjogrens syndrome, ulcerative colitis,
These observations raise important ques- and pernicious anemia. In this regard it is
tions regarding the possible efficacy of local of interest that secretory yA antibody capaimmunization against infectious diseases of ble of binding intrinsic factor has recently
the respiratory and gastrointestinal tract. been described in the gastric juice of a paIndeed initial studies have suggested that tient with pernicious anemia.26
aerosol immunization is more effective in
In clinical syndromes characterized by a
preventing influenzaz2 and t ~ l e r e m i a ~deficiency
~
of serum yA secretory yA is also
than is the parenteral route. Oral immuni- absent, although not infrequently replaced
zation may also be effective in preventing by other immunoglobulins ( particularly
diseases in which colonization occurs first yM) if these are present in the serum. It
in the gastrointestinal tract. This is par- seems likely that the deficiency of secretory
ticularly well demonstrated by the recent immunoglobulins participates in the lowstudies of Ogra et aLZ4showing the pres- ered resistance to infections which is often
ence of yA-type secretory antibody in GI manifested by patients with dysprosecretions following oral polio vaccination teinemias, although this has not been diwhich could be correlated with the ability rectly demonstrated.
to prevent the carrier state. Systemic imIn addition to its practical importance in
munization (Salk vaccine), although pro- human defense mechanisms and potential
ducing similar serum titers, did not result in in immunization programs, the presence of
coproantibody and was significantly less the secretory system raises many fundaeffective in preventing the carrier state. mental biological questions for future inFurther field trials are necessary in each of vestigation. How, for example, do the
the diseases discussed above in order to de- plasma cells which are in intimate associa-
49
ANTIBODIES I N EXTERNAL SECRETIONS
tion with the epithelial tissue differentiate
primarily into yA-producing cells? Do they
arise, as has been postulated for other immunocompetent cells, from bone marrow
precursors and colonize mucous membranes
such as those of the respiratory and GI
tracts? If this is so, do they arrive in the
GI and respiratory tracts precommitted to
synthesize yA or is there some influence of
the epithelial cells on the differentiation of
the secretory lymphoid tissue? What influence, if any, does the thymus have on
the differentiation of these cells? Alternatively, is it possible that the secretory
lymphoid cells differentiate directly from
epithelial tissue as has been suggested for
the bursa of Fabricius of chicken^?^' Once
SUMMARIO
IN
the yA is synthesized, what is its route of
transport through the epithelium and, since
evidence is available that only yA is secreted, what are the molecular receptor
mechanisms which determine this specificity?
Finally, although considerable emphasis
has been placed in this discussion on yA,
primarily because of its high concentrations
in external secretions and the present lack
of information concerning the other immunoglobulins, it should be pointed out
that the role of other immunoglobulins and
immunoglobulin fragments which are present in these fluids in small amounts may be
of considerable importance and deserves
more attention in future studies.
“TERLINGUA
Evidentia de discoperta recente suggestiona que le anticorpore presente in certe
secretiones externe es producite localmente e que le imrnunoglobulina predominante in
tal secretiones es YA le qua1 es complexe a un glycoproteina nonimmunoglobulinic
designate como “pecia” secretori o catena T. Le systema de secretion immunoglobulinic
es possibilemente de importantia in determinar le flora local e le resistentia de membranas mucose contra colonisation per potentialmente pathogene bacterios e virus e
ha possibilemente u n rolo in reactiones de hypersensibilitate a1 superficies mucose e
etiam in certe processos del typo appellate autoimmun.
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