peripheral self-tolerance and autoimmunity: the protective role of expression of class ii major...

Biomed. & Phonnacother., 43 (1989) 593-605 (B Elscvier, Paris

593

Dossier

Peripheral self-tolerance and autoimmunity :

the protective role of expression of class II major histocompatibility

antigens on non-lymphoid cells

Y. IWA’X’ANI’, N. AMINO and K. MIYAI

Deprfmenr of Laboratory Medicine, Osaka University Medical School, Osaka 553, Japan

(Received 30 August 1989; accepted 5 September 1989)

Summary - Immunologic self-tolerance is achieved mainly during development by clonal deletion in the thymus of T lymphocytes with receptors specific for self-antigens and with associated T-ceil markers CD4/CD8. However, T cells expressing 2 low level of these markers are allowed into the periphery still bearing their autospecilic receptors. Such clonal deletion, induced by cells bearing the class 11 antigens coded for by major histocompatibility complex (MHC) in the thymus, does not remove all autoreactive T cells specific for antigens of differentiated tissue expressed extrathymically. However, these autoreactive T cells are silent in the periphery. Peripheral non-lymphoid cells (e.g.. endocrine cells) can induce antigen-specific unresponsiveness in T cells and can specifically suppress production of autoantibody against their antigens when the non-lymphoid cells express class II MHC antigens on their surface. This class II MHC expression is induced by interferon-yproduced by T cells as a result of various immune responses, such as autoimmune reaction. Thus, the expression of class II MHC antigens on non-lymphoid cells may serve as a peripheral mechanism for the induction and maintenance of self-tolerance in autoreactive T cells that escape negative selection in the thymus or that are specific for extrathymic tissue antigens, in a fail-safe m~h~ism against autoimmunity~ Some autoimmune diseases, especially organ-specie ones, might be caused by a defect in this fail-safe mechanism.

self-toleraaee / autoimmunity f MHC class Ii l utlgeas

R&sum6 - L’auto tolbaace p&riphirique et I’auto-immunith : r6le protecteur de I’exprcssion des aatig&s de la clam II SUM des C&&S non lymphoides. L’auto toit+ance immunitaire s’&abiit principaiement au COW du d&loppement par d&Son cionaie d i’intdrieur du thymus de lymphocytes T porfeurs de rt+epteurs sp&@ques d’auto-antigtnes ainsi que des marqueurs CD4/CD8 des ceiiuies T. Des ceiiuies T exprimant ces marqueurs d faible taux sont nPanmoins e’pnrgnb duns les espaces ptiriphdriques jusquii ce q&lies commencent ci porter ieurs rtcepteun autosp&&mes. Un teiie d&tian cionale, provoquPe par des ceiiuies portant ies antigknes de ciasse Ii cod& par ie complexe d~istocompotibiiit~ majeure {MHC) du thymus, ne suppn-me pas routes ies ceihdes T autorPactives sptktifues d’anti@tes de tissus di~~~~~s qui s’expriment en dehors du thymus. L,es celluies T autor~actives restent rkanmoins siiencieuses dans ie secteur ~*n~h~~.que. Des ceflutes p~~h~~.~es non tymphoties (par exempie des ceihdes endocrines) peuvent provoker chez ies ceWes T une absence de rdponse spkctifiue d’antigkze et peuvent ~pp~rner ~~ci~quement ia production d&to-anticorps contre Ieurs antig&es quand ies ceiiules nou lymphoides exprimant des antigtks de ia ciasse ii du MHC h ieur surface. Ceirx expression de ciasse If du MHC est induite par i’interfdron y. iui-meme produit par des celhdes T b la suite de divers types de rkponses immunitaires telie, notamment. la rdaction auto-immune. Ainsi. ikxpression d’antigPnes de la cias~~ If du MHC sur des ceiiuies non lymphoides pourrait constituer un mdcanisme pc’rpht’riique provoquant et maintenrmc i’auto tokrance the;! les ceiiuies T autor&actives qui &appmt d la sdection th;w-ique, darts un mtkanisme de sr;C wire’ contre l’auto-immunitt!. Certaines maladies auto-immune& en partidier ceiles qui ont une sppcijicith d’orpane, po~w ient t?tre ii&s ri une deyaillance duns ce mdcanisme de stkurit~.

* Correspondence and reprints.

I ~Ct~QQ

The immune system is confronted with a variety of molecules, and it recognizes them as either self or non-self (foreign), taking action against the latter only. Recent experiments with transgenic mice have shed light on the mechanism by which this immunologic self-tolerance takes place. Self- tolerance is mainly achieved by clonal deletion or by donal anergy of autoreactive lymphocytes. In T-cell tolerance, however, this clonal deletion or anergy is induced by cells in the thymus that are positive for the class If antigens of major histocompatibility complex (MHC); whether thereis a mechanism to induce self-tolerance in the periphery is unknown [46,53]. A variety of peripheral non-:ymphoid cells, which are normally negative for class II MHC antigens, express these antigens in c~tain pathological conditions, including autoimmune disease. Class II MHC expression by non-lymphoid cells was originally suggested to be related to the induction of autoimmunity [ 131, but results from many studies, including transgenic ex~~ments, have not shown such a relationship. In this review, we will discuss recent advances in the understanding of immunologic self-tolerance and autoimmunity and, in relation to these topics, we will discuss both the significance of class II

A

-

MHC expression by non-lymphoid cells and the pathogenesis of autoimmune disease.

T-cell tolerance

Experiments with transgenic mice have shown that there is negative selection (clonal deletion) of autoreactive T cells in the thymus, which was proposed by Burnet (171 as the main mechanism of self-tolerance. Clonal deletion has been found in various T cells bearing antigen receptors speci- 5%~ for the class II MHC molecule I-E [57, 791, minor lymphocyte-stimuIating antigen (Mls) [SS, 771, the MHC class I molecule H-2Ld IlOl], and a complex of the male-specific minor histocompatibility antigen H-Y with the MHC class I molecule H-2Db [61]. The deletion occurs in CD4YJD21C thymocytes before they differentiate into CD4CD8* or CD4+CD8- cells [30, 57, 61, 69,79]. Markers CD4KD8 associated with T-cell precursors [30] and the class II MHC antigens [81] are important in clonal deletion. The cells re- sponsible for negative selection are positive for class 11 MHC antigens, and are mainly dendritic cells derived from bone marrow 161, 116]$ and possibly sometimes thymic epithelial cells 1104] (Fig. 1).

non-autospecific @WC-unrestroeted)

i

prethymocyte

Fig. 1. Model of T-cell differentiation. @I, T-cell @I receptor; $, T-cell J% receptor. CD4+8+, up receptors.

.

CD4+ and CDS’ cells have T-cell

Peripheral selfltolerance and autoimmunity 595

Positive selection of T cells specific for foreign antigens has also been found in experiments with both transgenic and normal mice 162, 76, lOl]. Positive selection splits the T-cell population into its 2 major functional subpopulations, CD4+ and CDS+ cells, and causes their proliferation; both processes are based on recognition of the different families of MHC antigens (class II for CD4+ cells and class I for CDS+ cells) by the T-cell receptor, which is created somatically. Positive selection may occur on the surface of thymic epithelial cells positive for class II antigens, and it may be followed by negative selection [79, 1041; the difference between these positive and negative selections is based on the affinity of thymocytes to cells in the thymus positive for class II antigens 11041 (Fig. 1).

Studies with transgenic mice on receptors of T cells with specificity for the male-specific H-Y antigen complexed with H-2Db have shown in- teresting results [61, 621, H-Y-specific thymocytes bearing relatively high levels of the CD4KD8 molecules were deleted in male mice, and such thymocytes (non-autospecific for females) were positively selected in female mice. Surprisingly, autospecitic T cells expressing a low level of these associated molecules were positively selected and allowed into the periphery still bearing their H-Y specific receptors in male mice, where they were, however, unable to fun~ion as mature T cells because of clonal anergy or active suppression (Fig. 1). These findings suggest that the CD4/CD8 molecules are part of the selection process for autospecific T cells and that some mechanism must maintain clonal anergy of these autospecific T cells that have escaped into the periphery.

These findings on T-cell tolerance were all related to self-antigens synthesized by thymic stromal cells. it is unlikely that every self-determinant expressed on extrathymic differentiated cells (e.g., in endocrine or neural tissues) would be encountered in the thymus. Of course, circula- ting soluble self-antigens produced extrathymically, such as thyroglobulin or complement C5, may be taken up, processed and presented in association with class II MHC molecules by cells that bring about negative selection in the thymus [ll]. However, recent evidence does not suggest that soiuble antigens induce tolerance in the thymus, at least for T cells with a capacity to recognize antigens restricted to MHC class I antigens [4]. Thus, an unidentilied process, which may involve clonal anergy or active suppression, could be involved in the indu~ion of T-cell

tolerance to self-antigens not expressed in the thymus [46,5 I]; this is called peripheral tolerance (Fig. 1).

B-cell tolerance B-cell tolerance is also achieved by clonal anergy and deletion (Fig. 2). Clonal anergy is the major mechanism for B-cell to!erance in double-trans- genie mice expressing the genes for a neo-self antigen then-egg lysozyme), and a high-afftnity anti-lysozyme antibody [36~. Most anti-lysozyme B cells do not undergo clonal deletion, but they cannot secrete anti-lysozyme antibody, and have low levels of surface IgM, while continuing to express high levels of surface IgD; this suggests that IgD is important in the anergic process. Clonal deletion has been found in H-2’x H-2d transgenic mice bearing the genes for the IgM anti-H-2k idiotype, which lack B cells bearing the anti-H-2k idiotype and have no serum anti-H-2’ antibody [SS]. These lindings suggest that immature B cells may be deleted when they encounter antigens at the earliest stage of development, and may instead be inactivated when they encounter the antigens in the brief period following the start of membrane IgM expression. Only B cells that do not come into contact with antigens until they reach the mature B-cell stage can respond to antigens in conjunction with helper T cells, producing antibodies specific for them 1441 (Fig. 2). However, many self-antigens that are sequestered inside cells or in certain organs may not encounter immature B cells which develop in the bone marrow. Furthermore, autospecilic B cells in healthy subjects without evidence of autoimmuuity can be induced to produce autoantibodies [49, 1181. Thus, suppressor T cells might be important. in maintenance of clonal anergy in B-cell tolerance [25, 98, 1071, as Wd! ~3s

in the regulation of the production of antibodies to foreign antigens 16, 1061.

Aut~immune diseases arise from a defect in self-tolerance [IS, 651, progress slowly with prolonged latency periods [27], and are sometimes aggravated under the influence of an environmental factor such as microbes 1941 or drugs 1391 or of some physiological change in the body such as puberty, pregnancy, or puerperium [3]. Trans- ient autoimmune phenomena often follow infection and drug administration even in otherwise healthy subjects [94]_ The transient aggravation of a~toimmune diseases and transient autoimmune phenomena after exposure to some envir~)nme.~t~l factor may be explained by the breakdown of self-tolerance in which the factor in question mimics a self-antigenic determinant [94], alters a self-antigen [99], acts as a polycionai immune activator [119], or induces an idiotype cross-reaction to self-antigens [24]. Transient aggravation of autoimmune diseases in early pregnancy and puerperium [51] may be induced by the physiological increase of large granular lymphocytes [S4], which have a variety of cytotoxic activities (those of Pd# [50], K [5], and cytotoxic T cells},

the capacity to regulate B-ceil response. ever, these active autoimmune reactions

usually do not continue even in autoimmune disease and are generally limited to a transient non-pathological process, especially in healthy subjects.

Autoimmune diseases progress steadily, but not are self-limited. Thus, the primary defect in autoimmune diseases is most likely present in a critical point of the induction of self-tolerance [92] and is probably different from the breakdown mechanisms that trigger the aggravation of autoimmune diseases and autoimmune phenomena. Immunologic self-tolerance is generally believed to be induced during the perinatal period when immature lymphocytes are exposed to self-antigens [92]. Probably some abnormalities during this perinatai period that interfere with the estab- lishment of self-tolerance by cionai deletion or anergy of autoreactive T cells in the thymus cause T-ceil-dependent autoimmune diseases. This hypothesis may be true of some systemic autoimmune diseases, but cannot explain the pathogenesis of all autoimmune diseases, especially organ-speci~c ones, in which the tissue-speci~c antigens are not expressed in the thymus. Thus, another basic mechanism to induce and maintain self-tolerance {which could be c~!li;d peripheral tolerance) in which a defect causes organ-specific autoimmune disease may exist in the periphery.

On the other hand, certain MHC (or human leukocyte antigen, HLA) haplotypes (e.g., HLA-BS, DR2, DR.3 and DR4) [IOS, 1101, certain Gm aiiotypes of immunoglobulins (e.g., Cm !,2 :21) [iO8] or an inclzase in CDVB cells [55], which produce autoantibodies and have an immunoreguiatory function, predispose to autoimmune disease and may be related to the pathogenesis of autoimmune disease.

The expression of class II MHC antigens is usually limited to thymic epitheiial ceils and immune ceils derived from bone marrow [33, 1111. However, a variety of non-lymphoid ceils can also express class II MHC antigens under various pathological condition, such as autoimmunity, infection, and neoplasm, and some of them do so under physiological conditions (Table I). Inter- feron-y can induce the expression of class II MHC antigens on non-Iymphoid cells both in vim [103, 1211 and in vitro [33, 11 I]; such cells include endotheliai cells, ~broblasts, keratinocytes, glial cells (astrocytes, oligodendrocytes, and microgiial ceils), renal tubular epithelial cells, small-bowel epitheiiai ceils, pancreatic epitheliai ceils, hepato- cytes, pneumocytes, adrenal cells, and thyroid epitheliai ceils. Thus, the expression of class II MHC antigens on non-lymphoid ceils seems to be secondary to interferon-y produced by T iympho- cytes as a result of a specific or non-specific immune response under such pathological cir- cumstances.

First hypothesis The significance of class II MHC expression on non-iymphoid ceils was first explored in relation to the induction of autoimmunity [13], because aberrant expression of class II MHC antigens was observed on thyroid epithelial ceils in situ in autoimmune thyroid disease [2, 41, 56, 951. This hypothesis suggested that aberrant expression of these antigens on thyrocytes would enable the thyrocytes to present thyroid-speci~c antigens directly to helper T cells, thus initiating and maintaining autoimmune thyroid disease. It also suggested that the defect in suppressor T cells specific to the thyroid observed in autoimmune

Pet$piwal selfrtolerance and autoimmunity

lhhrle I. Expression of class II MHC antigens on non-lymphoid cells,

SW

Pathokqical conditions

~~~~~~~~~~~~ H~s~~rno~o*~ &ease Graves’ diseSe Jns~I~~-dependent diabetes meJ&us Sjligren’s syndrome Primary biJiary cirrhosis Multiple sclerosis

Rheumatoid arthritis Psoriasis

Discoid lupus erythematosus Jnflammatory bowel disease Celiac disc;;se

Alopecia areata

Infe&xt Urixxqy traCt i&ction Parasitic infection

LeprWy

Neophm

Melanoma

Glioma Thyroid CarCinoma Breast carcinoma

Ce& expressing class ill MHC nniigtm

T&r02 epirh&& &Is Tkyroid ep~t~eI~aI &Is Riocreatic iskt @ c&s SaIivary epithefiaf ceJJs Biie-duct epithelial celfs Gliaf cells fastrocytes)

Synovial cells Keratinocytes Keratinocytes Colon crypt epitheliwl cr?lJs Jejunum crypt epithelial cells J-k&folkle hratinoqtes

Renal tob&ar epitfreliaf a& G& e~it~e~i~~ 43%~

~e~~~~es

Tumor cells 69 73 9

Other pathological tmditions Emenatous dermaGtis Renal transplant Graft- vs.-host disease lane marrow transpJant Tuberculin reaction

Ph~~~oJo~~~J conrfidons

Keratinocytes 68 Renal tubular epith@linl cells 38 Keratinocytes 113 Salivary epitheJiaJ cells 78 Ke~~~~~ Jo0

Mammary epithetid c&s 88 Deeidual ceJJs 105 Adrenocortical eelis 60

thyroid disease [45, 84,91,93, 109, I 121 may be a secondary phenomenon caused by this abnormal presentation of autoantigen outside of the normal ~mm~~oregu~at~on circuits.

However, this hypothesis is unlikely to be correct, becaose ckss fI MHc= ~~~~e~s are also expressed on non-~~~~~d ‘cefb in @her non- autoimm~ne diseases and even in be&h [Ta- bfe 1). Furthermore, in auto~mmu~e thyroid disease, thyrocyte HLA-DR expresian can be induced by interferon-y produced by autologous lymphocytes (CD4+ and CD16”) in response to class-II-negative thyrocytes via mnnocytes [47], and such expression can also stimulate autologous lymphocytes (CD4+) directly to produce interferon-)r 1471. Therefore, if the r?xpresssion of class If MHC antigens on nob-l~m~hoid cells were to induce a~to~mrn~~e responses specific for

these cells, autoimmune diseases would progress rapidly and autoimmune phenomena following viral infections would not be limited to a non- pathological p~~ess. However, these are aat the cl&zica~ characteristics of ~uto~rnrn~n~~; in fact, there is a prolonged later~cy period in a&&m- mtme disease 1273, and the a~toi~u~~ phenomena ~~lt~~~g viral infections are transient [94& Farthermore, experiments with transgenic mice have given direct evidence contradicting this first hypothesis. The expression of class II MHC antigens cm non-lymphoid cells does not initiate autoimmunf: responses against the tissue-specific antigens 112, 74, SO]. In addition, recent observations of tolarance in transgenic mice expressing class I or IT AAHC antigens on islet /I ceIl$ Aave supported the idea of there being a ~eripb~ra~ tolemnce mecba~~sm [78, S3J.

59s Y. Iwutuni et al.

Antigen-presenting function There are many studies on the activities of non-lymphoid cells positive for class IJ MHC antigens in their functioning as antigen-presenting cells [33, 1111. These experiments have used ailoantigens or exogenous antigens, not autoanti- gens and have measured the proliferative response of T cells. The results obtained have varied depending on the capacity of the non- lymphoid cells to take up and process antigen and to deliver a co-stimulatory second signal and also depending on the stage of differentiation of the responding T cells. On the whole, endothelial cells can function as antigen-presenting cells and can initiate immune responses [35], but the other cells, which lack the capacity to deliver a co- stimulatory second signal, are inefficient antigen-presenting cells by themselves [S6]. However, they may also function as antigen-presenting cells in the presence of monocytes or endothelial cells [34]. The expression of class II MHC antigens on antigen-presenting cells is required not only for presentation of foreign antigens but also for presentation of self-antigens [19, 751. It is also required not only for the activation of helper T cells but also for the induction of suppressor T cells 167, 701. From these results, therefore, we cannot tell what kind of immune reaction is finally induced by an interaction between autologous immune cells and non-lymphoid cells positive for class II MHC antigens, especially in terms of the production of autoantibodies specific fot the non-lymphoid cells and of cytotoxicity against these cells.

Fail-safe mechanism against autoimmunity For clarification of the role of class II MHC expression on non-lymphoid cells, the effect of thyrocytes positive for class II MHC antigens on thyroid autoanribody production has been ex- amined in vitro [52]. In that study, thyrocytes expressing both class II MHC antigens and ihyroid-specific antigens [48] did not induce or enhance thyroid-specific autoantibody production by autologous lymphocytes [52]. The expression of class II MHC antigens on thyrocytes suppressed the production of thyroid-specific zntibodies ripecifically, but not the production of total IgG by B lymphocytes, which include various stages of thyroid-specific B cells [49], via an interaction between autologous thyrocytes and lymphocytes [52]. This specific suppression was not induced by allogeneic interaction, suggesting that there was MHC restriction [52]. Thus, in contrast to the pathological role in the first

hypothesis [1.3], these findings suggest that class II MHC expression on non-lymphoid cells serves as an extrathymic mechanism for the maintenance of self-tolerance (i.e., a fail-safe mechanism against autoimmunity [53]) and may be related to the induction of T-cell tolerance to extrathymic self- antigens in peripheral tolerance.

Figure 3 illustrates possible mechanisms for a fail-safe mechanism against autoimmunity. One is the induction of unresponsiveness in CD4+ CD29+ helper T cells that are autoreactive and specific for the antigens on extrathymic differentiated cells, by the expression of class II MHC antigens on the cells in response to interferon-y produced by T lymphocytes, which is a result of an evoked autoimmune reaction or other pathological immune reactions. Another is the induction of T-cell suppression against the autoimmune reaction specific for the antigen on extrathymic differentiated cells, by the expression of class II MHC antigens on the cells, which probably stimulate antigen-specific CD4+CD45 RAf suppressor-inducer T cel!s and then antigen-specific CDS+CD28- suppressor T cells. In support of these possibilities, it has been reported that, as observed in non-lymphoid cells expressing class II MHC antigens [32, 781, occupancy of the T-cell ab receptor in the absence of a co- stimulatory signal from the antigen-presenting cells induces a state of proliferative unresponsiveness in the T cells [S6]. Furthermore, when autologous T cells are co-cultured with gut epithelial cells expressing class II MHC antigens, the proliferating T cells are CDS+CD2S- suppressor T cells [SO], which are usually induced by CD4+CD45RA+ suppressor-inducer T cells 1851.

This fail-safe mechanism against autoimmunity might explain the maintenance of unresponsiveness to self-antigens in subjects without autoimmune disease under continuous attack by environmental and other factors (e.g., infection, drugs, sunlight, tissue or organ transplantation, immunization, and aging), which may mimic self-antigenic determinants, alter self-antigens, act as polyclonal immune activators, or induce an idiotype cross-reaction to self-antigens (Fig. 3). Even if an autoimmune reaction is strongly induced by some factor, interferon-y produced by T cells attacking the self or the affected (target) cells would induce expression of class II MHC antigens on the intact target celis nearby, which would then drive the fail-safe mechanism to resolve the evoked autoimmune reaction non- pathologically in healthy subjects. In that case the suppressor circuit amplified by this autoimmune

Environmental

factor

\ Physiological

change

Peripheral self-tolerance and autoimmunity 599

Induction of Autoimmune Reaction

Fail-Safe Mechanism against Autoimmunity

Genetic factor

hduction of T-cell Suppression .----1

IFN-r

tnduction of Unresponsiveness

in Autoreactive Helper T Celt

Fig. 3. k%ibsafe mechanism against autaimmunity. APC, Antigen-presenting cell (macrophage or dendritic cell); TH, helper T eelI: R, I3 cell; Tc, cytotoxic T cell; K, K cell with antibdy-dependent cell-mediated cytotclxic activity; Tg, suppressor-inducer “I’ cell; Ts, suppressor T cell; II, class II MHC antigen; I, class I MAC antigen; TCR, T-cell t@ receptor; C. complement.

reaction would maintain the unresponsiveness to the self-antigen more steadily. This fail-safe mechanism against autoimlnunity might hasten tumor progression of neoplasms expressing class II MHC antigens by suppressing local immune response against them [15, 1201, and also might help in the successful transplantation of organs matched for class II MHC antigens [38]. Further- more, organs that differentiate relatively late, such as mammary glands [88] and decidua [105], might protect their new antigens (which may appear for the first time when they begin to function) by expression of class II MHC antigens on their surface. In deeidua, in particular, this protective mechanism of &ss II MHC expression on both fetal and mother cells might be a major mechanism for maintenance of the fetal semi- ailograft during pregnancy [22].

Pathogen&s of autoimmune diseases: 8 hypothesis

Some ~~t~j~~~~~ diseases, especially organ-specific ones, might be caused by a defect in a fail-safe mechanism against autoimmu~i~. If

such a defect were present in certain cells, the cells could not completely suppress autoimmune reactions specific for the antigens on their surface by induction of the expression of class II MHC antigens on the cells, resulting in the development of the disease. Autoimmune diseases that are caused by such a defect would progress slowly, because a strong autoimmune reaction induces strong suppression even if the induction of suppressor cells is incomplete. Thus, this hypothesis could explain the prolonged latency period 1271 and the continuous expression of class II MI-K antigens on target cells observed in auto~i~rn~~e diseases (Table I),

Defects in this fail-safe mechanism against autoimmunit~ might be based on an abno~ali~ in self-antigens, class II MHC antigens, a eom- plex of a self-peptide and a class II MHC antigen, T-cell receptors, or the suppressor circuit induced by T-cell recognition of such a complex. In this regard, the association between class II MHC antigens and autoimmune diseases [l IO] and the defect in genes coding T-cell receptors [65, 1221 or MHC class II antigens [lo] in some autoimmune diseases are evidence for this notion. Self-antigens, which are targets in autoimmune diseases,

Peripheral Self -Tolerance

by

e , I 8 I P-

Fetal Petinatal Remainder of Life Period Period

Defective Enhancement of

Induction Autoreactivity

600 Y. haiani et al.

may be the same as those in healthy subjects [31, 961. in organ-specific autoimmune disease, a functional defect in antigen-specific suppressor T cells has been reported 14591,931, which would &v&e the suppressor circuit. If a defect in antigen-specific suppressor T cells is the basis of the autoimmune disease, this would help explain the characteristics of autoimmune diseases, expe- cially the antigenic specificity [ 114, 11.51. There are several hypotheses about the pathogenesis of autoimmune diseases [16,26,87, 1171; one is that such a defect in antigen-specific suppressor T-cell clones is genetically determined 1114, 1151. How- ever, it is unlikely that defects in several different genes, each of which is presumably related to each suppressor T-cell clone specific for the antigenic dete~inant on tissue-specific antigens of one tissue, would occur simultaneously in one patient. It has, however, been suggested that there are several different antigenic dete~inants that are not tolerated on a tissue-specific antigen of target cells 197, 1021 or several different autoantibodies specific for the same antigen [28, 40, 1231 in certain autoimmune diseases, and also that autoreactive T cells are polyclonal [S9]. Thus, in an opposite way, a basic defect in antigen-specific suppressor circuits might be caused by the target cells themselves.

a Fail-Safe Mechanism against Autoimmunity

Fig. 4. Hypothesis on peripheral self-tolerance and autoimmune disease.

Basic immunologic self-tolerance seems to be induced during the perinatal period, when immature lymphoc~es are exposed to self-antigens (921. Thus, when the first autoreactive T lymphocytes attack target cells at a critical point during the ontogenic development of the immune cells, the cells might induce and establish a basic suppressor circuit that inhibits the autoimmune reaction against them by a fail-safe mechanism against autoimmunity (Fig. 4). Then, when the autoreactive T cells attack the target celils afterward, the activity of this basic suppressor circuit might be evoked by the fail-safe mechanism, which main- tains peripheral tolerance during the remainder of the life of the organism (Fig. 4). Therefore, some abnn~a!ity of the fail-safe mec~~anism against autoimmunity in certain cells at this critical point during the perinatal period might cause a defect in the basic suppressor circuit, which results in a defect in the fail-safe mechanism to maintain self-tolerance, giving rise to autoimmune disease (Fig. 4).

critical period of the immune system for some reason such as the delayed development of differentiated antigens on a specific organ (endocrine glands or neural tissues) or because of transient changes in or blocking of certain self- antigenic determinants by microbes, drugs, or so on. In support of this possibility, a transgenic experiment has shown that delayed onset of the neo-self antigen, the simian virus 40 large T antigen, which is expressed specifically on islet /I cells during development, induces autoimmunity in fl cells [l]. This hypothesis might explain the mechanism of organ-speci~c autoimmune diseases induced by neonatal thymectomy at the critical point [64]. According to this way of thinking, target self-antigens in autoimmune diseases are not necessarily different from those in healthy subjects.

There are several possible defects in the induction of the basic suppressor circuit. One likely one is that some self-antigen&z determinants in association with class II MHC antigens may not be expressed on certain cells in the body at this

In conclusion, (1) expression of class II MHC antigens on non-lymphoid cells induced by autoimmune reactions against them might induce basic suppressor circuits against the autoimmune reactions (giving rise to peripheral self-tolerance) at a critical point during the perinatal period, and might maintain the self-tolerance by induction of T-cell suppression against the autoimmune reaction evoked by environmental factors and so on during the remainder of the life of the organism. Last, (2) a defect in this fail-safe mechanism against autoimmunity during the perinatal period, which also results in a defect in this mechanism during the remainder of the life of the organism, might be the pathogenesis of autoimmuue diseases, especially organ-specific autoimmune diseases.

“Recognize self first, and the road to self- tolerance will be open.”

Peripheral self-tolerance and autoimmunity 601

Ackaowkdgments

We thank Noriko Yokota and Yuki Hirano for secretar- ial assistance.

1 Adams T.E., Alpert S. 8 Han&an D, (f987) Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic B cells. Nature 325,223

2 Aichinger G., Fill H-L. & Wick 0. (1985) In situ immune complex, Iymphocyte subpopulations, and HLA-DR-positive epithelial cells in Hashimoto’s thyroid&. fmit hv&= 52, 132

3 Amino N, Mari H., Iwatani Y,, Tanizawa O., ~wu~~~a &If., Tsw f, Xaragi K, Kumalmra Y. & Miyai #, (1982) High p~~a~e~~ of frank&

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