IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 14. Immunological Tolerance

■ Tolerance mechanisms are essential because The Immune System generates a vast array of diverse antigen-specific receptors, some of which inevitably recognize the body's own Antigens; tolerance prevents unwanted immune responses against the Organism's own Organs and Tissues.

■ Central (thymic) tolerance to self-antigens (autoantigens) is achieved through the deletion of differentiating T Cells whose antigen-specific receptors exhibit high affinity for self-antigens localized within the Thymus. Low-affinity autoreactive T cells, as well as T cells bearing receptors for antigens not presented in the thymus, mature and enter the peripheral T-lymphocyte pool.

■ Post-thymic tolerance to self-antigens relies on three mechanisms: circulating autoreactive T cells may simply "ignore" self-antigens—

for instance, if the antigens are localized in tissues isolated from the Circulation; under certain conditions, autoreactive cells are deleted or rendered anergic, losing The ability to interact with the antigen. A manifested state of tolerance to self-antigens can also be maintained through The Mechanism of immune deviation.

■ B-Cell deletion takes place in the Bone Marrow; B cells that express surface immunoglobulin receptors with high affinity for self membrane-bound antigens are deleted at an early stage of differentiation.

■ Autoreactive B AND T cells can evade deletion in the periphery by downregulating the expression of their antigen receptors.

■ Tolerance can be artificially induced through various approaches, some of which have clinical Applications in preventing foreign graft rejection and treating autoimmune and allergic diseases.

INTRODUCTION

Immunological tolerance refers to a state of unresponsiveness to a specific antigen induced by prior exposure to that antigen. Actively functioning tolerance mechanisms are necessary to prevent inflammatory reactions against the many harmless antigens entering the body via air and food that encounter the mucosal surfaces of the respiratory and gastrointestinal tracts. However, tolerance to the body's own antigens is the most critical, as it prevents immune responses against self-tissues. Nevertheless, the potential for such responses exists because the immune system produces A wide variety of antigen-specific receptors (see Chapter 8), including those capable of reacting with autoantigens. Consequently, cells carrying such receptors must be functionally or physically eliminated.

The capacity of an organism to prevent immune responses directed against self-antigens is not genetically programmed from the start, but rather develops during ontogeny. For instance, homozygous mice from histocompatible strains A and B mutually reject Skin grafts from the other strain, whereas their F1 hybrids (expressing antigens from both parents, A and B) accept grafts from both strain A and strain B. Rejection of both graft types reappears in F2 homozygotes. Thus, the ability to distinguish between "self" and "non-self" is acquired during ontogeny: all epitopes (antigenic determinants) encoded in the organism's DNA must be immunologically defined as "self," while all others are designated as "non-self."

However, the ability to differentiate between self and foreign antigens is determined not solely by The Structure of their molecules per se. Alongside Structural Features of epitopes, several other factors play a crucial role:

✵ the stage of lymphocyte differentiation upon its first contact with the specific epitope;

✵ the anatomical site in the body where this contact occurs;

✵ The Nature of the cells presenting the epitopes; and

✵ the number of lymphocytes reacting to these given epitopes.

History of Discovery

Shortly after antibody Specificity was discovered, it became apparent that mechanisms must exist to prevent The production of autoantibodies. As early as the beginning of the 20th century, Ehrlich proposed the term "horror autotoxicus," postulating the necessity of a regulatory mechanism to prevent autoantibody production. In 1938, Traub induced specific tolerance by injecting lymphocytic choriomeningitis virus into mouse embryos, establishing a lifelong infection. Unlike normal mice, adult animals infected in utero failed to produce neutralizing Antibodies upon re-exposure to the virus. In 1945, Owen reported on an experiment set up by nature itself—non-identical twin calves whose Blood contained cells bearing both "self" and "non-self" antigens. During embryonic development, these calves shared a common placental blood supply, allowing the exchange of hematopoietic (stem) cells. The animals developed lifelong tolerance (erythrocyte mosaicism): as adults, they mounted no humoral response to the transfusion of red Blood Cells from their embryonic parabiosis partner. (In the absence of a shared placental circulation, cross-transfusion of red blood cells between adult dizygotic twin calves elicits antibody production.) Building on this observation, Burnet and Fenner postulated that the age of the animal at the time of first contact with an antigen is the decisive factor in shaping immunoreactivity and acquiring the ability to recognize foreign antigens. This hypothesis seemed logical, given that the immune system typically encounters most self-antigens before birth and interacts with foreign antigens only later.

Experimental support for this hypothesis came in 1953, when Medawar and his colleagues induced tolerance to allogeneic (i.e., non-identical, but from an animal of the same species) skin grafts in mice by injecting allogeneic cells into newborn animals (Fig. 14.1). Such tolerance is readily explained by Burnet's clonal Selection theory (1957), which proposes that an immunocyte (such as a B or T cell) undergoes selection upon encountering an antigen, after which it divides to form a clone of daughter Cells of the same specificity. One of the postulates of this theory states that contact with specific antigens after birth activates the corresponding lymphocyte clones, whereas contact before birth results in the deletion of clones specific for those antigens (termed "forbidden clones" by Burnet). It follows from the theory that the entire repertoire of specificities must be generated before birth; however, lymphocyte differentiation actually continues for a long time after birth. Thus, the key determinant of immunoreactivity is not the developmental stage of the organism, but the maturation state of the lymphocyte at the time it encounters the antigen. This hypothesis was advanced by Lederberg in 1959 in his modified version of the clonal selection theory: immature lymphocytes contacting an antigen undergo clonal deletion, whereas mature ones are activated. Today, the immunocompetence of the newborn organism is a firmly established fact. Tolerance to specific antigens can be induced prenatally simply because immune responses in newborns and adults can be functionally distinct. Consequently, the INDUCTION OF TOLERANCE in newborns can be viewed as one of the earliest Examples of this type of "immune deviation" (see below).

The foundational discoveries of the 1960s included the immunological competence of lymphocytes, the pivotal role of the thymus in The Development of the immune system, and the existence of two interacting lymphocyte subpopulations—T AND B cells. These breakthroughs provided the basis for extensive research into the cellular mechanisms of "tolerogenesis."

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Fig. 14.1. Induction of specific skin graft tolerance in newborn mice injected with Spleen cells from donor mice of different strains. Strain A mice normally reject strain B skin grafts. However, if they receive an injection of strain B mouse cells at birth, they exhibit tolerance to strain B skin when tested at 6 weeks of age, while skin grafted from strain C mice is rejected. This phenomenon is due to immune deviation (see text).