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Leukocyte Вsense organs.

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CURRENT COMMENT
Leukocyte “Sense Organs”
Erik E. Carlson and Ronald P. Messner
A clearer understanding of the immune
and inflammatory responses active in many
diseases has been delayed by our incomplete knowledge of how lymphocytes recognize specific antigens and how phagocytic
cells select the particles which they engulf.
The development of methods for the precise therapeutic manipulation of these processes has been similarly hampered. Significant advances have recently been made in
these areas. Currently available evidence
indicates that structures providing the specific recognition systems necessary for their
function exist on the surface membranes of
lymphocytes, monocytes, and granulocytes.
According to the clonal selection theory,
the immune response to a specific antigen
is mediated by lymphocytes genetically precommitted to recognize and react to that
antigen. It now appears that the primary
unit of recognition in this system may be
preformed antibody on the lymphocyte surface. In 1965 Sell and Gell (1) first demonFrom the Arthritis Unit, Department of Medicine,
University of New Mexico School of Medicine,
Albuquerque, NM 87106.
Supported in part by Grant AM1-8789-02 from
the Department of Health, Education and Welfare
and a Post Doctoral Fellowship from the Arthritis
Foundation.
ERIK E. CARLSON, MD: Research and Education Associate of the Veterans’ Administration, VA Hospital, Albuquerque, NM 87115. RONALD P. MESSNER,
MD: Director of the Arthritis Unit, Assistant Professor, Department of Medicine, University of New
Mexico School of Medicine, Albuquerque, NM
87106.
Reprint requests should be addressed to Ronald
P. Messner, MD, Department of Medicine, 5th floor,
2211 Lomas Blvd, NE, Albuquerque, NM 87106.
Submitted for publication May 18, 1971; accepted
August 8, 1971.
strated indirectly the presence of an immunoglobulin determinant on the surface of
rabbit lymphocytes. In the rabbit there are
six different genetically determined yG allotypes. Chromosomal locus “a” controls
allotypes As-1, As-2, and As-3 on the rabbit
yG heavy chain. Chromosomal locus “b” is
generally considered to control allotypes
As-4, As-5, and As-6 on the light chain.
Specific antiallotype sera to each of these
six rabbit YG allotypes will produce blast
transformation of lymphocytes. Taking advantage of the fact that serum yG in the
newborn rabbit and thus its allotypes are
received via maternal placental transfer,
these investigators mated homozygous As-4
females with homozygous As-5 males to
produce heterozygous As-4-5 rabbits. U p to
5 weeks of age these rabbits had only
maternal YG of allotype As-4 detectable in
their serum. Their lymphocytes, however,
could be stimulated to undergo blast transformation by anti-As-5 as well as anti-As-4
sera despite the fact that IgG bearing the
paternal As-5 marker was not yet present in
the serum. Sell and Gell concluded that the
allotype of peripheral blood lymphocytes is
not due to serum or environmental yG
which has become adsorbed into the cell
membrane; rather, since blast transformation presumes a reaction of some form
between the allotypic determinant of YG
molecules and specific anti-allotype antibody, they felt that the surface membrane
of lymphocytes from newborn rabbits must
have the capacity of producing part, if not
all, of the yG molecules associated with the
cells.
Arthritis and Rheumatism, Vol. 14, No. 6 (November-December 1971)
773
CARLSON & MESNER
Subsequently, the existence of immunoglobulin determinants on the surface of
living lymphocytes has been confirmed in
several laboratories using the techniques of
mixed-antiglobulin agglutination, autoradiography (2) immunofluorescence (3), and
reverse immune cytoadherence (4). T o
date, antigenic determinants of both classes
of light chains and the heavy chains of
IgG, IgM, and IgA have been found on
human and mouse lymphocytes. They are
most commonly distributed in isolated
areas of the cell surface giving a cap-like
appearance when seen by immunofluorescent microscopy. In the mouse it has been
determined that each positive lymphocyte
carries surface immunoglobulin of only one
class (5).
Thus far, surface immunoglobulins have
been directly identified on small lymphocytes derived from bone marrow, but similar attempts to identify them on thymicdependent lymphocytes have been unsuccessful. There is, however, a significant
amount of indirect evidence that thymusderived lymphocytes bear antigen receptors
made u p of at least part of the immunoglobulin molecule (6). Plasma cells from
both mouse and human myelomas have
been shown by Paraskevas and co-workers
to contain large amounts of intracellular
7-globulin but lack immunoglobulin receptors on their surfaces (4). They postulate
that the receptor may be lost or blocked
during the differentiation of a lymphocyte
to a plasma cell. Rabellino et a1 ( 5 ) on the
other hand, found that cells from a mouse
plasmacytoma stained in a continuous rim
pattern with anti-immunoglobulin sera,
suggesting the presence of immunoglobulin
receptors. Whether the membrane recep
tors of neoplastic cells differ from normal
plasma cells or vary with the tumor under
study remains to be determined.
Evidence that membrane-bound immu774
noglobulin is the antigen receptor of lymphocytes comes from several experimental
models. I n 1969 Greaves, Torrigiani, and
Roitt (7) demonstrated that the in vitro
mitogenic response of lymphocytes to antigen can be blocked by preincubation of the
lymphocytes with anti-immunoglobulin
sera. They showed that although antisera
to light chains will induce blast transformation of lymphocytes, a submitogenic dose
will diminish the mitogenic response to
antigens such as PPD or to HLAincompatible lymphocytes. T h e Fab monomer of anti-light chain antibody which will
not stimulate lymphocytes completely
blocks transformation by these antigens.
Greaves et al suggest that anti-light chain
serum and its Fab monomer act by steric
hindrance or induction of a configurational
change in the receptor site to block combination with antigen and subsequent blastogenesis. T h e work of Zoschke and Bach (8)
has clearly demonstrated that the mitogenic response of leukocytes from an antigensensitized individual is mediated by a small
subpopulation of precommitted cells.
Using 5-bromodeoxyuridine (BUdR), a thymidine analog which when incorporated
into the DNA of cells undergoing mitotic
division renders the cells light-sensitive,
they were able to kill selectively populations of cells responding to specific antigenic stimuli. Stimulation by optimum concentrations of one antigen followed by BUdR
and light treatment consistently allowed
restimulation by heterologous antigens or
phytohemagglutinin but not by the initial
antigen.
Another approach to study of the antigen receptor has been to block the uptake
of radioactively labeled antigens by lymphocytes. Polyvalent anti-immunoglobulin
sera or antisera to L or p chains will block
the uptake of certain antigens by mouse
lymphocytes while anti-a or
chain sera
Arthritis and Rheumatism, Vol. 14, No. 6 (November-December 1971)
LEUKOCYTE "SENSE ORGANS"
are ineffective. Anti-immunoglobulin sera
which block antigen uptake also suppress
formation of antibody to those antigens by
lethally irradiated mice who are subsequently injected with the treated lymphocytes and antigen (9). Antigen-coated
columns have also provided information on
the nature of the antigen receptor on lymphocytes. Using this technique, Wigzell and
Makela (10) separated sensitive and
tolerant populations of lymphocytes derived from normal or immune mice. Passage through the column will separate the
cell population into two subgroups. Those
cells capable of forming antibody to the
antigen coating the column are selectively
retained. Cells lacking such membrane receptors pass through the column unaffected
and are found in the effluent. T h e binding
characteristics between the retained cells
and the antigen column closely resemble
the reaction of humoral antibody produced by that subpopulation of cells with
that same antigen. In particular, the recep
tor could distinguish isolated haptenic
groups on a foreign carrier and could be
inhibited by free hapten in the column.
Similarity between the membrane-bound
immunoglobulin and that produced by the
lymphocyte has been demonstrated by Walters and co-workers ( 1 1 ) who also used
antigen-coated columns to separate specific
populations of immunologically committed
lymphocytes. They showed that adherence
of lymphocytes to the column could be
blocked by antisera to the specific subclass
of the 7 chains of the IgG antibody produced by that population of cells but not
by antisera to the y chains of different IgG
subclasses. These experiments strongly suggest that the immune response to a specific
antigen is restricted to a small subpopulation of lymphocytes that are able to recognize the antigen by virtue of surface immunoglobulin receptors composed of mole-
cules with precommitted specificity for that
antigen.
In addition to receptors for antigen,
bone marrow-derived lymphocytes also possess receptors for the third component (CS)
of complement (12). These receptors have
not been found on cells associated with the
thymic-dependent system. They are also
absent from antibody-forming cells taken
from the spleen of mice immunized with
heterologous erythrocytes. In contrast to
the immunologic specificity of the immunoglobulin antigen receptors, the complement
receptor probably allows these cells to c a p
ture C3-containing complexes made up of a
variety of antigen-antibody combinations.
Complement receptors may play a role in
localizing immunologically competent lymphocytes in areas of inflammation or antigen-antibody-complement complexes in the
follicular areas of lymph nodes.
Recognition structures are also found on
the surface of macrophages, monocytes,
and granulocytes. They are, however, different from those on lymphocytes. A receptor for CS, which in contrast to that on
lymphocytes requires divalent cations for its
function, is found on macrophages, monocytes, and neutrophils (13, 14). These active
phagocytic cells have, in addition, receptors
for IgG and are capable of binding free or
antigen-bound IgG to their surface via the
Fc portion of the IgG molecule (15). In
man the Fc receptors on neutrophils and
monocytes have specificity for IgG of the y1
and ys subclasses (16). Both the complement and IgG receptors provide specific
mechanisms for capture and phagocytosis
of a wide variety of antigen-antibody complexes by these cells. Human basophils on
the other hand, lack receptors for the Fc
portion of IgG but have instead receptors
for the Fc portion of IgE (17). In this
instance the Fc receptor and the IgE bound
by it seem to play a critical role in hista-
Arthritis and Rheumatism, Vol. 14, No. 6 (NovembecDecember 1971)
775
CARLSON & MESSNER
mine release and basophil degranulation
(18).
A variety of clinical diseases have been
associated with altered immune responsiveness, including many of the collagen
diseases and lymphomas. Many workers
have suggested a viral etiology for these
conditions. If connective tissue disorders
are related to viral infection, one might
expect to find subtle alterations in lymphocyte kinetics similar to those recently reported in certain viral diseases. Investigation of the immunologic response of lymphocytes from infants prenatally infected
with Rubella virus has shown a poor response to phytohemagglutin (PHA) stimulation (19). Recent studies have demonstrated that in vitro Rubella virus infection
of normal adult human lymphocytes
markedly impairs lymphocyte transformation when stimulation with PHA is performed (20). Other RNA viruses such as
mumps and polio viruses (20) as well as
nonviable mycoplasma (PPLO) (21), produce similar inhibition of lymphocyte transformation.
Astorga and Williams (22) have demonstrated an interesting unresponsiveness in
studies with lymphocytes from patients
with rheumatoid arthritis using the oneway stimulation mixed leukocyte culture
(MLC) technique of Each and Voynow
(25). Comparing their results with cultured
pairs of rheumatoid and normal lymphocytes, they found that in 19 of 22 experiments rheumatoid lymphocytes obtained
from unrelated patients showed no transformation. Yet normal lymphocytes produced stimulation of rheumatoid lymphocytes and conversely rheumatoid lymphocytes produced transformation of normal
lymphocytes. Further experiments along
this line have been done with rabbit antisera made against pooled normal human
lymphocytes and against those from pa776
tients with active rheumatoid arthritis.
These experiments have shown that the
antisera made against rheumatoid lymphocytes are strikingly deficient in the ability
to produce blast transformation of normal
lymphocytes in vitro (24). These studies
apparently indicate the presence of subtle
alterations in the reactivity of lymphocytes
and mononuclear cells from patients with
rheumatoid arthritis.
Another recently described group of clinical disorders which is characterized by
recurrent infections differs from the immune deficiency diseases in that the defects
are in the many steps of the inflammatory
process. T h e “lazy-leucocyte” syndrome
(25) is a newly described disorder of neutrophi1 function that is characterized by recurrent infection and fever in the presence of
normal humoral and cellular immunity.
Neutrophils from these patients demonstrate normal phagocytic and bactericidal
activity but markedly impaired chemotaxis.
Impaired chemotaxis has also been described in polymorphonuclear leukocytes
from patients with diabetes mellitus and
rheumatoid arthritis (26). T h e nature of
the defect in chemotaxis is unknown but
may represent a deficient receptor for chemotactic factors.
It is relevant to note that during infection by influenza virus (27) viral proteins
become firmly attached to, or even a part
of, host cell plasma, nuclear; mitochondrial, and microsomal membranes. In those
discrete portions of the plasma membrane
from which progeny virus are released,
viral proteins completely replace host cell
membrane proteins. It is intriguing to
speculate that the common denominator of
these diverse clinical diseases is an alteration in membrane receptors making them
unresponsive to normal antigenic stimuli
or chemotactic factors.
T h e emergence of the concept of the
Arthritis and Rheumatism, Vol. 14, No. 6 (November-December 1971)
LEUKOCYTE “SENSE ORMNS”
leukocyte surface as a complex, specialized
“sense organ” tailored to the function of
the cell may be an important step in the
quest for means to control the immune
system therapeutically. Laboratory studies
clearly demonstrate that it is now possible
to isolate and destroy populations of lymphocytes in vitro on t h e basis of the specificity of these membrane receptors. Hopefully, increasing o u r knowledge of the structure a n d function of these recognition
units may provide the means to alter selectively the behavior of lymphocytes, macrophages, a n d granulocytes in vivo to the
benefit of patients suffering from collagen,
neoplastic, a n d allergic diseases.
REFERENCES
1. Sell S , Gel1 PGH: Studies on rabbit lymphocytes in vitro. IV. Blast transformation
of the lymphocytes from newborn rabbits
induced by antiallotype serum to a paternal IgG allotype not present in the serum
of ,the lymphocyte donor. J Exp Med
122:923-928, 1965
2. Raff MC, Sternberg M, Taylor RB: Immunoglobulin determinants on the surface of
mouse lymphoid cells. Nature (Lond)225:
553-554, 1970
3. Coombs RRA, Feinstein A, Wilson AB: Immunoglobulin determinants on the surface
of human lymphocytes. Lancet 2:1157-1160,
1969
4. Paraskevas F, Lee S-T, Israels LG: Cell
surface associated gamma globulin in lymphocytes. J Immunol 106: 160-170, 1971
5. Rabellino E, Colon S, Grey HM, et al:
Immunoglobulins on the surface of lymphocytes. I. Distribution and quantitation.
J Exp Med 133:156-167, 1971
6. Greaves MF: Biological effects of antiimmunoglobulins: evidence for immunoglobulin receptors on ‘T’ and ‘B’ lymphocytes. Transplantation Rev 5:45-75, 1970
7. Greaves MF, Torrigiani G, Roitt IM:
Blocking of the lymphocyte receptor site
for cell mediated hypersensitivity and
transplantation reactions by anti-light
chain sera. Nature (Lond) 222:885-886,
1969
8. Zoschke DC, Bach FH: Specificity of antigen recognition by human lymphocytes *in
vitro. Science 170: 1404-1406, 1970
9. Warner NL, Byrt P, Ada GL: Blocking of
the lymphocyte antigen receptor site with
anti-immunoglobulin sera in vitro. Nature
(Lond) 226:942-943, 1970
10. Wigzell H, Makela 0: Separation of normal and immune lymphoid cells by antigen-coated columns. J Exp Med 132:llO126, 1970
11. Walters CS, Wigzell H: Demonstration of
heavy and light chain antigenic determinants on the cell-bound receptor for antigen. J Exp Med 132:1233-1249, 1970
12. Bianoc C, Patrick R, Nussenzweig V: A
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132:702-720, 1970
13. Lay WH, Nussenzweig V: Ca++-dependent
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to macrophages. J Immunol 102:1172- 1178,
1969
14. Huber H, Polley MJ, Linscott WD, et al:
Human monocytes: distinct receptor sites
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man. Science 158:1582-1585, 1967
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18. Ishizaka T, Tomioka H, Ishizaka K: Degranulation of human basophil leukocyte
by
anti-yE
antibody.
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Immunol
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Arthritis and Rheumatism, Vol. 14, No. 6 (November-December 1971)
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Olson GB, Dent PB, Rawls WE, et al:
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Copperman R, Morton HE: Reversible inhibition of mitosis in lymphocyte cultures
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Williams RC, Jr, Emmons JD, Astorga GP:
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Miller ME, Oski FA, Harris MB: Lazy
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Arthritis and Rheumatism, Vol. 14, No. 6 (November-December 1971)
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