The failing immune system

0021-9681/83/010129-07$03.00/0 Copyright 0 1983 Pergamon Press Ltd

J Chron Dis Vol. 36, pp. 129-135, 1983 Printed in Great Britain. All rights reserved

THE FAILING IMMUNE SYSTEM Kenneth

W. Walton

Department of Investigative Pathology, IMedical School, University of Birmingham, Birmingham B15 2TJ, England

ABSTRACT Parallels have been drawn between aging and auto-immunity. Decline in immune competence has also been held to account for the incidence of certain diseases occurring in later life. The normal immune response in man, its development, and changes occurring with age are surveyed and the significance of decline in immune reactivity with age reexamined. It is regarded as “not proven” that the activity of the immune system governs the lifespan.

KEY WORDS Immunocompetence; macrophages; immune

humoral aging.

and

cellular

immunity;

B-cells;

T-cells;

stem

cells;

INTRODUCTION Gerontology has long been concerned with attempting mechanisms controlling the cellular processes of aging. attention has been given, in recent years, to the possible determining senescence.

Immunocompetence

and Age-Related

to identify the mechanism or Among theories of aging, much effect of the immune system in

Processes

A parallel has been drawn by several authors (Burnet, 1959; Comfort, 1964; Walford, 1962; 1969; 1974) between aging and the effects of auto-immunity. It has also been proposed that alteration in age-related immune competence may contribute to the pathogenesis of various diseases which show a peak incidence late in life (Kay, 1979; Makinodan, 1980). For example, increases in susceptibility to infection, to diffuse connective tissue diseases and to cancers have all been suggested to bear an inverse temporal relation to failing immune capacity. However, the causal nature of this inverse relationship cannot be established by this kind of correlative evidence. It is as well to remember that, in man, it is equally possible that some of the diseases mentioned may themselves accelerate (rather than arise from) decline in

129

KENNETHW. WALTON

130

immunological competence. In order to overcome this difficulty, much experimental work on immunological changes in relation to aging has been carried out in mice. In this species, components of the immune system can conveniently be ablated and then restored, or otherwise manipulated and the effects related to senescence. However, all strains of mice are very short-lived as compared to man. Moreover, different strains vary markedly, within this short span, in longevity. The choice of strain may thus very much influence the apparent effect of a given manipulation upon the aging process. This probably accounts for some of the conflicting reports in the literature attempting to relate particular aspects of immunological reactivity to age (e.g., see Kay, 1979) in mice. For the purposes of this presentation, which is primarily humans, an attempt will be made to review the evidence with only passing reference to work with animals.

The Normal

Immune

concerned with problems in aged relating mainly to our own species

Resnonse

For the benefit of those current state of knowledge

who are not immunologists, it may be useful to summarise concerning the normal immune response and its development.

the

It is now recognised that immunological reactivity is mediated through humoral and cellular components. Material “foreign” to the body which is not immediately engulfed and disposed of by polymorph leucocytes is “processed” by macrophages and either reacts with sensitised lymphocytes forming the cellular component of the system, or evokes the production of antibodies, which serve as the humoral component, by other lymphocytes. Antibodies occur as a group of plasma proteins which are The Humoral Component. functionally and physicochemically heterogenous but which share certain characteristics so that they are known collectively as immunoglobulins. In humans, five classes of immunoglobulin are recognised (Table I), each produced by separate cells (clones) in lymphoid tissues. TABLE I Some characteristics

of human

immunoglobuiins

Class

Sedimentation Constant

Molecular Weight

Cont. in serum (mg/dl)

IgG IgA IgM Ig” IgE

7s 7s 19s 7s 8.S

160,000 150,000 900,000 150,000 196,000

800-1500 100-400 50-200 l-40 0.01-0.04

The cells concerned with antibody production (plasma cells) arise from bone-marrow in man and which are known as “B-cells”. They circulate other lymphoid organs (spleen, lymph-nodes and other reticuloendothelial rise to antibody production at these sites.

cells to,

originating in and populate, tissues) to give

of the immune response is mediated through lymphocytes The cellular component originating in the thymus (T-cells). These cells migrate freely into tissue compartments and over the surface of, or even within, other cells (Pulvertaft, 1959). From the work of Gowans (see Gowans and Knight, 1964), it has become evident that lymphocytes in general recirculate between the tissues and the blood stream via lymphatics so that they have maximal At sites where insoluble or “indigestible” antigen opportunities for contact with antigens. persists, in conjunction with macrophages they give rise to the tissue reaction described as a

The Failing Immune System

131

“granuloma”. In some T-lymphocytes sensitised by antigen, the “memory” of antigenic exposure appears to be retained for an indefinite period. Renewed contact with antigen evokes an accelerated and augmented response, even in vitro, with enlargement and proliferation. In viva, certain forms of immune response -delayed or tuberculin-type hypersensitivity, contact dermatitis, homograft reactions and certain auto-immune responses) are predominantly mediated by T-cells (Roitt and co-workers, 1969). In man, populations of B- and T-cells co-exist in peripheral blood, B-cells accounting for about one-third of the total circulating lymphocytes (Wilson and Nossal, 1971). B-cells are recognisable because they carry a high surface density of immunoglobulin while T-cells (and thymocytes) have very little (Rabellino and colleagues, 1971). The surface coat of B-cells is thought to be capable of antigen recognition and this interaction with antigen is thought to serve as the stimulus to activity and proliferation of the cells so that, at suitable sites (germinal centres) in lymphoid tissue, the activated &cells undergo further development to plasma cells which produce immunoglobulin (and specific antibody). On the other hand, T-cells (forming the preponderant proportion of the circulating pool of lymphocytes) when suitably sensitised are also capable of reaction to stimulation by antigen so as to proliferate, forming an enlarged population of primed antigen-sensitive cells. Activated T-cells release soluble factors known collectively as lymphokines (Dumonde and others, 1975) which are vaso-active and which control the activity of macrophages and other lymphocytes. For example, subsets of T-cells are concerned in the activation or suppresslon of B-cell activity or the mediation of cytotoxic activity (“killer” cell activity). T-cells carry specific receptors on their surface membranes allowing their reactivity with plant lectins, sheep erythrocytes, the F portion of immunoglobulins and other “markers” which allow their identification and enuheration. Both B- and T-cells originate from a common stem cell and interact with one another and with macrophages to determine immunological reactivity. The efficiency of the immune system in the aging animal can thus be regarded as dependent on preservation of the full biological activity of each of these varieties of cells.

Development

of the Norman

Immune

Mechanism

Although lymphoid tissue appears early in foetal life, the normal foetus synthesises little or no immunoglobulin in utero. Antibodies in the blood of the new-born at birth have been transferred transplacentally from mother to infant and reflect the mother’s antibody pattern. The initial absence of synthesis of immunoglobulins is presumably due to the sterile environment in which the normal foetus exists and the consequent lack of stimulus to intrinsic immunoglobulin production. Little or no immunoglobulin or antibody is detectable even in maturing animals maintained in a germ-free environment. But if the foetus is infected in utero after the 20th week of gestation (as in rubella, congenital syphilis or toxoplasm-hen antibodies of foetal origin are demonstrable at birth. Nor mai development of the immune response is thus a reaction to the stimulus of emergence into an environment full of antigenic material. In adults, the reaction to antigens gives rise to antibodies which may be of more than one immunoglobulin class and which, within a given class, show molecular heterogeneity since they arise from different groups of B-cells (i.e., they are polyclonal in origin). The reaction to first exposure to an antigen (primary response) is expressed in the immunoglobulin M (IgM) class of antibodies whereas subsequent exposure (secondary response) is in immunoglobulin G(IgG) antibodies. This secondary response requires the co-operation of T “helper” cells with antibody producing B-cells in the case of certain (so-called T-dependent) antigens (Clamon and Chaperon, 1969). Delayed hypersensitivity responses, which are an index of cellular in normal children but have been reported to increase in intensity in older age groups (see below).

immunity, can be evoked in adults and then decline

KFNNCTH

132

Changes

in the Immune

System

W.

WAL~OF~

with Age

Lymphoid organs can be expected to “age” in line with other tissues and therefore to show waning reactivity. However, an alternative possibility is that lymphoid involution or failure might accelerate senescence by predisposing to infection, and neoplastic or degenerative diseases. Decline in immune capacity might result from changes in the cell types mediating immune responses, or in thier environment, or both. In mice, cross-over experiments, involving the transfer of immunocompetent cells between syngeneic young and old animals prior to testing their immune responses, have suggested that the last of these possibilities applies (for review, see Makinodan and Kay, 1980) although intrinsic changes in the cells are probably more important than environmental changes. In man, such manipulations, or investigation of the stem-cells givin, u rise to B- and T-cells, are not possible. Since macrophages are thought, in most instances, to “process” antigens before B- and Tcells deal with them, theoretically macrophage defects could influence immune functions without any alteration in B- and T-cells. However, no consistent or significant changes in macrophages in relation to their role in immune responses have been demonstrated either in mice or man (Callard, 1978; Makinodan, 1979). t)-cells and Humoral Immunity. The total numbers of circulating B-cells show relatively little change with age in man (Weksler and Hutteroth, 1974; Becker and others, 1979). On the other hand, the level of serum IgA and IgG tends to increase with age whereas the level of IgM shows little change, suggesting some fluctuation in sub-populations of B-cells. Circulating levels of iso-antibody (such as those directed at blood group substances) and hetero-antibody (as, for example, antibody to sheep erythrocytesj decline with age (for references, see Makinodan and Kay, 1980). 13~ contrast, many varieties of auto-antibodies and anti-tissue antibodies increase in frequency with age (for references, see Walton, 1968). It has been suggested that this simply reflects a normal removal mechanism of tissue breakdown products produced by the increased “wear and tear” of tissues with age (Weir and others, 1966). In support of this proposition, induced damage to specific organs and tissues is known to be associated with the production of particular anti-tissue antibodies. For example, carbon tetrachlorideinduced liver darnage induces anti-liver antibodies experimentally (Weir 1961, 1963); myocardial infarction in humans is associated with the appearance of antibodies reactive with cardiac muscle (Ehrenfeld, Gery and Davies, 1961) and severe burns can evoke antibodies to skin components (Pavkova, 1962). There is also in man an increased frequency with age of the occurrence of benign gammopathies characterised by the appearance in the blood of markedly homogenous, and therefore presumptively monoclonal, immunoglobulins. Similar monoclonal immunoglobulins also occur with neoplastic transformation of plasma cells in myelomatosis or in macroglobulinaemia. Myelomatosis is frequently attended by the occurrence of amyloid deposits in certain sites. Walford (1969, 1974) has stressed the occurrence of amyloidosis in many tissues of aged animals and man, even in the absence of myelomatosis, and has suggested that such “senile” amyloid may result from auto-immune reactions within, and against, body components. However, immunochemical and immunohistological investigation has revealed that amyloid deposits may contain three immunochemically different types of proteins and that only deposits related to myeloma/macroglobulinaemia contain immunoglobulin lightchain components while these are absent f ram “senile” amyloid (Cornwell and others, 1977). T-cells and cell-mediated immunity. There are conflicting reports concerning alteration with age in the total number of circulating T-cells in man (cf. Carosella, Mochanko and Brown, 1974; Weksler and Hutteroth, 1974). In contrast, there appears to be something approaching consensus concerning an age-related decline in many of the various kinds of immune reactivity shown by subsets of these cells. For example, depression of delayed-type hypersensitivity to common and ubiquitous antigens (Roberts-Thomson and co-workers, 1974) or to synthetic and uncommonly encountered compounds such as dinitrochlorbenzene

The Failing Immune System

133

(Grossman and colleagues, 1975); decline in responsiveness to plant mitogens or allogenic cells (Roberts-Thomson and co-workers, 1974; Smith, Steel and Evens, 1974; Tice and others 1979); and reduced cell-mediated cytotoxicity (Becker and colleagues, 1979) have all been reported. It has been suggested that these qualitative changes in the functional capacity of T-cells may be related to the involution of the thymus which occurs with age and to the decline in output of thymic hormones (Bach and colleagues, 1975). Evidence for similar qualitative changes in mice indicative of a shift in sub-populations of T-cells with age and thymic involution, or following thymectomy, have been comprehensively reviewed by Makinodan and Kay (1980).

Significance

of Decline

in Immune

Reactivity

with Age

One of the major protagonists of the immunological theory of aging has conceded that “It is uncertain whether decline in immune function (either thymus-related, or a more general decline with loss of the homeostatic control of tolerance) precedes the onset of autoimmunity in normal aging, or the reverse” (Walford, 1974). A survey of the current literature, particularly as this relates to man rather than inbred strains of mice, leads one to conclude that the evidence that aging is due, as suggested, to minor grade histocompatibility reactions, is still far from compelling. Such auto-immune phenomena have been proposed to account for the incidence of amyloidosis, cancer and certain connective tissue diseases, such as rheumatoid arthritis, in older age groups. However, as already noted, only the variety of amyloidosis secondary to myeloma or macroglobulinaemia can be shown to contain immunoglobulin components. With regard to neoplasms, it has been suggested that these arise because of an age-related failure of immune surveillance (i.e., a failure of the immune system to eliminate neoplastic clones). However, even where tumours possessing cellular antigens which evoke a detectable immune response in the host (Ristow and McKhann, 1977) are encountered, there is no evidence that the prognosis is worse than where no auto-antibodies are demonstrable. Indeed there have been claims that immunotherapy by the stimulation of production of anti-tumour antibodies produces favourable responses in some varieties of tumours. Lastly, as Schofield and Davies (1978) have pointed out, both auto-antibodies and the connective tissue diseases most commonly and extensively associated with auto-immune phenomena (systemic lupus erythematous and rheumatoid arthritis) are commoner in women than men and are not confined to older age groups. On this basis, men should live longer than women if auto-immunity is the most important pathogenetic factor in aging, yet the converse is the case. In summary, therefore, in the opinion of the writer the case is not proven for the proposition that the thymus serves as the biological clock controlling the life span and that its effect is mediated through the running-down of the immunological mechanism.

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