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Medical Hypotheses 7: 555-590, 1981
THE REVERSAL IMMUNE SURVEILLANCE HYPOTHESIS : PART II
B. Daunter and E. V. Mackay, University of Queensland, Department of Obstetrics and Gynaecology, Clinical Sciences Building, Royal Brisbane
Hospital, Herston, Queensland 4029, Australia.
ABSTRACT
The first part of the reversal immune surveillance hypothesis (RISH. I) describes the conceptual framework of the immune system as a
homoeostatic mechanism for the control of cell differentiation and
replication. The thymic dependent lymphocytes (T-cells) are considered
to be tissue specific and identify aberrations in the cell surface
pattern (antigens), that represent that particular cell type. The
T-cells may then recruit antibody forming B-lymphocytes (B-cells) to produce antibodies (humoral response) to the cell surface antigens in order to return the cell surface pattern to its correct state. The antigens may also be removed from the cell surface as immune complexes by the complement system, which under normal conditions does not cause cell lysis. The cellular arm of the immune system, that of killer cells or activated macrophages are considered to be primarily involved with tissue remodelling. Whether or not the humoral or cellular arm of the immune system is activated depends upon the antigens displayed by the stimulating cell. The proposed system, which is self monitoring, is considered to have evolved from the invertebrates through to the vertebrates to become more complex in the mammals. Therefore the immune system is considered to be based on the identification of self and self-foreignness, rather than on foreignness per se.
In RISH. II the original concept of RISH. I has been refined and discussed in mOre detail. The necessity for lymphocyte motility, .in order to inspect cells in their care, and the effect of antigen stimul-
555
ation on this motility is considered in terms of tissue specific T-cells. Although lymphocyte motility does not depend upon major histocompatability antigens (MHCA), these antigens do appear to be involved in tissue specific cell surface patterns. It is possible that the MHCA evolved among single cellular organisms , as a clone or species identification system and with the evolution of multicellular organisms, these antigens become partly incorporated into tissue specific cell surface patterns. Such a situation may explain the presence of a common T-cell antigen which may enable T-cells to identify and monitor each other. In addition thymic dependent lymphocytes may undergo maturation in the thymus to become cell surface pattern restricted, which may involve some MHCA.
The tissue specific T-cell is considered to function both as a helper and suppressor cell in the humoral response by increasing or down regulating its receptors for IgM and IgG respectively. The regulation of the immunoglobulin receptors on the T-cell being determined by the amount of antibody synthesised by the B-cell, which may regulate its own antibody synthesis by a similar immunoglobulin receptor mechanism. Depending on the antigen eliciting the immune response, the tissue specific T-cell may also function as a killer cell (tissue remodelling) using a mechanism of immunoglobulin receptor regulation for IgM and IgG. If "free" antigen or immune complexes are available the macrophages may enter the system described and act as an amplification step. Both the humor-al and cellular response can be intergrated by the macrophage and thus both types of responses may occur at similar times. The regulation of the proposed system is considered to operated on a feedback network, whereby the first set of responding cells is inhibited by a second set in an exponential fashion. Based-on the above system antibody synthesis would follow a pulsatile pattern. In addition such antibodies may be involved in regulating enzyme activities and the transcription of DNA in modulating cell surface patterns.
Based on RISH the immunology of pregnancy, embryogenesis, ageing, autoimmunity and cancer are discussed.
cell differentiation immune response self-foreignness
INTRODUCTION
The Reversal Immune Surveillance Hypothesis (1) is based on the identification primarily of self, and secondarily of foreignness, unlike the original hypothesis that is based on the identification of foreignness per se. It involves the identification of cell types by specific T-lymphocytes (cells) through their cell type surface complementary pattern and major histocompatibility antigens (MHCA)
556
(Figure 1). The T-cells in conjunction with B-cells and macrophages. regulate cell replication and differentiation by the synthesis of specific antibodies for the maintenance of cell surface character- istics and by the same mechanism the immune system may monitor itself. The ability of certain lymphocytes or macrophayes to "1 yse" or induce cells to undergo apoptosis represents a tissue remodelling component of this sytem. In addition, the whole system may be regulated by suppressor lymphocytes (Figure 2).
The hypothesis explains why spontaneously occurring tumours may not be antigenic, in the sense of eliciting their own destruction, and is consistent with the destruction of tumour cells that display significant amounts of viral antigens, or gross antigenic changes induced by carcinogenic agents (1). It is also able to explain the stimulation and inhibition of tumour development, autoimmunity, immune disorders (l), immuno-reproduction and ageing. Thus the hypothesis explains the presence of serum antibodies to normal lymphoid, non- lymphoid (2 - 7), and tumour cells (8 - ll), and immune complexes in healthy human subjects. Similarly, the presence of immune complexes in the serum of patients with, for example, benign disease (12), neurological disorders, heart infarction {13), vitiligo (14), or malignant disease (15 - 20) may also be explained by the Reversal Immune Surveillance Hypothesis.
Tissue Specific T-Lymphocytes
In 1957, Moscona (21) demonstrated that a suspension of dissociat ed embryonic avian or murine cells in a rotation culture, would recon- stitute the organised structural characteristics of the organ from which they were obtained_ Similarly, it was shown that like cells will associate with like, rather than unlike cells (22). The results of these investigations (21, 22) and others (23, 24), demonstrate that cells have organ specific cell-surface patterns for identificat- ion, not only in organogenesis, but also in the adult state. These cell-surface patterns may be predominantly composed of glycoproteins and involve glycosyltransferases in the recognition phenomenon (25 - 30). It is this cell-surface pattern that tissue-specific T-cells are postulated to recognize by their complementary cell-surface pattern (1). Therefore, T-cells would need to be highly motile in order to inspect the cell-surface patterns of the particular organ in their care.
Lymphocytes can specifically bind to, and migrate through, endothelium of post-capillary venules in lymph nodes during their recycling from blood to lymph (30). This type of binding is not performed by any other cells in the blood, and similarly, lymphocytes
do not bind to other vessel walls (30). Therefore, this allows
lymphocytes free access to other organs, as in the case of leucocytes
in general. In addition, fewer B-cells and an increased number of la positive cells have been found in peripheral lymph compared with peripheral blood (31). This suggests that the circulation of lympho-
cytes through tissue is a selective process.
557
Some lymphocytes become highly motile upon immune stimulation in vivo or in vitro, and in murine studies have been observed to crawl over fibroblasts in vitro at speeds of up to 20 m/min. The lymphocytes which were predominantly T-cells , were observed to crawl "on top of, along the edges of, and preferentially beneath the attach- ed fibroblasts". Surface contact between the cells was observed and
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sometimes this contact involved fine cellular T-cell processes. The intensity of the crawling activity was correlated with the intensity of the homologous, but no heterologous antigenic stimulation in 260. In addition, the crawling activity of the lymphocytes did not depend upon autologous or allogeneic MHCA (32). The crawling activity of lymphocytes was rarely displayed by those from the thymus or spleen of nonimmunized mice (32). These organs, however, appear to be involved in the maturation of lymphocytes, especially the thymus for T-cells which have been shown to have contact with what has been termed nurse cells (33). Therefore, only a small percentage of the large lymphocyte population in these organs would have crawling activity. That is, those lymphocytes that are the tissue-specific lymphocytes for that organ.
Tissue Specific T-Lymphocyte Receptors
The identification of cell-surface patterns by tissue-specific T-cells may involve MHCA. If we consider that the tissue-specific cell-surface pattern forms part of the MHCA, the "individual" will not be concerned by the fact that MHCA form an allelic series. It is interesting to note, that several cell-surface molecules are found in association with BZ-microglobulin which have a structural similarity to MHCA (34). It is possible therefore, that a continuous Spectrum of cell-surface patterns and MHCA may emerge. The variability of the MHCA is reflected by their species allelic polymorphism, whereas cell-surface patterns will be common within a species. Therefore, it is unlikely that MHCA are of great importance per se, since the fusion of two allogenic murine blastocysts gives rise to a healthy mouse (35). Presumably such an animal would be mosaic in terms of the MHCA derived from each blastocyst. This suggests that the immune system in such an animal recognizes both MHCA as self. It. is possible that the MHCA may have arisen among single cellular organisms as a clone or species identification system. With the evolution of multicellular organisms these MHCA may have been partly incorporated into tissue-specific cell-surface patterns. For example, in all mammalian cells carrying the Y chromosome, a cell-surface antigen is expressed (normally only on male cells), which is a minor histocompatibility antigen (36). This has been demonstrated by skin grafts of male mice being rejected by allogenic females (37).
If the T-cells are to monitor other T-cells, then there should
be a T-cell specific antigen Common to all sub-populations of T-cells
and linked to their complementary tissue-specific cell-surface
pattern. such an antigen has been identified on human T-cells (36,
37), but the importance of this antigen has yet to be established- AlSo sub-population.5 of T-cells will monitor the cell-surface of B-
cells (1). This self-monitoring may therefore aCCOUnt for the
presence of antibodies to lymphocytes in healthy human subjects
(2 - 7).
T- and B-Lymphocyte Co-operation
It has been demonstrated that T-cells produce factors which induce haematopoietic (38) and B-cell (39) colony formation, in
560
T AND B-LYMPHOCYTE CO-OPERATION
LYMPHOKINES
PRIMARY ANTIBODY SYNTHESIS
SECONDARY ANTIBODY SYNTHESIS
RESPONSE
# REACTS WlTt4 FREE ANTIGEN
FIG. 3. Primary and secondary antibody synthesis.
addition to regulating B-cell responses to antigens (40). Consider
that when a B-cell associates with "free" antigen by its surface- bound immunoglobulin, its cell-surface pattern is out of synchroniz ation. This cell-surface aberration is then detected by a B-cell specific T-cell and lymphokines are produced by the T-cell, to recruit other B-cells to produce antibodies. The recruited B-cells become plasma cells secreting antibody and eventually become memory cells. This may explain why it appears that the initial production of antibodies does not react with the antigen inducing the response
(41); the initial antibodies being concerned with modulating the initial B-cell surface pattern, which may involve other B-cell surface components. Once this has been achieved the responding B-cells may continue to secrete antibodies that react with the stimulating antigen (Figure 3). Thus the initial stage of antibody synthesis may involve the pathway previously discussed (1) (Figures 1 and 2). Similarly, this may explain the idiotypic restrictions between so-called T-helper cells and B-cells (42). That is, the
561
T-cell must identify the B-cell surface pattern for which it is specific before antibody synthesis can occur. This has been referred to as anti-idiotypic T-cell helper effect (43). The idiotype of B-cells may be a differentiation pattern between uncom- mitted (immature or null cells) and committed (mature or memory cells) B-cells.
Macrophages
It is well. documented that macrophages can present antigens to T- and B-cells, which results in the development of antibody secreting B-cells (44). In the absence of macrophages the presence of antigen may lead to early antigen-specific suppressor T-cell activity (44). In the proposed system this is to be expected, since the free antibody and immune complexes may induce suppressor T-cell activity at an earlier stage because they will not be removed by macrophages. Therefore IgM rheumatoid factor (Rf) and anti-antibodies (IgG) would not be produced (Figure 2). This suggests that the macrophage may amplify the humoral immune response. If antigens are shed from the surface of cells, which is a phenomenon of normal (47 - 47) and cancer (48 - 53) cells, they may be phagocytosed. The macrophage may become involved in this phagocytosis and eventually become overloaded and insert the antigen into its cell surface. Thus the macrophage will
attract macrophage-specific T-cells and enter the system for antibody synthesis (Figure 2). This may explain the clustering of T-cells around in vitro antigen pulsed macrophages (54). Similarly, this applies to antigens that activate memory B-cells. Both the memory and non-memory B-cells will require B-cell specific T-cell interact- ions for antibody synthesis, but the memory B-cell may respond sooner than the non-memory B-cell. Alternatively, memory B-cells may synthesize antibody on contact with the initial antigen, which is the generally accepted view.
When the macrophage inserts the antigen on its surface, it may produce specific (44) or non-specific (55) activating and/or prolifera- tive factors for both T- and B-cells. It is also possible that these factors may be produced by the macrophage specific T-cell. Thus the system may explain why "fed" macrophages are able to specifically activate non-sensitized lymphocytes (56). If the antigen is not cell- surface associated, and memory B-cells are not involved, only the macrophage arm of the immune system will be activated, that is, macrophage/T-cell/B-cell interaction (Figure 2) and not B-celll/T-cell/ B-cell2 interaction (Figure 3). If the antigen is persistent other macrophages may become overloaded with immune complexes and produce Rf and anti-antibodies, which together with immune complexes will induce immunosuppression (Figure 2). In addition, macrophages may also release factors that inhibit lymphocyte proliferation (56). Finally, it appears that HLA-D (MHCA) identification between macro- phages, T-cells and B-cells is necessary for optimum co-operation (55, 57, 58). Again, this emphasizes the self identification and self foreignness concept of the proposed system.
562
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Helper, Suppressor or Tissue-Specific T-Lymphocytes
In humans, two sub-populations of T-cells have been identified on the basis of cell-surface FC receptors for IgM and IgG, referred to as Tu or TM and T
I or TG, respectively (59). The TV cells appear
to enhance and Tr ce 1s appear to suppress the response of B-cells (59). It is possible that Tp and TV cells are not separate populat- ions per Se and are in fact tissue-specific T-cells. with Fc receptors for both IgM and IgG.
Consider that in the proposed system (Figure 4), a tissue- specific T-cell identifies that the cell-surface pattern of a particu- lar cefl is out of synchronization: lymphokines are produced by the tissue-specific T-cell in order to recruit B-cells which proliferate and produce iso-IgM. The "free" iso-IgM may react with the few available IgM-Fc receptors on the T-cell to induce more IgM-Fc recept- ors to be displayed. This results in increased lymphokine production by the tissue-specific T-cell to recruit more proliferative B-cells and initiates tissue-specific T-cell proliferation. A point may be reached when the "free" IgM and immune complexes of IgM, resulting from cell-surface antigen shedding, may down-regulate the IgM-Fc receptors on the tissue-specific T-cells. This would result in a decrease in synthesis of lymphokines for B-cells. At this point the B-cells switch from iso-IgM to iso-IgG synthesis, if the original antigenic stimulation persists. At the same time, more IgG-Fe receptors start to appear on the tissue-specific T-cells. The "free"
iso-IgG complexes the IgG-Fc receptors on the tissue-specific T-cells to induce the appearance of more IgG-Fc receptors and synthesis of factors to suppress B-cell proliferation per se (59). If the original
antigen persists, the B-cells will eventually synthesize complement
fixing IgG. At this stage, the IgG-Fe receptors on the tissue- specific T-cells may start to be down-regulated by the increasing amounts of IgG and its complexes. This may result in the reappearance of IgM-Fc receptors and production of factors for B-cells if free IgM is still available. However, the down-regulation of IgG-Fc receptors on T-cell,s may be negated to some extent. This may be achieved by
the IgG immune complexes fixing complement which will prevent the FC portion of IgG from reacting with the IgG-Fc receptors of the T-cells. Nevertheless, an equilibrium TV 5 q may be established, possibly in favour or TV, since there may be insufficient amounts of free IgM to activate a T-cell helper function.
The above may explain why IgM-Fc receptors on T-cells usually become detectable after incubation in IgM free media, whereas T-cells with IgG-Fc receptors are normally present (59). Similarly, it has been shown that when peripheral blood lymphocytes are preincubated (24 hours, 37OC), rosettes can be formed with ox-erythrocytes (OE) coated with IgM or IgG (59). However, OE-IgM rosette formation is completely inhibited by incubation with OE-IgM and markedly decreased with incubation with OE-IgG. The GE-IgM rosette formation can be restored by preincubation of the lymphocytes with OE-IgG (59). In addition, it was found that the presence of lymphocytes with PC receptors for IgG were not themselves inhibitory (59). Similarly,
564
5 cells may not function as helper cells unless IgM is present. Also free IgM can inhibit OE-IgM rosette formation whereas free
IgG does not (59). However, the effect of free IgG on lymphocyte IgG-Fc acceptors does not appear to have been investigated. Similarly, it has been demonstrated that primed T,J cells can result in feedback inhibition (60). That is, TV cell activity prevails at low antigen concentrations, whereas TV prevails at high antigen concentrations (1). In addition, such immune modulation appears to involve immune complexes (61).
The ttmcrophage may also enter the T,, 5 Tr equation. Consider
that "free" complement-fixing immune complexes may be phagocytosed to the point where the macrophage becomes overloaded and the IgG is inserted into its surface (Figure 4). The macrophage will then enter the system described with its own specific T-cell. However, the Rf/IgM synthesized may be against the Fc or variable portion
of IgG. The Rf will not only prevent IgG from fixing complement, but will also prevent IgG from reacting with IgG-Fc receptors on the first stimulated tissue-specific T-cell. This may prevent the down-regulation of IgG-Fc receptors on the T-cell by reducing the amount of available IgG. However, the free Rf may also upgrade the IgG-Fc receptors on both the initial and macrophage tissue- specific T-cells, resulting in B-cell factor production. It is therefore proposed that the "pressure" for IgG-Fc receptors on the initial tissue-specific T-cells (optimum levels of free IgG, com- plexed IgG and Rf-IgG-antigen complexes) is maintained and the Rf only upqrades the IgM-Fc receptors on the macrophage specific T-cell.
Alternatively, the iso-IgM/iso-IqG switch may occur at an earlier stage by the B-cells associated with the macrophage, if the antigenic stimulation persists. The IgG produced will be an anti-antibody (as was Rf), which may also be directed to the Fc or variable region o.f the IqG. This anti-IqG will counter any of the effects the Rf (IgM) would have on the initial tissue-specific T-cell. At this stage, the initial tissue-specific T-cells and associated B-cells may be suppressed in this system before the macrophaqe/T-cell/B-cell system. Other macrophaqes may be recruited and the resultant antibodies would suppress the first macrophaqe specific T-cells and associated B-cells. Thus there would be an ever-increasing iso-IyM and iso-IqG production and the time to achieve irmnunosuppression would reduce as an exponent- ial function, until the "local" immune system would not respond. AlSO in this system the amplifying effect of the macrophaqe may also be included if free antigen is available (Figure 4).
Finally, the proposed system may explain antigen-specific (Bl, T, B2 interaction), and non-specific (amplification by macrophaqes) immunoreyulation (62, 63, 64, 65), and Rf idiotypes (66). In addition, Fc receptors for IgM have also been found on B-cells (67). It is possible therefore, that B-cell IyM-Fe receptors may also be induced to appear with increasing concentrations of IqM, only to be down- regulated as the optimum level of IqM synthesis is exceeded, which may trigger the IqM/IqG switch. Similarly, this may apply for the switch from non-complement fixing IqG to complement fixing IqG. Thus both TyM and IqG would be requlatinq not only their own synthesis but also modulating the TV 5 TV equilibrium (Figures 3 and 4).
565
SL;ontaneous Lymphocyte Cytotoxicity and Killer Cells
We have described spontaneous lymphocyte cytotoxicity or natural killer cells (NK) and killer cells (activated macrophages = AM) as tissue remodelling components of the immune system, their induction depending on cell-surface antigenic expression (1). If a cancer cell displays antigen(s) to elicit NK and/or AM activity it will be removed. Similarly, if any invading organism induces NK or AM activity by cross-reactive cell-surface patterns, they too may be removed. However, from an evolutionary point of view, it is doubtful if such a high degree of cross-reactivity in cell-surface patterns would occur, for example, in fungal or bacterial infections. It is more likely that products of the organisms themselves would be partly or wholly phagocytosed and macrophage overloading may occur. Thus the cell-surface of the macrophage would be out of synchronization which may then result in NK and AM activity. The macrophage may be destroyed along with the invading organism, since the NK and AM are tissue-specific and antigen- specific. It must be stressed that this is immunopathology because normal self cells have also been destroyed.
The tissue remodelling component of the immune system is emphasized by the fact that NK cells appear to be cytotoxic, not only for some malignant cells, but also for some non-malignant cells (68, 69). The evidence at present suggests that these NK cells are T-cells with Fc receptors for IgG (68, 70), and possibly IgM (71). We propose
that NK cells arise in a similar fashion to TV $ Tr. That is, the tissue-specific T-cells have Fc receptors for various isa-IqM and iso-IqG, and depending on which iso-IgM or IgG is elicited by the antigen(s), determines if 5 f Ty or NKP f NKv systems are activated. The NKp activation would result in an increase in NK~J receptors and proliferation of NKP cells, B-cell proliferation and iso-IgM synthesis induced by factors synthesized by NKu cells. These factors will be similar, if not identical to factors synthesized by TP cells as in the murine system (72). Down- regulation of the NKll receptors and the appearance of NKv receptors may occur if the antigen is still persistent, due to free IgM and its complexes as in the TV f Tr system. This will result in a decline in NKV cell synthesis of B-cell factors. At this point the B-cell switches to iso-IgG production. However, unlike the 5 5 Tr system, the NKy cells do not appear to have an immuno- suppressive effect per se, but merely decrease NK,, receptors and thus B-cell factor synthesis, due to an increase in IgG synthesis. In this system, the NKP and NKV cells may attack target cells coated with antibody (NK antibody independent attack) or the NK cells may carry the antibody (NK antibody dependent attack) (Figure 5). The switch from non-complement fixing IqG to complement fixing IyG by the B-cells will prevent IgG from being identified by NKr cells. Thus, the Fc region of the IgG will be blocked and NKp $NKv will be achieved. At this stage their participation in cytotoxicity may be prevented or limited, especially if free IqM is not available. At this stage the activation of macrophages to killer cells (AM1 may occur.
566
FIG. 5.
Tissue specific T-eelIs : NK function and intergration
of cellular and
humoral response.
Macrophages contain surface Fc receptors for aggregated or antigen-bound IgG to which these complexes or IgG opsonized material bind in order to undergo pagocytosis (73). These macrophage IgG-Fc receptors also appear to be involved in antibody dependent macrophage cytotoxicity, activated macrophages (AM) (73, 74). In addition, macrophages have receptors for the C3 component of complement (73, 74). Therefore, the iso-IgG and complement fixing IgG may induce AM activity (Figure 5). Thus macrophages cannot be cytotoxic unless they carry the NKy IgG or complement fixed NKy IgG. Should excess tissue remodelling occur, the local phagocytic system may be over- loaded, especially the macrophage. The macrophage will insert various cell components onto its surface and the TV 5 TV system may be activated as previously discussed, and autoimmunity may develop (Figure 5). If the antigen(s) that activate NKv 5 NKy are inserted on the macrophage surface, the macrophage will be removed by its own tissue-specific NK,, 5 NKY cells, be reacti.vated,
but also the original NKP f NKY may because antibodies are not tissue-specific but antigen-
specific (Figure 5). However, some macrophages would also insert the IgG of the immune complexes on their surface resulting from excessive tissue remodelling. This would result in Rf (IgM) and anti-antibodies (IgG), being synthesized, as discussed previously, and will not be NKIJ 5 NKV activating, but TV f TV activating. The Rf may then complex the Fc region of the IgG involved in activating AM cells and NKV cells, thus preventing further tissue remodelling. In addition, the B-cells reacting with the macrophage may undergo an IgM/IgG switch, anti-IgG synthesis. This may also act in a similar manner to Rf as previously described (Figure 5). Also it must be remembered that it is the TV 5 TV system that is now also operating and the Rf and anti-IgG will suppress this system as previously discussed.
The above pathways allow for the integration of both the humoral and cellular arms of the immune system. It explains the helper effect of macrophages in NK activity (75) by production of iso-IgM and IgG resulting in the removal of macrophages
(Figure 5), and the apparent selectivity of NK and AM activity
(76). Finally, we consider that NK cells also form part of the background noise in normally healthy individuals and that the induction of so-called cytotoxic cells represents the enhancement of the NK and AM system. although it does not appear that NK cells are suppressive, a closer examination of the system may revea Y a TV type activity.
Tissue Remodelling
We have discussed the possible immunological mechanisms for tissue remodelling, but we have not defined nor described the result of this action. That is, is tissue remodelling lysis, necrosis, or apoptosis, of cells? Lysis of cells may be an in vitro effect and like necrosis, also a pathological event, both of which may be medi-
ated by complement fixation (1). Apoptosis appears to be a mechanism for the control of cell populations, and may be considered the antag- onist of mitosis. Apoptosis involves nuclear and cytoplasmic conden- sation and fragmentation into membrane-bound particles (apoptotic bodies), which are shed from epithelial-lined surfaces, and taken up by other cells or undergo autolysis (77). This process occurs in
568
healthy adult tissue, embryogenesis, spontaneous, and therapeutically- induced tumour regression, and as a pathological entity in atrophy of
various tissues (77). The most intriguing aspect of apoptosis is that it appears to be induced by cell-mediated immunity (77, 78, 79). If apoptosis is a normal event occurring in healthy tissue, so is cell- mediated "immunity", thus NK and AM are normal responses in tissue remodelling.
Antibodies
The survival of multicellular organisms depends on an integrated communication system between each cell and each organ, which consists of cell contact and chemical signals. The chemical signals may be fat-soluble and will diffuse through the plasma membrane of cells, and bind to specific cytoplasmic receptors (e.g. steroid hormones), or water-soluble and bind to receptors on the cell surface (e.g. neurotransmitters, growth factors). It is this latter case, the water-soluble signals, to which the antibodies belong. Therefore, when an antibody binds to a cell surface receptor, it must bring about changes within that cell. This suggests that the receptor must be a transmembrane protein, more likely a glycoprotein, or the receptor antibody complex must be internalized by the cell to bring about changes within that cell.
Antibodies are divalent, that is, they have two binding sites for the antigen, which may be a cell surface receptor, and a special FC portion which binds to receptors of immunological cells. Thus non-immunological and immunological cells may be brought into contact and indeed immunological cells themselves. It is established that when anti-antibodies bind to cell surface immunoqlobulins on B-cells, clustering of the complexes are seen, which has been referred to as patching. This demonstrates that antibody receptors are diffuse- ly and randomly distributed over the cell surface. Similarly, immuno- globulin receptors on B-cells may be induced to form "caps", which are transferred to the rear of the cell over the Golqi complex. This process, capping, unlike patching, requires metabolic energy. In addition, it has been shown that anti-antibodies to B-cell immuno- globulins will induce the cell to ingest part of its membrane (pinocytosis), bearing the immune complex (80) which causes the reversible disappearance of the immunoqlobulin receptor. It is possible that this mechanism may explain immunosuppression by Rfs (iqM-anti-IgGI, and anti-antibodies (IgG-anti-IqGf, that is, removal of antibody receptors from immunocompetent cells in both the humor-al and cellular response. Similarly, it has been shown that IqG specific for a sub-set of T-cells inhibits the mixed lymphocyte culture reaction by binding to the responder cells without killing them (81).
It is also possible that antibodies may down-regulate non-lymphoid receptors as in myasthenia qravis. These patients produce antibodies to their own acetylcholine receptors in muscle which leads to a re- duction and/or inactivation of the receptors (821, giving rise to muscular weakness. Antibodies may also be involved in the induction of receptors or antigens (1). For example, insulin receptor anti- bodies have been found in patients with a rare form of extreme insulin resistance and these antibodies mimic many of the insulin's short- and long-term biological effects (83). It is possible that some dysfunct-
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PULSATILE ANTIBODY SVNTHESIS
iNlTlAL !~IMuLATION ANTIGEN MACROPHADE OVERLOAD
IMMUNE COMPLEX MACROPI+ADE OVERLOAD
I mmunosuppression
FIG. 6. Antibody synthesis : Initial response, macrophage amplification, Rf and anti-IgG production.
ion has occurred in terms of the cell's ability to display sufficient insulin receptors, therefore its cell surface pattern may be out of synchronization. The resultant antibodies mimic some of the biological effects of insulin, but their main function may be the induction of insulin receptors.
It would appear that antibodies directed against B-cell immuno- globulins (anti-antibodies) of guinea pig leukaemia lymphocytes, result in the increase of intracellular CAMP and the inhibition of immunoglobulin production (85). It may be possible that the Fc receptors of the B-cells may also be modulated by antibodies via CAMP after internalization of the complex by pinocytosis. Thus antibody regulation of antibody synthesis may account for the presence of antibodies to lymphocytes in healthy human subjects (2 - 7). There is also evidence for the direct interaction of antibodies with nuclear material. It has been shown that anti- ribonucleoprotein IgG from patients with connective tissue disease can penetrate mononuclear and TY (suppressor) cells via their FCY receptor, in the latter case resulting in a loss of T suppressor cell activity (86). It is possible that the IgG is preventing the function of mRNA in the synthesis of suppressive factors. A similar mechanism may operate in systemic lupus erythematosus (SLE)
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in which intranuclear inmunoglobulins have been found (871. In addition, human Rf (I@) has been found which cross-reacts with anti-nuclear IgG and its corresponding antigens in rat liver and kidney (88, 89). This suggests some regulatory role for IgG and Rf for non-immunocompetent cells at the nuclear level. This
may involve interaction with the nuclear material per se or via an enzyme system, or both.
In E. coZt systems, it has been shown that antibodies may effect transport of substrates and enzyme activities. For
example, the binding of D-galactose to its transport protein can be enhanced in the presence of antibodies to the transport prote.in
(90). Antibodies to the tetrameric form of B-D-galactosidase can bring about inactivation of the enzyme by causing its disassociation into subunits (91). The opposite can also occur as in the activation of a defective B-D-galactosidase by its antibodies (92, 93). Accord- ing to Rotman (90) (personal communication), from the point of view of this hypothesis, protecting, inactivating and dissassociating antibodies would be the most likely candidates for effector molecules
Pulsatile Antibody Synthesis
The synthesis of antibodies by the proposed immune system should follow a pulsatile pattern. The introduction of a new antigen should result in IqM/IgG synthesis. If the macrophaqe then becomes over- loaded with antigen, IgM/IgG synthesis to the same antigen should occur (macrophage amplification). Next, macrophages overloaded with immune complexes of IqG, results in Rf and anti-antibody synthesis (Figure 6). Similarly, this applies in the case of NK and AM cells. Another aspect of the proposed system is that if a cell displays an antigen that is represented by some other normal cell of different tissue, autoimmunity may develop.
DISCUSSION
The hypothesis considers immunoqlobulin synthesis at the site of immune stimulation when the antigen is bound to the surface of cells. However, it is consistent with the view that B-cell, and possibly macrophaqe interactions with free antigen, are involved in circulation through local lymph nodes, allowing their inspection by resident specific T-cells. In fact, one of the main functions of the lymph nodes may be the bringing together of lymphocytes on a regular basis for self inspection and simultaneous exchange of resident and circulatory lymphocytes. This self-regulatory system for lymphoid and non-lymphoid tissue is based on the use of anti- bodies, which in terms of current terminology, would be referred to as autoantibodies.
In the proposed system, there are normal regulatory "auto- antibodies" and disease "orientated auto-antibodies". The latter will arise from some dysfunction or excess synthesis of the former. Autoantibodies may arise from excessive tissue damage unless the immune system undergoes suppression, as in macrophaqe phaqocytosis,
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in excessive burn injury (94). Unlike the general theory of immune surveillance, the proposed hypothesis explains the occurrence of idiotypic and anti-idiotypic antibodies (95) in which antibody variable regions are complexed by antibody as a regulatory mechanism: the regulation of cell-mediated immunity by antibodies (96) and anti- body receptor induction on lymphocytes (97). Similarly, the phenomenon of apoptosis is accommodated as the tissue remodelling arm of the immune system, for example, in the formation of the corpus luteum (1) and to some extent, in the shedding of the endometrium (98) during menstruation. This arm of the immune system also represents tissue- specific T-cells which upgrade their NK receptors, if the antigen elicits the synthesis of the correct antibodies.
During embryogenesis, stem cells migrate from the blood stream into the embryonic thymus and differentiate into T-cells. It is generally accepted that in the thymus the T-cells "learn" to recognize their own MHCA and become MHCA restricted (99). We have discussed the possibility that MHCA are of little interest to the "individual", and may be involved in the cell surface tissue patterns of cells. There- fore, it is possible that the lymphocytes in the thymus undergo maturation into tissue-specific T-cells and do not become MHCA restricted per se, but rather cell surface pattern restricted, which may involve some MHCA.
We have stated that the immune system is a hemostatic mechanism for cell replication and differentiation. Consider that in embryo- genesis, one of the main aims of organogenesis is to differentiate, to achieve the adult form which will involve tissue remodelling, apoptosis. Although it has been proposed that some cells, especially embryonic cells, may have the intrinsic ability to undergo apoptosis, a more logical explanation would be controlled apoptosis by the immune system. Thus cells during embryogenesis may selectively insert antigens into their cell surface in the process of differentiation to activate cell-mediated immune apoptosis. This poses the question, at what stage of embryonic development is the fetal immune system active?
The development of immunocompetence in the human fetus has been recently reviewed (100). The thymus first appears by the 6th week of gestation and is populated by lymphocytes by the 9th week. The first lymphocytes are possibly produced by the liver, since this organ con- tains more lymphoid cells during the first half of fetal development than all the other lymphoid organs. Small lymphocytes appear in fetal peripheral blood at 7 - 8 weeks of gestation, and by the 10th week, constitute over 50% of the leucocyte population. Many of these lymphocytes have been demonstrated to be T-cells. It appears that these T-cells will respond to stimulation as early as the 10th week of gestation, and are more reactive than adult cells. Also these cells are reactive in mixed lymphocyte cultures (MLC) at 7 - 15 weeks of gestation. Similarly, B-cells have been identified in fetal liver at 9 weeks of gestation, IgM and IgG producing cells and IgA cells at 11% weeks. The immunoglobulin IgD is present on a larger portion Of fetal B-cells than adults, and this may be predominantly a fetal immunoglobulin giving way to IgM synthesis as differentiation approach- es its zenith (1). However, the evidence suggests that both IgD and IgM may be present simultaneously, but this does not distract from
572
the idea that IgD synthesis gives way to IgM synthesis. By 14% weeks
of gestation, the percentage of cells in the fetal spleen and blood staining for each class of iannunoglobulin is at a level for that of neonates and adults.
There does appear to be a controversy as to whether the fetus contains plasma cells (B-cells) secreting immunoglobulins. However, recent studies suggest that immunoglobulin synthesis by the fetus may take place from the 10th - 20th week of gestation for IgM and IgG. It does not appear that IgD plasma-secreting fetal cells have been investigated, which is surprising considering the possible importance of IgD (1). Finally, the evidence suggests that the fetus can synthesise complement from 8 weeks of gestation, and therefore appears to precede immunoqlobulin production (100).
The development of immune competence by the fetus allows the immune system to take control as the embryogenesis proqramme "de- clines". Thus in the adult, the immune system will have different degrees of emphasis, depending upon the replicative capacity of the tissue. For example, the liver will command more attention than the brain. An immune response in the brain will take longer to develop because of the small number of tissue-specific T-cells, and possibly memory B-cells relative to the liver lymphocytes. It is of interest that selective adherence of lymphocytes to myelinated areas of rat brain have been identified (101).
The above discussion may present a paradoxical situation, in that it is considered by some investigators that pregnancy involves fetal and/or maternal immunosuppression (100). Similarly, other investigators have not found immunosuppression in preqnancy (100). The in Vitm assessment of maternal lymphocyte responses to plant mitoqens has been shown to be dependent on the dose of plant mitoqens used, and that individuals belong to low, medium, or high responder groups (102, 103). Therefore, these results (102, 103), and those of others (loo), can only be interpreted in terms of lymphocyte response to plant mitogens reflecting immune modulation. It is therefore proposed that the fetus and mother are capable of a two- way immune response.
Mammalian blastocysts can survive in ectopic sites and in the presence of blastocyst antisera so long as the zona pellucida remains intact (104, 105, 106). This suggests that MHCA may not be present on the zona pellucida. In the human, the full complement of MHCA is possibly expressed on the blastocyst after the shedding of the zona pellucida before implantation (107, 108), which occurs at the 186 cell stage (109). At this time, the blastocyst is surrounded by maternal lymphocytes (llO), which may become sensitized to the paternal MHCA of the blastocyst. The immune response therefore, may suppress the expression of paternal MHCA on the trophoblast cells in an attempt to induce the correct cell-surface pattern- linked maternal MHCA. Since the genetic information for the remaining half of the maternal MHCA is not available, they will obviously not appear. In the mouse this immune response may account for the loss of some blastocyst preimplantation MHCA after implant- ation (111, 112), and the survival of fused allogenic murine
573
blastocysts (35). Similarly, this maternal immune response may also account for the survival of a rabbit allogenic blastocyst trans- ferred to recipient parents sensitized to allographs of the donor parents (113). In the case of the fusion of allogenic murine blasto- cysts (35)‘ only the homologous maternal MHCA would be expressed on the trophoblast cells. In the donor-recipient blastocyst situation, none of the donor MHCA would be expressed, and the recipients would still reject skin grafts from the neonate as demonstrated (113). Therefore, one may consider the trophoblast to be MHCA restricted as determined by the maternal immune system by an immune response.
In the human situation, antigenic stimulation would also be enhanced by syntrophoblast cells entering the maternal circulation (lo4 cells/day) 10 - 14 days after implantation (114). The continued stimulation by the syntrophoblast cells may also elicit NK and AM activity, resulting in apoptosis of the syntrophoblast. This may account for the thinning out of syntrophoblast cells as pregnancy progresses, being replaced to some degree by the cytotrophoblast (115). This may be a prelude to parturition and involve histamine release from mast cells by IgE, causing contraction of uterine smooth muscle (1). That the proposed immunoregulation is occurring during pregnancy is supported by the presence of immunoglobulins on the syncytiotrophoblast from the 8th week of gestation (1, 116).
The immune response in pregnancy may represent half the magnitude of the normal immune response, since the fetus and mother are compatible for only half the MHCA. As discussed previously, for an optimum immune response to occur, there must be MHCA compatibility. This may explain why maternal versus fetal cell-mediated lympholysis activity is half that against unrelated adult cells (117)'. Similarly, the proposed system may also account for T- and B-cell proliferation in synergistic and allogenic pregnant rats (118), which suggests sensitization during pregnancy. Finally, the proposed system may explain why there does not appear to be any change in total maternal T- and B-cells during pregnancy, although there may be an increase in T-cell suppressor activity in a small population of lymphocytes (119). This proposed low level of fetal or maternal immune response to each other may result in the production of Rf (120) as well as antibodies to paternal MHCA (100). The situation may also involve the production of anti-idiotypic antibodies, that is, antibodies to the variable region of the antibodies. Therefore, such a mechanism may offer advantages in tissue transplantations.
If the immune system is involved in embryogeneiss and modulation of adult tissue (l), we may consider it also as an hemostatic mechanism for ageing. Consider that cells do have a finite life span in that they complete a number of cell divisions and then die. This was first demonstrated by Hayflick and Moorhead (121) in which fibroblasts re- moved from a human fetus will divide approximately 50 x and no more, and those from older persons divide fewer times before senescence sets in. Thus if cells have a built-in redundancy, then they must perform their specialized functions efficiently, that is, they must display all the characteristics of the cells they purport to be. Any deviation from their true characteristics may result in inefficiency, in terms of their specialized function. Therefore, the immune system
574
maintains the cells' characteristics so they may function at an optimum level before being discharged. It would be interesting to compare chronological age with immune status and health of individuals. Thus the efficiency of the immune system, in terms of monitoring itself and the cells in its care may determine one's "tissue age", as opposed to one's chronological age.
It has generally been accepted that the decline in immune competence with age offers an explanation for the increase in cancer. However, recent work suggests the decline in immune com- petence per se does not contribute to a higher incidence of cancer (122). In addition, the decline in immune competence with age is qualitative at the level of both T- and B-cells, and appears to be associated with the appearance of new or altered antigens on the surface of some lymphocytes (123). This may represent ageing of the immune system and therefore its ability to monitor cell differentiat- ion and replication will be diminished. Although a decline in immune function and/or immune suppression may at times be associated with cancer, this usually reflects the extent of the disease and no clear antecedent immunosuppression has been observed. Immunodeficient patients exhibit a restricted range of cancers, for example, in patients with organ transplants who are immunosuppressed, approximate- ly 60% of the tumours are of lymphoid origin (124), which is not com- patible with general immunosurveillance. In addition, many of the immunosuppressive drugs are carcinogenic.
Immune surveillance has been considered as an effective mechanism for the elimination of cancer cells by thymus dependent lymphocytes (T-cells). However, studies of neonatal thymectomized and congenitally athymic mice do not support this concept. In a study of 15,700 such mice, equivalent to 5,600 mouse years, no increase in cancer, relative to mice with an intact thymus was seen (125). Although the lifespan of athymic mice is reduced, an increase in spontaneous tumours should have been seen according to the genera.1 immune surveillance hypothesis. Another interesting aspect of athymic mice is that they mimic in appearance and pathology, the ageing pro- cess (126). In addition, it has also been shown that mouse embryos transplanted to extrauterine sites in athymic mice, slowly develop into benign, instead of malignant teratomas (127). This demonstrates the influence of the immune system, or rather partial lack of the immune system in this case, on tumour development, as previously discussed (1). Similarly, in patients with myasthenia gravis, in which antibodies to acetycholine receptors appear to prevent their insertion into muscle membrane, improve after thymectomy (128). 'The disease itself is associated with an increased risk of cancer, wh~ich is reduced by thymectomy (129, 130).
A dysfunction in the immune response resulting in increased apoptosis may also accelerate the ageing process. This may be reflected in an increased production of "auto-antibodies", for example, in premature menopause (131/, or in disease-induced "auto-antibody“ production as in leprosy (1321, systemic lupus erythematosus (133), or rheumatoid arthritis (134), which may suggest lack of suppressor cell function.
575
As discussed previously, the immune response under certain con- ditions can enhance or suppress tumour growth (1). The enhancement of tumour growth by auto-antibodies has been demonstrated (135), and the expression of fetal differentiation antigens (neural crest) in human lung and colonic cancer tissue (136) may be further examples of tissue de-differentiation (1). Similarly, further examples of tissue re-differentiation may be the production of pepsinogen (137) and thyroglobulin (138) by some ovarian tumours. It has been proposed that metastasis of tumour cells is the result of cell re-differentiation and/or de-differentiation (1). That is, the change in cell surface characteristics of the tumour cells results in loss of cell adhesion allowing the tumour cells to settle in other tissue sites with similar cell surface patterns. This
suggests that metastatic tumours will metastasize to specific sites. This has generally been observed in humans and in well defined animal experiments. For example, B16 melanoma contains a large population of cells that can be isolated, that specifically colonize the lungs in rats, regardless of the capillary routes they have to pass; smaller populations of cells colonize the ovaries, body cavities, liver and brain (139). It has been shown that each of the three melanoma lines, those that colonize the lung, the brain and the ovaries, show a different pattern of specific cell surface proteins (139). Similarly, it has been shown in avian studies that a cell surface antigen detectable by a monoclonal antibody, is correlated with specific liver metastasis (140).
In the first part of the "Reversal Immune Surveillance Hypo- thesis" (1) the role of interferons was briefly mentioned in terms of possible endonuclease activity. Interferons are a family of glycoproteins which are synthesized by various cell types in the vertebrates and their ubiquitousness is paralleled by their multi- functional roles. For example, they may act as inhibitors of cell growth, have selective effects on protein synthesis and are produced in many immune reactions in which they have a modulating effect (141, 142).
It appears that the immune system is able to produce two groups of interferons, types I and II, which differ in their physiochemical and antigenetic properties (143 - 146) and may possibly function as lymphokines. This is supported by the fact that approximately 50 lymphokines have been described (147), many with properties similar to interferons (148). Type II interferons are produced in response to mitogenic (149 - 152) and antigenic (146, 153, 154) stimulation by macrophages and B- and T-lymphocytes (145, 149). Whereas type I interferons are synthesized in response to viruses or double- stranded nucleotides (144, 146). In addition, types I and II inter- ferons appear to use different mechanisms in the activation of cells (155). It is also important to remember that interferons may be tissue-specific, for example, human leucocyte and fibroblast inter- ferons differ in their physiochemical and immunological properties and action on transformed cell lines (156). Thus the interferons may be tissue-specific in that they may prevent DNA-aberrations in the cells which produce them (1). Finally, interferons do not appear to have an action per se on cells but rather result in the
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accumulation of a particular mRNA and the corresponding protein, which has yet to be characterized (1957).
The writing of the second part of this hypothesis has taken courage from the overwhelming response for reprint requests for RISH. I. In addition, the format for RISH. II has partly been developed around some of the questions proposed by readers of “Medical Hypotheses" and
those from colleagues and associates. It is hoped that RISH. II has satisfactorily answered most of those questions, or at least provided food for thought. Although RISH appears to have been accepted by some people in terms of its possible potential, there are obviously some constructive criticisms. These criticisms are concerned with RISH. I in that it is too embracing and optomistic and possibly simplistic. RISH. I was simplistic in terms of the lack of mechanistic detail. This was deliberate in order to add emphasis to the concept. Therefore, RISH. II hopefully has supplied a more mechanistic approach of desired complexity without sacrificing conceptualism. The RISH concept allows immunology to be placed into a biologically intergrated system on an evolutionary scale and not isolated as a separate entity as a defence mechanism. Therefore RISH does embrace other aspects of biology not accessible to the general theory of immune surveillance.
It must be remembered that RISH does not differ greatly from the accepted mechanism of immune responses, but rather places immunology in a different frame of reference. Such attempts to place immunology in its correct perspective are not new, as was pointed out by Professor Burch in his personal communication. In fact Grabar in 1957 - 1959 (158, 159) viewed autoantibodies as a pathological version of a normal physiological function. This concept was developed further by others (160 - 162) who proposed that an equilibrium may normally exist between the immune system and parenchymal cells, which if disturbed could give rise to autoimmunity. Similarly Burch in 1965 (163) proposed that the immune systems prime function was to regulate and coordinate the size of "distinctive tissues throughout the body" via "mitotic control proteins (MCP)" produced by "small" lymphocytes. In addition auto- immunity was considered to result from a mutation converting an MCP
into an autoantibody. This hypothesis also requires the existence of at least three distinct immune systems in mammals.
The various immunological hypotheses (158 - 163), including RISH, are in agreement in that the immune system has other functions, in addition to that of defence. However some of the main points where RISH differs from other hypotheses (158 - 163) is that RISH does not consider the immune system to be primarily a defence system, or to exist as a number of separate systems. Similarly RISH does not consider the immune system to be involved in the elimination of forbidden clones of lymphocytes to prevent autoimmunity or that mutation can explain autoimmunity. In addition RISH does not consider that the immune system directly controls cell division.
Finally the application of RISH to other aspects of biology has yet to be reported. This is important because one exception to any hypothesis may modify or destroy it, and thus we begin again.
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Acknowledgements
We wish to thank those persons who sent personal communications for their favourable ratio of encouragement to discouragement.
We apologize for the delay in meeting requests for reprints of RISH Part I, but demand has now exceeded supply.
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