Immunity to bacteria and fungi

Immunity to bacteria and fungi

Immunity to bacteria and fungi S.H.E. Kaufmann Department University of Medical Microbiology of Ulm, Oberer Current Opinion in Immunology Int...

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Immunity

to bacteria and fungi S.H.E. Kaufmann

Department University

of Medical

Microbiology

of Ulm, Oberer

Current

Opinion

in Immunology

Introduction

and Immunology,

Eselsberg, Ulm, West Germany 1989, 1:431%440

genesis will be included in the discussion, although emphasis will be put on immune mechanisms.

The sequence leading to an Infectious disease caused by non-toxigenic bacteria and fungi can be divided into the following steps: (1) uptake of pathogens; (2) adhesion to host cells; (3) invasion of adequate niches; (4) colonization of these niches; (5) evasion from host-defence mechanisms; (6) stable infection, and (7) disease. Once a pathogen has resided in its host lon enough (i.e. once it has established a stable infection5:, an in-mune response is generated which enables the host to intervene with this sequence. The kind of immune response which contributes most to protection greatly depends on the type of pathogen. Extracellular microbes preferentially live in the extracellular space, and engulfment by professional phagocytes generally results in their elimination. Accordingly, inhibition of phagocytosis represents a major survival strategy of these pathogens and opsonization by antibodies, and complement is a major host-defence mechanism. Intracellular pathogens, on the other hand, are capable of entering and replicating inside host cells. Pathogens of non-professional phagocytes have to actively induce their uptake. For others, professional phagocytes provide the preferred habitat and these cells are entered via phagocytosis. These pathogens often attempt to improve phagocytosis. Mononuclear phagocytes (MP) can be activated by interleukins from helper T cells and this event represents a major defence mechanism against microbes residing in professional phagocytes. In contrast, non-professional phagocytes, as well as certain tissue macrophages, frequently cannot be activated adequately. In this case the host may have to accept destruction of infected cells by cytolytic T cells in order to make these pathogens accessible to more potent phagocytes. The possible relevance of this latter mechanism to protection has only recently been noted. Under certain conditions the hosts may also suffer from the immune response against infectious agents. For a long time, cross-reactivity between antigenic epitopes of pathogens and the host have been implicated in the development of certain autolmmune diseases. One of the best studied examples is that of post-streptococcal autoimmune diseases. Evidence is emerging that, in certain infections, heat-shock proteins (hsp) provide a link between infec tionand autoimmune diseases. In this review I shall attempt to highlight recent studies concerned with the relation between the host and Pathogenic bacteria and fungi. Not all aspects of this relationship are immunological by nature. Therefore, some studies on the molecular mechanisms underlying patho-

Phagocytosis

and invasion

Pathogens enter host cells either by invasion or by phagocytosis, which are both receptor-mediated endocytotic processes. In the case of invasion, pathogen-derived molecules induce endocytosis, whereas in the case of phagocytosis uptake is a sole function of the host. Phagocytosis is accomplished by professional phagocytes and facilitated by opsonizing antibodies for which complementary receptors exist on the cell surface of professional phagocytes. These are Fc receptors for im munoglobulins and receptors for the C3b (CRl) and the C3bi fragment (CR3). Figure 1 illustrates important events related to phagocytosis, invasion, and intracellular replication.

Inhibition

of phagocytosis

by streptococcal

M-proteins

Extracellular microbes rapidly succumb to intracellular killing by professional phagocytes and hence for these microbes it is important to prevent phagocytosis by socalled antiphagocytic mechanisms. These include the Mprotein of streptococci. In the naive host, phagocytosis of streptococci is promoted by alternate pathway activation and C3bCRl interactions. M-proteins interfere with this activation sequence. Streptococci expressing M-proteins (M+> or lacking them (M-) bind purilied C3b equally well [ 11. When incubated in whole serum, however, M+ streptococci bind double the number of C3b molecules and lo-fold more factor H. These data indicate that streptococcal M-protein binds factor H on the bacterial surface in the vicinity of fixed C3b and C3bBb. Factor H then inhibits and reverts C3bBb formation and allows inactivation of C3b by factor I. Thus, M-proteins prohibit C3bmediated phagocytosis by depriving the bacterial surface of C3b.

Pathogen-facilitated

phagocytosis

Intracellular pathogens, which preferentially abuse professional phagocytes as host cells, do not depend upon particular invasion molecules since they can enter these cells via phagocytosis. Evidence is accumulating that many intracellular pathogens increase their own phagocytosis by binding to complement receptors. This can be

Abbreviations MHC-major

C[tcluster designation; hsp-heat-shock histocompatibility complex; MP-mononuclear

@ Current

Science

proteins; IF&interferon; phagocytes; TNLtumor

Ltd ISSN 0952-7915

necrosis factor.

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Immunity to infection

Fig. 1. Simplified scheme of important events that can happen when a microbe meets a host cell: (I)Activation of the alternate complement pathway and binding of C3b. (2) Adherence of microbes via interaction of bound C3b with its receptor, CRI, on the surface of professional phagocytes. (3) C3bCRl interaction triggers phagocytosis. (4) Inactivation of bound C3b via binding of factor H by strptococcal M-proteins inhibits phagocytosis. (5) Direct binding to CR3 and other cell adhesion receptors. (6) Binding of a microbial protein, invasin, to a yet unknown ligand on the cell surface induces endocytosis. (7) Invasion of non-professional phagocyttes occurs via endocytosis. (8) After invasion and phagocytosis, microbes end up in a phagosome. (9) Activation of reactive oxygen metabolites. (IO) Fusion with lysosomes results in killings of many microbes. (11) Microbial molecules which interfere with these events facilitate survival in the phagosome. (12) Evasion into the cytoplasm, e.g. by means of listeriolysin, also facilitates intracellular survival. (13) Stimulation of CD4 T cells by microbial products plus class II MHC molecules. (14) Macrophage activation by interleukins from CD4 T cells. (15) Association of products from intracellular pathogens with class I MHC molecules stimulates CD8 T cells. (16) Target-cell lysis by CD8T cells. 1), lysis; -), leads to the next step;::::.. ., activation.

achieved either by direct interaction with receptors on the phagocyte surface or indirectly via binding of complement components. The opportunistic fungi Curzdti albicarrsand Cryptococcus neofirmunsuse the latter way. C albicuns activates and binds C3b (Kozel and Pfrommer, Infect Immun 1986, 52:1-5) and C neo~mactivates and binds C3b as well as C3bi [2], Hence the former fungus can be internalized by CR1 and the fatter one by CR1 and CR3. In addition, C neoformuns binds to human monocytes via another complement component, Clq [3]. Since these fungi can be killed by many professional phagocytes, uptake seems to be primarily of benefit to the host. However, in immunocompromised individuals, at least some phagocytes may serve as niches which

protect the fungi from the humoral defence mechanism and the pathogens may benefit from this mechanism. The intracellular bacterium, Legionella pneumqln’~ binds both C3b and C3bi and hence is taken up via CR1 and CR? [4]. Uptake does not interfere with the typical coiling mechanism by which this pathogen is engulfed and could even be responsible for its induction. In many cases bind ing to CR1 and CR3 does not result in the generation of reactive oxygen metabolites and hence may facilitate evasion from this killing mechanism. The intracelMar fungus, Hktop~ cujxukztum directly binds to three cell surface receptors of MP, CR3, LFA-1 and p150,95 which function as cell adhesion molecules (Bullock and Wright, J E~LIMed 1987, 165:195-210).

Immunity to bacteria and fungi Kaufmann Invasion

Invasion of cells serves two major functions: (1) penetration of cells which separate the preferred niche from the site of entrance, e.g. the intestinal epithelial cells (in most cases these cells are only transiently infected), and (2) invasion of non- rofessional phagocytes which serve as preferred niche Pthese cells are Inhabited permanently). Ymsiniu pseudotuberc~ is taken up by contaminated food and invades the host from the gastrointestinal tract by penetrating intestinal epithelial cells. The bacteria subsequently replicate in extracellular and intracellular niches with MP serving as the major habitat. At least two proteins are involved in the in vitro invasion of host cells by Y pseudduberculasis Both proteins are located in the outer membrane; one-called Yop l-is plasmid encoded, whereas the other one-termed invasir-is encoded chromosomally. The genes encoding both proteins have been cloned and sequenced (Isberg and Falkow, Nature 1985,317:262-264; Bolin et al, Infect Immun 1982, 3756512). Molecular clonescontaining the inv gene confer the capacity to invade HEp-2 cells to E. coli [ 51. In contrast, inv- muCants of Ypseuab tuberculosh can no longer penetrate these cells, although they still avidly adhere to them. It appears that invasins mediate adherence to certain (yet undefined) host-cell receptors and that this interaction triggers the endocytotic machinery of the host cell. Thus, invasin is different from the pili of E. coli and other microbes, which only serve as adherence factors and do not induce entry. Interestingly, mutations in either the inv or the wl gene fail to intluence the course of I! pseudotubercukxis infection significantly in a mouse model [6]. More importantly, I: pseuhtuberculos~ organisms carrying mutations in both the inv and the JC$J1 must contribute to virulence in vivo. Moreover, these mechanisms must be counteracted by inv and JX$ 1 since they are only active when the two molecules are not expressed. Based on DNA hybridization data, Yersiniupestzk, the etiological agent of bubonic plague, is highly similar to I: pseudo tubwcul& However, the two species differ from each other in the expression of the inv and yap genes. Y pest& carries a non-functional JX$ gene caused by single base pair deletion. Introduction of a functional fl gene to Y pestis reduces its virulence. On the basis of these findings, Rosqvist et al. [6] speculate that I: pest& may have derived from a less virulent strain by single-point mutation and that mutations of this kind could have contributed to the rapid rise and fall of plague epidemics.

Intracellular

A low molecular weight component of M. hprae, phenolic glycolipid, acts as a scavenger of reactive oxygen metabokes and in this way contribute to intracellular survival of this organism““(r121. Among non-oxidative mechanisms, inhibition of phagosommsome I%sion seems to be a major factor. In the case of tubercle bacilli, this type of inhibition has been traced to the blocking of lysosomal movements [ 131. In interleukin-activated macrophages, the capacity to restrict the intracellular growth of many pathogens is increased (see also later section on CD4 T-lymphocytes and interleukins) and evidence for the importance of non-oxidative mechanisms has been presented in some systems [14,15]. Accordingly, macrophages become tuberculostatic once osome-lysosome fusion has beeninitiated artikially 14 . Mutants of Legione& pneum@ih have been ob!?? tained that are still able to enter monocytes by coilin phagocytosis and that can still survive intracellularly 116 B. However, these mutants are no longer able to replicate in monocytes, probably because they have lost their capacity to inhibit phagosome-lysosome fusion.

Evasion into the cytoplasm

Until recently, very little has been known about the molecular mechanisms responsible for evasion into the cytoplasm. Transposon mutagenesis has been used successfully for identifying the role of hemolysin in intracellular replication of Lkteriu monocytogenes This pathogen has been responsible for several recent outbreaks of food-borne diseases (summarized in [ 171). Usteriolysin is a 58kD pore-forming cytolysin that shares a high degree of similarity with the SH-activated toxins streptolysin 0 and pneumolysin [ 181. It had been found earlier that Listeria strains lacking hemolysin are avirulent and loss of hemolysin by transposon mutagenesis renders L monocyto enes avirulent in vivo (Gaillard et al, Infect Immun 198%, 52:50-55) [ 19,201. Listeriolysin seems to be involved in intracellular survival rather than invasion, since non-hemolytic insertion mutants are still able to invade host cells [21]. Non-hemolytic mutants, however, lose their abili to grow in murine macrophage and fibroblast cell lines 7 19,201. Non-hemolytic L mono cytogenes mutants remain in the phagosome, whereas hemolytic listetiae can be identiiied in the cytoplasm. With respect to survival in human cell lines heterogeneity exists [ 20,211. Thus, listeriolysin seems to mediate evasion from the phagosome into the cytoplasm by forming pores in the phagosomal membrane.

replication Acquired

There are many mechanisms that contribute to the intracellular survival of certain micro-organisms. They can be broadly divided into three major groups: (1) interference with oxidative mechanisms; (2) interference with non-oxidative mechanisms, and (3) evasion into the cytoplasm. In general, several mechanisms participate in intracellular survival and their relative roles still remain controversial. Uptake of pathogenic mycobacteria is not paralleled by increased levels of oxygen radicals [7,8,9] and sulphatides of Mycobacterium tubercuti as well as lipoarabinomannan from Mycobacterium lepr-ae can inhibit macrophage priming for several functions [lO,ll].

cellular

resistance

T lymphocytes are the crucial mediators of protective immunity to intracellular bacteria and fungi, Peripheral effector T cells segregate into two major subsets of distinct phenotype: (1) CD4 T cells, which see antigenic peptides in the context of class II molecules of the major histocompatibility complex (MIX), and (2) CD8 T cells, which recognize antigenic peptides together with class I MHC molecules (see also Fig. 1). It is currently believed that acquired resistance to intracellular bacteria and hmgi is a function of CD4 T cells, which activate antimicrobial capacities in infected MP via interleukin secretion.

43:

434

Immunity to infection CD4 T lymphocytesand interlwkins Class II restricted CD4 T cell clones with specificity for

a variety of bacteria and fur@ have been isolated and during the period covered by this review work has continued. The availability of recombinant lrrterleukins has made it possible to assess directly the relative role of inter1eukIn.sln the host defence against intracellular bacteria and fungi both in vitro and in vivo. Since this topic is to be coveted more extensively by Tracey and Cerami in this issue (pp 454-461), only a few Iindings will be considered here. Interferon (IFN)y, known to be a major mediator of MP activation, has recently been shown to activate tuberculostatic and fungicidaVfungistatic capacities in murine macrophages in vitro [14,15,22-241. It also seems to be active in vivo, since application of r-IFIVy before in-? fection results in increased resistance to L monocyt~ genes (Kiderlen et al, Eur J Immunoll984,14:964-967) ’ and application of anti-~~~y antibodies worsens listeriosis (Buchmaler and Schreiber, Proc Nat1 Acad Sci US4 1985, 82:7404-7408). IFNy is produced in SCID mice lacking detectable T or B cell function and seems to contribute to the partial resistance of these mice to L mono cytogenes infection [ 251. However, in other studies, IFNr failed to Induce listerial killing by macrophages from normal mice, indicating that other factors are Involved [26,27]. Application of antibodies against tumor necrosis factor (TNF) worsens listeriosis [28], and killing of atypical mycobacteria can be induced by r-TNF, suggesting that this interleukin also contributes to antibacterial resistance [29]. IFNy fails to activate tuberculostasis in human MP [ 301; instead, 1,25dihydroxyvitamin D3, a potent activator of many MP capacities (reviewed in [31 I), seems to fulfill this function (Rook et al., Immunology 1986, 57:15%163) [30]. 1,25dihydroxyvitamin D3 is the biologically active metabolite of vitamin D3. Cl-hydroxylation of the circulating metabolite 25-hydroxyvitarnin D3 leads to the biologically active form, 1,25dIhydroxyvitamln D3. This step was orIginally thought to be restricted to the kidney; however, recently it has been found that activated MP, including MP activated by IFNy, possess Cl hydroxylase activity. It is therefore possible that in human monocytes activation of mycobacterial growth inhibition is accomplished by IFNy indirectly via 1,25dihydroxyvitamin D3.

CD8 T cells

Intracellular bacteria do not only live in MP. Some pri marily reside in non-professional phagocytes, and many microbes which preferentially inhabit MP can also infect other cells. Many non-professional phagocytes do not express class II MHC molecules and cannot be stimulated by interleukins in the way MP are activated. Even the MP system is quite heterogeneous and comprises cells of different antimicrobIal efficacy. In these situations interleukln activation may not be sufficient and may depend on additional T cell mechanisms. Earlier studies with negatively selected T cell sets had already implied a role for both CD4 and CD8 T cells ln adoptive protection to L monocytogenes and M. tubercukxis (e.g. Kaufmann et aA, J Exp Med 1979, 150:10331038; Kaufmann et al. Infect Immun 1985,48:263-266; Orme and Collins, Cell Immunol1984, 84:113-120). More recently, it has been shown that cloned CD8 cells alone [32], as well as CD8 T cells restimulated by mitogens [33], can confer a

sign&ant degree of protection against listeriosis alone. Participation of both CD4 and CD8 T cells ln tuberculosis and listeriosis is further suggested by studies usin mice selectively depleted of CD4 or CD8 T cells [34-36 F. Some studies, however, indicate that the relative role of CD8 T cells in resistance . t tuberculosis varies with the stage of disease [35,37aYms . A protective role for CD8 T cells has now been noted In several Infections with intra cellular bacteria and protozoa (reviewoJ in [38] >. CD8 T cells with speciliclty to several Intracellular bacteria et al, J Exp Med 1986, 164:363368; De&&rnann Libero and Kaufmann, J Zmmunoll986, 137:2688--2694; Chiplunkar et al, Infect Zmmun 1986, 54:793797; Rollwagen et al, J Zmmunol 1986, 136:14X+-1421) [32,39-41] and protozoa (see [38] and review by Liew in this issue, pp 441-447) have been shown to lyse target cells expressing homologous antigens, In some cases, class I restriction has been demonstrated suggesting that exogenous antigens of bacterial or protozoal origin can associate with MHC class I molecules, although it is unclear how this may happen. As described above, listenolysin is a pore-forming molecule that allows transmission of L monocytogenes from the phagosome into the cytoplasm. During listeriosis strong T cell responses to listeiiolysin are Induced [42]. At the same time, this cy tolysin Interferes with class II antigen presentation [43]. Thus, during bacterial infections, microbial proteins pass into the cytoplasm, and this event could allow class I presentation at the cost of class II presentation. What is the function of CD8 T cells? As has been found in other models, CD8 T cells with

specificity to microbial antigens can secrete IFNr after appropriate stimulation [32,39]. Hence the main function of CD8 T cells (similar to that of CD4 T cells) could be their capacity to activate antibacterial mechanisms through interleukin secretion. The advantage of CD8 T cells over CD4 T cells would then be limited to their broader target spectrum since virtually all host cells express class I molecules. In addition, target-cell ly sis may be relevant to antibacterial resistance [38]. Lysis of Infected host cells could directly affect intracellular pathogens, and particularly obligate intracellular para sites. At the same time, the host could suffer from targetcell lysis for two reasons. Firstly, excessive lysis can af feet tissue functions. For example, M. leprae preferentially inhabits Schwann cells, and Schwann-cell destruction resulting in nerve damage is a major pathogenic fea ture of leprosy. Cytolytic T cells could be involved in this damage since specific lysis of Schwann cells presenting M leprae antigen by CD8 T cells has been demonstrated in vitro [4I]. Secondly, lysis of host cells containing intracellular pathogens within discrete foci could result in bacterial dissemination and hence facilitate colonization of secondary tissue sites. Target-cell lysis therefore appears as a double-sided sword requiring scrupulous regulation. Lysis of infected host cells, which by themselves are unable to restrict the growth of their intracellular parasites, may be an unavoidable step, since it allows uptake of these microbes by MP better equipped for intracellular killing. These cells could then be activated by lnterlet&ins and other factors (see previous section on CD4 T lymphocytes and interleukins). These different T cell functions are summarized in Fig. 2. Immunohistological

Immunityto bacteriaand fungiKaufmann

Fig. 2. Possible role of T cell functions in antimicrobial immunity. (a) T cells activate antimicrobial capacities in infected MP via interleukins. (b) Lysis of infected host cells directly affects microbial growth. (c) Tissue destruction by cytolytic T cells. (d) Microbial dissemination after lysis of infected host cells. (e) Coordinated lysis and activation allows microbial transmission from a cellular niche to a more aggressive effector cell.+, lysis;+, activation;:::, , interleukins.

analysis has revealed the presence of CD8 T cells in grarulomas of tuberculoid leprosy patients, which express a marker typical for cytolytic T cells [ 441. In murine listeriosis, granuloma formation depends on CD8 T cells (Ntier et al, J Immunoll985,134:569-572) 1361.Some studies indicate that human and murine CD4 T cells with specificity to bacteria can express cytolytic activity (Kaufmann et al, Eur J Zmmunoll987, 17:237-246) [45,46]. Thus, CD4 T cells could fi_W both lysis and activation. Direct application of tuberculin into lesions of lepromatous leprosy patients induces the influx of blood monocytes and CD4 T lymphocytes, which is followed by lysis of parasitizedtissue macrophages and reduction of intact M. @rae organisms [47]. The fact that in this case a soluble antigen was applied could explain why only CD4 T cells were found. Protection versus autoimmunitv The search for protective antigens is an important strategy towards understanding of virulence factors, host-parasite relationship and vaccine development. In the case of extracellular pathogens, adherence factors and antiphagocytic factors are of major relevance

to virulence, and antibodies against these molecules often confer protection. Accordingly, these molecules can be termed protective antigens. Protection against group A streptococci exclusively depends on opsonizing antibodies with specificity for M-proteins. M-proteins, however, do not only contain protective epitopes but also those which cross-react with human tissue, and antibodies against these cross-reactive epitopes have been implicated in the pathogenesis of the post-streptococcal autoimmune diseases, rheumatic cardiac disease and glomerulone h&is. In addition, cytolytic T cells may be involved [40 P. In the case of intracellular bacteria the situation is far more complicated and there is no reason to assume that T cells relevant to protection are directed against microbial components related to intracellular parasitism. For T cells do not protect by interfering with microbial functions directly, but rather set into motion non-specific effector mechanisms aimed at the eradication of the pathogen (MP activation and target-cell lysis, see above). Thus, it is not surprising that as yet protective antigens of intracellular pathogens have been elusive. Very recently, indications have been gathered that hsp may provide a possible link between infection, immune response, and autoimmunity, Thus, both in hu-

435

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Immunity to infection

moral and cellular immunity, beneficial and detrimental sequelae can be very closely related.

Dissociationof protectiveand autoreactitieepitopeson streptococcalh&proteins

For several years, efforts have been made to identify and dissociate protective and autoimmune epitopes on streptococcal M-proteins. Such studies form the basis for a rational vaccine design against group A streptococci but they may also facilitate our understanding of antigenic mimicry. The COOH terminal region of M-proteins is highly conserved and hence cross-reactive epitopes should cluster in this part of the molecule. An epitope which is both protective and cross-reacts with myosin has been located in this part between amino a&l residues 84-l I6 and (Dale and Beachey, J Exp Med 19E$ N&1785-1790) and another protective epitope which cross-reacts with cardiac sarcolemmal membranes between residues 164 and 197 [48]. In contrast, the NH2 terminal portion of various M-proteins is quite variable and hence the search for exclusively protective epitopes has focused on this region, However, a heart cross-reactive epitope has recently been identified between amino acid residues l-24 of type 19 M-protein [ 491. This linding questions the applicability of an undefined NH2 terminal fragment for vaccination since it may contain potentially autoreactive epitopes. Less is known about epitopes of M-proteins which crossreact with renal tissue. However, monoclonal antibod ies against streptococcal membranes cross-react with glomerular antigens (Fitzsimons et al., Hybridom 1987, 6:61-69) and, conversely, monoclonal antibodies against renal glomeruli recognize streptococcal M-proteins [ 501. In the NH2 terminal end of type 1 M-protein, a protective and renal cross-reactive sequence has been defined [51]. It is located between amino acid residues 1 and 26. The cross-reactive entity is made up of a tetrapeptide be tween positions 23 and 26 only. The rest of this peptide (amino acids l-20) is still protective but lacks autoreactivity. These hndings indicate that protective and autoim mune epitopes may be separable entities and hence underline the importance of exact epitope mapping for rational vaccine development.

Heat-shockproteins as a possible link betweeninfection, protection and autoimmunity These studies began with the cloning of the mycobacte-

rial genes and the expression and identification of their products (Young et aC, Nature 1985,316:450+52; Pnx NatlAcud Sci US4 1!%5,82:2583-2587). Subsequent analyses have shown that recombinant proteins of M. tuberculosis and M. lepae are T cell antigens (for summary see [52,53]). Sequence analysis of the mycobacterial65 and 71 kD proteins revealed a striking homology with hsp of E. cob and it is likely that they are hsp themselves [54,55]. The 18kD protein of M. kp-ae has been found to display homology with a hsp of plants [ 54,561. Hsp are evolutionary hlghly conserved and similar molecules have been found in different prokaryotic and eukaryotic species. They are induced by a variety of stress conditions including not only heat, but also attack by reactive oxygen metabolites, anaerobiosis or deprevation of nutrients, es-

sential ions and metabolites (for review see [57] >. These latter insults can occur inside activated MR. It is therefore reasonable to assume that microbes suffering from such adverse effects abundantly produce hsp to protect themselves from host attack. These molecules could then be subjected to intracellular processing and could be presented in the context of MIX molecules on the surface of infected cells. In agreement with this assumption, T cells with specificity to the 65 k~ hsp are commonly isolated from patients and immune mice (for review see [ 521). Using a variety of monoclonal antibodies against the mycobacteriaI65 kD, hsp cross-reactivity with a large variety of path enic and non-pathogenic microbes has been found [58 o? . Furthermore, a similar molecule has been identified in several microbes [ 53-611. Thus, the 65 kD hsp is an ubiquitous bacterial protein. Recently, it has been found that the 65 kD hs (as well as other recombinant mycobacterial antigens7 are recognized by T cells of many healthy individuals indicating that these T cells are not indicative for active tuberculosis [62]. It is therefore likely that infection with a variety of microbes can induce T cells with specificity for the 65 kD hsp. Certain bacteria of low virulence may survive in the host for a restricted time and induce T cell immunity without causing disease. These cross-reactive T cells could then contribute to early immunity against various pathogens (see Fig. 3). Clear-cut proof for a protective role of hsp-specilic T cells, however, is still lacking. Hsp could also provide a link between infection and certain autoimmune diseases. Increased titers of antibodies to autologous hs have been found in certain autoim 3,641. Recently, it has been shown that mune diseases [ 6p T cells from synovial fluids of patients with rheumatoid arthritis and other chronic inllammatory arthritis recognize the 65 k~ hsp [65]. In a rat model of experimental rheumatoid arthritis induced by mycobacteria, T cell lines, which either induce or protect against disease, ret ognize an epitope of the mycobacterial 65 kD hsp [66]. The human homologue of the bacterial 65kD hsp has been cloned and sequenced and shows surprisingly high sequence homology (Hgindal and Young, 1988, personal communication). Viral infections indce hsp and it can be assumed that similar events are stimulated in host cells suffering from intracellular bacterial infections. Stressed cells could then become targets for hsp-specific T cells induced by infectious agents (see Fig. 3). Individuals with human leukocyte antigen predilection for shared epitopes could be at risk of developing an autoimmune response. Human T cells which cross-react with delined epitopes shared by the mycobacterial and human 65 kD hsp have been isolated [ 531. Furthermore, murine T cells with reactivity to the mycobacterial65 kD hsp recognize stressed but not resting macrophages in the absence of the mlcrobial antigen, indicating that the 65 kD hsp is presented on the surface of these cells in the context of MHC molecules (Koga et al, 1988, personal communication). Although much more work will be required, the possible role of hsp in linking intracellular infection, protection and autoimmunity is an interesting question to pursue.

Acknowledgement S.H.E. Kaufmann is a recipient of the A. Krupp Award for young professors. Thanks to R. Mahmoudi for her secretarial assistance.

Immunity to bacteriaand fungi Kaufmann Fig. 3. Possible functions protein

(hsp)-specific

specific

T

with

a

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of

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cells

mononuclear

microbial

MP

pathogen. T

infected

agent

(2,

other

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but

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leads to next step.

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( Stress

Annotated

references

and recommended

reading 0

00

Of interest Of outstanding interest

1. a

HORSTMANN RD, SEVERTSENHJ, KNOBIOCH J, FLsCHETTIVA: Antiphagocytic activity of streptococcal M protein: selective binding of complement control protein factor H. Proc Natf Acad Sci USA 1988, 85:1657-1661. A streptococci of different serotype expressing the M-protein as well as baked M-proteins bind factor H, which controls C3b in the vicinity of bound C3b. In thisway, opsonization by C3b can be prohibited. 2.

KOZEL TR, BROWN RR, PFROMMERGST: Activation and bind-

inp of C3 by Candida albicuns. Infect Immun 1987, 55:189&1894. C. albicuns activates and binds C3b and in this way promotes its phagocytosis via CRl. ??

3.

BOBAK DA WASHBURNRG, FRANKMM: Clq enhances the phagocytosis of cfypt ocoaxs neofkvnans blastospores by human monocytes. J Itnmund 1988, 141:592-597. C ne~&rmans activates Clq and is taken up via the corresponding receptor.

MA: Phagocytosis of Legionella pneumopbffa is mediated in human monocyte complement receptors. J EQ Med 1987, 166:1377-13&V. Inhibition studies with monoclonal antibodies against CR1 and CR3 indicate that these complement receptors promote uptake by human monocytes of L pneumopbila. 4.

PAYNE NR, Horwnz

0

ISBERGRR, VOORHIS DL, FAIKOWS: Identification of invasin: a protein that allows enteric bacteria to penetrate cultured mammalian cells. cell 1987, 50:769-778. Genetic and functional analysis of the Y pseuaUuberc&sfs invzsinindicates that this molecule is invohed in host cell invasion and that it induces endocytosis by adhering to adequate surface structures of the host cell.

5. 0

6.

ROSQVISTR, SKURNIKM, WOIFWA’IZ H: (Letter to the Editor)

Increased virulence of Yersfnia pseudotubetwlosfs by two independent mutations. Nature 1988, 3%:522-525. Mutants of X pseu&tuberculaciis lacking invAn expression show simk lar virulence as the wild type. Doubte mutants not expressing you 1 and invasin show increased virulence. Introduction of the JK@ A gene into I: pest& reduces its virulence. Thus, expression of invasin and YCY,1 may reduce virulence of Yersinia sp. ??o

??

7. 0

ZHANG L, GOREN MB, HOUER TJ, ANDERSENBR: Effect of My

cobacteriutn tubenzulosfsderived Sulfolipid I on human phagocytic cells. Infect Immun 1988, 56~2876-2883.

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Immunity to infection Describes effects of M. tubercuhisderived fessional phagocytes.

sulfolipid on human pro-

PI.EsCHI, KAUFMANN SHE: Mycobacterial growth inhibition by interferon-y-activated bone marrow macrophages and di&rential susceptibility among strains Iof Mycobacterfum tubexul& J Immunol 1987, 138~4408-4413. IFNy-activated murine macrophages inhibit the gmwth of some, but not all, strains of M. tubenxti Uptake of mycobacteria together with IFNy fails to trigger release of reactive oxygen metaboiites.

8. 0

PABST MJ: Mycobactehm leprae murfum activates macrophages but fails to trigger release of superoxide anion. J Immund 1988, 140:3956-3961. Uptake of M. kpraemurft4mby murine macrophages fails to trigger release of reactive oxygen metabolites.

9. 0

MOR N, GOWN MB,

SIBLEY DL, HUNTER SW, BRENXANPJ, KRAKENBUHL JL Mycobacterial Iipoafabinomannan inhibits gamma interferoamediated activation of macrophages. Infwt Immun 1988, . 56:1232-1236. Iipoarabiiomannan affects macrophage activation by IFNy. 10. 0

PAE~STMJ, GROSS JM, BROZNAJP, GOREN MB: Inhibition of macrophage priming by sulfatide ftom Mycobacterium tuberculosis J Immunol 1988, 140:634&O. Sulfatidesof tubercle bacilli interfere with several functions of activated human mononuclear phagocytes. 11. 0

12. 0

NEILLMA, KIEBANOFF SJ: The effect of phenolic glycolipid-1 from Myco6acterfum leprae on the antimicrobial activity of human macrophages. J Exp Med 1988, 167z3Ck-42. Phenolic glycolipid of M. Zeprae acts as a scavenger of reactive oxygen metabolites and inhibits killing of an appropriate test organism. This mechanism may facilitate intracellular sunival of M .@+ae.

HART D, YOUNG MR, GOWN AH, SULLIVAN KH: Inhibition of phagosome-lysosome fusion in macrophages by certain mycobacteria can be explained by inhibition of lysosomal movements observed after phagocytosis. J Exp Med 1987, 166:933-946. M tubercuhfs and M. micwtii interfere with saltatoly movements of lysosomes, and in this way possibly inhibit phagosomelysosome fusion in macrophages. 13. 0

FLE~CHEA, KAUFMANN SHE: Attempts to characterize the ?? mechanisms hwoIved in myobacterial growth inhibition by gamma-interferon-activated bone marrow macrophages. Infect Zmmun 1988, 5631464-1469. Experimental evidence against participation of reactive oxygen metalxlites in tuberculostasis by IFNY-activated murine macrophages. Induction of phagosome-lysosome fusion by Iysosomotropic agents results in tuberculostasis. 14.

BRUMMERE, STEVENSDA Fungi&&I mechanisms of activated macrophages: evidence for nonoxidative mechanisms for IdIIing of Blas~myces dermatftfdfs Infect Zmmun 1987, 55:3221-3224. Experimental evidence against panicipation of reactive oxygen metabo lites in the killing of a fungal pathogen by IFNy-activated murine macrophages. 15. ??

16. a

Hoawnz MA Characterization of avirulent mutant Legfonella pneumopbfla that survive but do not muItipIy w&h human monocytes. J Exp Med 1987, 166:131&1328. An avirulent mutant of I. pneumq&ka fails to replicate intracellularly in human professional phagcqtes. Mutants are still capable of entering phagocytes by coiling phagocytosis. 17. KAuFMANN, SHE: Listeriosis: new findings, current concern. 0 Micrcb Pathogen 1988, 5~225231. The role of virulence factors of the immune response against L mOno cymgenes a5 well as the importance of Iisteriosis as food-borne disease are discussed. 18. 0

MENGAUD J, CHENEVERT J, GEOFFREYC, GALLL~RD JL, COSSART P: Identification of the structural gene encoding the SH-

activated hemoIysin of Listeria monocytogenes IisterioIysti 0 is homologous to streptolysin 0 and pneumoIysin. Infect Immun 1987, 55~3225-3227. ListeriolysIn 0 is homologous to streptolysin 0 and pneumoIysin. KUHNM, KATHARIOU S, GOEBELW: HemoIysin supports survivaI but not entry of the inuaceIIulat bacterium Lkterfa monocy@enes Znfect Immun 1988, 56~7-2. Hemolysir-negative transposon mutants of L monocytogenes still invade non-professional phagoqte cell line although they can no longer survive in professional phagocytes. 19. e

20.

POKINOYDA, JACKS PS, HINRICHSDJ: Role of hemolysti for the intracellular growth of Lfsterfa monoqtogenes. J Exp Med 1988, 16731459-1471. Hemolysin negative tmnsposon mutants of L monocytogmtes fail to grow in murine cell lines but retain the ability to grow in the human cell lines examined. ??

GAILIARD JI, BERCHEP, MOUNIERJ, RICHARDS: In vitro model of penetration and intracellular growth of Lfsterla man@ qtogenes in the human entemcyte-like cell line Caco-2. Infect Zmmun 1987, 552822-2829. Hemolysin-negative transposon mutants of L mcmocytogenes fail fo grow in a human cell line but can still penetrate this line. 21. ??

BRU~~MER E, HANSONL, RESTREPOA, STEYENSDA: in uiuo and in vftro activation of pulmonary macrophages by IFNy for enhanced IdIIing of Paracoccidiotoides brasiliensis or Blastomyces dermatitidfs J Immunoll988, 140~27862789. IFNy-activated mudne macrophages kill the pathogenic fungi, P. basilien.& and B. akrmatitidis 22. ??

BENNN LV: FungicidaI activation of murine macrophages by recombinant gamma interferon. Infect Immun 1987, 55:2951-2955. IFiVy-activated murine macrophages kill the pathogenic fungus, Coccidiodes immitik 23. 0

WU-H~IEHBA, HOWARDDH: Inhibition of the intracellti growth of HistopIasma capsuIatum by recombinant interferon. InfeCr Immun 1987, 55:1014-1016. IFNy-activatedmurine macrophages inhibit but do not kill the pathogenic fungus, Histqhsma cupsulatum.

24. ??

BANCROFTGJ, SCHREIBERRD, BO?NA GC, BOSMAMJ, UNANUE ER A T cell-independent mechanism of macrophage activation by interferon-y. J Zmmunol 1987, 139:1104-1107. FNy is produced in SCID mice suffering from listeriosis and may contribute to their partial resistance. 25. 0

VAN DISSELJT, STMKELBROE!CK JJM, VAN DEN BARSEIAARMT, MICHELBC, LEIJH PCJ, VAN FURTH R Inability of recombinant interferonyto activate the antibacterial activity of mouse peritoneal macrophages against Lfsterfa monoq togenes and Salmonella typbimurfum. J Immunol 1987, 139:16731678. IFNy-acmted murine macrophages fail to IdII L monocytogenes or S. *mu&m.

26. ??

CAMPBELLPA, CANONOBP, COOK JL: Mouse macrophages stimulated by recombinant gamma interferon to IdII tumor cells are not bactericidal for the facuItative intraceIIular bacterium Listerfa monoqvtogenes. Infect Immun 1988, 56:1371-1375. Murine macrophages fail to express listericidal activity after stimulation with IFiVy. 27. 0

HAVEU EA: Production of tumor necrosis factor during murine listeriosis. J Zmmund 1987, 1394225-4231. kpiication of anti-TNF antibodies worsens Iisteriosis In mice, suggesting that this interleukin contributes to resistance. 28.

BERMUDEZLEM, YOUNGIS: Tumor necrosis factor, alone or in combination with IL-2, but not IFN-y, is associated with macrophage killing of Mywbacterlum avfum complex. J Zmmunol 1988, 140:3&3013. TNF, but not IFNy, stimulates killingof M avium in human and murine macrophages. 29. ??

lmmunitv to bacteriaand fungi Kaufmann CROWIB AJ, Ross EJ, MAY MH: Inhibition by 1,25(0H),2vitamin D13 of the multiplication of virulent tubercle bacilli in cultured human macropbages. In&t Zmmun 1987, 55:2%5-2950. In human mononuclear phagocytes, the steroid, 1,25-dihydroxyvitamin D3, rather than IFNy, induces tuberculostasis. 30. ??

RIGBYWFC: The immunobiology of vitamin-D. Imnunol To 31. 0 day 1988,9:54-57. Summary of the multiple biological activities of vitamin D3. This steroid may also be required for the activation of antimicrobial macrophage functions. KAUFMANN SHE, RODEWALD H-R, HUG E, DE ~~BEROG: Cloned Lh-tetiu mfmocytogenes specific non-MHC-restricted Lyt2+ cells with cytolytic and protective activity. J Immunof 1988, 140:3173-3179. A CD8 T ceU clone with specilicity to Lz&riu monczyfogenes, but lacking apparent MHC restriction, not only lyses antigen primed target cells, but also produces IFNy and adoptively protects mice against Usteriosis. 32. 0

DJ: Adoptive transfer of immunity to Listeria motwcytogenes the influence of in vitro stimulation on lymphocyte subset requirements. J Zmmund 1987, 1392005-2009. After mitogenic restimulation, CD8 T cells from L monocytogenes immune mice show an increased capacity to adoptively transfer antilisterial immunity.

33. 0

BISHOP DK, ~CHS

M~~UERI, COBBOID SP, WALDMANN H, KAUFMANN SHE: Impaired resistance to MycolxuSrium tuberculosis infection after selective in vivo depletion of L3T4-+ and Lyt-2-+ T cells. Znfect Zmmun 1987, 55:2037-2041. Depletion of CD4 T cells and less so of CD8 T cells exacerbates i&c tion with M. tuberculasis in mice. 34. ??

PEDRWINI T, HUG K, LOUISJA: Importance of L3 + and Lyt-2T4+ cells in the immunologic control of infection with Mycobucterium bovis strain bacillus Calmette-Guirin in mice: assessment by elimination of T ceU subsets in viva. J Zmmund 1987, 139:2032-2037. In CD4 T cell depleted mice, M. bovis baccillus Calmette-Gu&in (BCG) infection is markedly increased. CD8 T cell depletion has far less dramatic effects.

35. ??

MIEUCEMEA, EH~RS S, HAHNH: T-cell subsets in delayedtype hypersensitivity, protection, and granuloma formation in primary and secondary Listeriu infection in mice: superior role of Lyt-2+ cells in acquired immunity. Znfect Zmmun 1988, 56:192&1925. Depletion of CD8 T cells in mice exacerbates listeriosis, while CD4 T ceU depletion is of marginal effect. Depletion of either CD4 or CDS T cells affects granuloma formation. 36. 0

41. .

STEINHOFFU, KAUFMANN SHE: Specilic lysis of CD8+ T cells of Schwann cells expressing Mycobacterium reprae antigens. Eur J Zmmund 1988, l&%9-972. Murine cytolytic CD8 T cells with specificity to M. kprae lyse Schwann cells expressing homologous antigens in the context of class I molecules in vitra This killing mechanism could contribute to nerve damage in leprosy patients. 42. 0

BERCHE P GA~ILARD J-L, GEOFFROY,AKXJF JE: T ceU recog nition of listeriolysin 0 is induced during infection with Lfsteria motwcytogenes. J Zmmund 1987, 13938153821. The hemolysin of L -genes is a major T cell antigen, as assessed by delayed type hypersensitivity reactions. 43. ??

CLUFF CW, ZIEGIER HK: Inhibition of macrophage-mediated antigen presentation by hemolysin-producing Listeriu

monoqtogenes

J Zmmund 1987, 13933083812.

The hemolyslm of L monccytogenesseems to interfere with the processing and presentation of exogenous antigens through the ‘MHC class II pathway’. 44. ??e

MODLINRL, MEIANCON-KAPLAN J, YOUNGSMM, PIRMEZC, KINO H, Cow J, REA TH, BLOOMBR: Leaming from lesions: patterns of tissue in0ammation in leprosy. Prw Nat1 Acud Sci USA 1988, 85:12131217. Describes the proportion of CD4 and CD8 T lymphocytes in leprosy lesions: the majority of T cells in tub&culoid lesions are CD4+ and 4B4+ (helper/inducer T cells> and the CD8+ cells are primadly 9.3- (cyto~ toxic T cells); in lepromatous lesions CD8+ T cells predominate, which are 9.3+ (suppressor T cells) and the CD4+ T cells are 2H4+ (suppressor/inducer T cells). MUSTAFA AS, GODALT: BCG induced CD4+ cytotoxic T cells from BCG vaccinated healthy subjects: relation between cytotoxicity and suppression in vit*o. Clin Exp Zmmunol 1987, 69255262. CD4 T lymphocytes from BCG-immune individuals lyse antigen-pulsed mononuclear phagocytes.

45. ??

46.

CARLM, ROBBINSF-M, HARTMAN RJ, DA.SCHGA: Lysis of cells infected with typhus group Rickettsiae by a human cytotoxic T cell clone. J Immund 1987, 1394203-4207. Human class II restricted CD4 T lymphocytes kill target cells infected with Rickettsh lypbi ??

47.

KAPLWG, SHELL G, JOB CK, MATHURNK, NATHI, COHNZA:

Efficacy of a cell-mediated reaction to the purified protein derivative of tuberculin in the disposal of Mycobuctedium reprae from human skin. Prcc Nat1 Acud Sci US4 1988, 85:521&5214. Injection of tuberculin into lesions of lepromatous leprosy patients induces h-&x of fresh CD4 T cells and blood monocytes and results in local destruction of tissue macrophages and reduction of M. @rue. ??

SARGENTSJ, BEACHFI EH, CORBE?T E, DALEJB: sequence of protective epitopes of streptococcal M proteins shared with cardiac sarcolemmal membranes. J Zmmunol 1987, 139:1285-1290. Identification of a heart cross-reactive protective peptide in the COOH terminal region of streptococcal M-proteins. 48. ??

ORME UI: Characteristics and specificity of acquired immunologic memory to Mycobacterium tuberculosis infection. J Zmmund 1988, 140335893593. Evidence that protective memoty against tuberculosis in mice depends on CD4, and not on CDS, T cells.

37. 0

KAUFMANN SHE: CD8 T lymphocytes in intracellular micro38. ??a bial infections. Zmmund To&y 1988, 9:168-173. Review and summary of possible role of CD8+ cells with cytolytic activity in bacterial and protozoal infections, DELBERO G, FLESCHI, KAUFMANN SHE: Mycobacteria-reactive Lyt-2 + T-cell lines. Eur J Zmmund 1988, l&5+66. Murine CD8+ T cells with reactivity to M tu&rcu.&s which lyse mycobacteria primed macrophages and produce IFNy. Target lysii is paralleled by tuberculostasis. 39. ??

40. 0

DALE JB, BEACHEYEH: Human cytotoxic T lymphocytes evoked by group A streptococcal M proteins. J Exp Med 1987, 166:18251835. Cytolytic CD8 T cells can be generated against peptide fragments of streptococcal M-protein and these T cells lyse myocardial cells in vitro

BRONZE MS, BEXXEY EH, Dm JB: Protective and heartcrossreactive epitopes located within the NH1 terminus of type 19 streptococcal M protein. J Z@ Med 1988, 167:1849&O. Identification of an autoreactive epitope in the NH2 terminal end of type 19 streptococcal M-protein, which was previously thought to lack autoimmune activity.

49. ??

GORONCY-BERMES P, DALE JB, BEACHEYEH, OPFERKUCHW: Monoclonal antibody to human renal glomeruli cross-reacts with streptococcal M protein. Znfecf Zmmun 1987, 55:24162419. Murine monoclonal antibodies directed against human renal glomeruli cross-react with different types of streptococcal M-proteins. 50. ??

51. ??e

?&us W, BFACHFI EH: Renal autoimmune epitope of group A streptococci specified by M protein tetrapeptide Ile-ArgLeu-Arg. Proc Nat1 Acud Sci USA 1988, 85:451&4520.

439

440

Immunity to infection Identification of an autoreactive tetrapeptide in a protective peptide within the NH2 terminaI end of type 1 streptococcaI M-protein. 52. ?? o

YOUNG DB, IVANYI J, Cox JH, IAMB JR: The 65 kD antigen

of mycobacteria - a common bacterial protein? Immutwl Today 1987, 8:21>218. Discusses the relationship of the mycobacteri& 65 kD protein with E coli groEL and suggests that this protein belone to the hsp famiIy.

YOUNG DB, MEHUXRTA, BAL V, MEMIEZ-SAh4F’ERJO P, IVANYI J, LAMeJR: Stress proteins and the immune response to mycobacterial antigens as virulence factors. Antonie Van Leeuwenboek 1988, 54:431-440. Summaty of the possible relation between hsp and immunity to mycobacteria Prehminaty data with T cell clones, which cross-react be tween the 65 kD hsp of mycobacterial and human origin. 53. 0

54. 00

YOUNG D, JATHIGRA R, HENDRIX R, SWEETSER D, YOUNG m

stress proteins are immune targets in leprosy and tuberculosis. Proc Nat1 Acud Sci USA 1988, 85:4267-4270. The 7l,65 and 18 kD proteins of M. tuberculosis as well as the 70, 65, and l8kD proteins of M. kprue share sign&ant homology with hsp of other organisms indicating that they also act as stress proteins. ~HINNICK TM, VODKIN MH, WILLIAMSJc: The Mycohac?? tertum tuberculosis 6%Kilodalton antigen is a heat shock protein which corresponds to common antigen and to tbe Escbericbia coli groEL protein. Infect Immun 1988, 56446451. Evidence that the mycobacterial 65kD protein is a hsp, which corresponds to common antigen of Pseudomonas aeruginm and to groEL of E coli 55.

Boont RJ, Harris DP, LOVEJM, WAEQN JD: Antigenic proteins of MycobacEetium leprae complete sequence of the gene for the 18kD protein. J Immunol 1988, 140:597-601. Sequence of the 18kD protein of M. leprue which belongs to the hsp famiIy. 56. 0

POLLABS: A role for heat shock proteins in intkammation. 57. 0 Immunol Today 1988, 9:134-136. Review of the possible role of hsp in inflammation and Infection. 58. 0

THOLI?JER, HINDERSSON P, DE BRWN J, CREMERSF, VAN DER 2%~ J, DE COCK H, TOMMA%EN J, VANEDEN W, VANEMBDEN JDA AntIgenic relatedness of a strongly immunogenic 65kD mycobacterial protein antigen witb a similariy sized ubiquitous bacterial common antigen. Microbial Pathogen 1988,

4:71-83. The mycobactenai 65 kD hsp shares epitopes with a common antigen of a variety of bacteria. 59. ??

HANSEN K, BANGSB~RG JM, FJO~~DVANG H, PEDER~ENNS, HINbERsZQN P: ImmunochemicaI characterization of and iso-

lation of the gene for a Borteiia bu?gdo@ri immunodominant 60-kiloclalton antigen common to a wide range of bacteria. Infect Immun 1988, 56:2047-2053. Cloning of the gene of a 60 kD protein of L3.burgdwfen’ which corresponds to antigens of a variety of bacteria including the mycobacterial 65 kD hsp. 60. 0

HINDERSSON P, KNUTSENJD, A~I?ISENNH: cloning and expression of Ttqmnema pallidurn common antigen (Tp-4) in Escbericbia wli K12. J c&n Microbid 1987, 133587-596. Cloning and expression of a Z paUidum common antigen which shares epitopes with antigens of a variety of unrelated bacteria and probably belongs to the group of hsp. 61. ??

VODKIN MH, WILLIAMS JC: A heat shock operon in Coxiella bun&ii produces a major antigen homologous to a protein in both mycobacteria and Escberfcbia coli. J Bacterid 1988,

170:1227-1234. The gene of major antigen of C bunzelii has been cloned and found to be similar to the mycobacterial65 kD hsp. 62. 0

MUNK ME, SCHOEL B, KAUFMANSHE: T ceII responses of normal individuals towards recombinant protein antigens of M~obacterium tuberwlosis Eur J Immunol1988,

18:1835-1838. Peripheral blood T Iymphocytes from healthy individuab recognize recombinant proteins from M. tuberctdti including the 65 and 71 kD hsp indicating that these antigens ate not indicative for tuberculosis. 63. 0

MINOTA S, CAMERON B, WELCHWJ, WINFIELD JB: Autoantiobodies to the constitutuve 73-kD member of the hsp70 family of heat shock proteins in systemic lupus erytbematosus. J

lhp Med 1988, 168:1475-1480. IdentIIication of autoantibodies against 70 kD hsp in sera from patients with rheumatic or viral diseases. MINOTA S, KOYASUS, YAHARAI, WINFIELDJ: Autoantibodies to the heat-shock protein bsp90 in systemic lupus erythematosus. J C&z Invest 1988, 81:10&109. IdentRication of autoantibodies against 90 kD hsp in sera from patients with systemic lupus erythematosus. 64. ??

RES PCM, SCHAAR CG, BREEDVELD FC, VANEDENW, VANEMBDEN JDA PROF COHEN IR, DE VRIES RRP: SynoviaI fluid T cell reactivity against 65kD heat shock protein of mycobacteria in early chronic arthritis. Lancet 1988, ii:47%479. Evidence for an association between T ceII reactivity to mycobacterial 65 kD hsp and earIy chronic arthritis.

65. ??

66. 00

VAN EDEN W, Rio% JER, VANDER ZEE R, NOORDVJA, VAN EMBDENJDA, HENSENEJ, COHEN IR: (Letter to the Editor) Cloning of the mycobacterial epitope recognized by T lymphocytes in ajuvant arthritis. Nature 1988, 331:171-172. The mycobacterial65 kD hsp expresses an epitope which is recognized by T cells invoIved in experimental rheumatoid arthritis. Administration of this antigen renders rats resistant to arthritis induction.