- Email: [email protected]
Heat shock proteins and autoimmunity: facts or fiction?
STEFANH.E. KAUFMANN
AUTOIMMUNITY
Heat shock proteins
and autoimmunity:
facts or fiction?
The evidence from animal models suggesting the involvement of heat shock proteins in autoimmune disease is supported by some, but not all, data from autoimmune disease patients. The immune system must be able specifically to respond to a plethora of fore&r invaders, leaving ‘self structures untouched. Although self-reactivity is normally sufficiently controlled, autoimmune diseases do occur. Some may be caused by previous infection: pathogenic microbes and the host are d.iIferent enough to allow their distinction at the molecular level, yet microbial epitopes can share such a high degnee of similaritywith host molecules that the immune system may eventually be fooled. The term ‘molecular mimicry has been coined to describe this possibility. Recent interest in this area has focused on a group of omnipresent highly conserved polypeptides, the heat shock proteins (hsp) [ 11. Many heat shock proteins perform important functions in normal cells, but most of them are produced at increased levels when cells are subjected to stress A particularly well studied member of the heat shock protein family is hsp60, which was originally cloned from mycobacteria and then found to exist in different organisms, including man. The human and bacterial cognates are highly similar and share more than 50% sequence homology; hence, there is potential for molecular mimicry The heat shock proteins pose particular problems for the immune system. They are the dominant antigens of many infectious agents [l], but their similarity to mammalian heat shock proteins demands that they should be ignored by the immune system to avoid autodestruction. Surprisingly, however, the immune response is directed not only against microbe-specifjc epitopes but also against those shared with the mammalian cognate. Some hsp-reactive T cells seem to recognize unprimed host cells, particularly after they have been stressed. These findings suggest that processing and presentation of self-hsp occurs; that T cells with specificity :for selfhsp exist; and that such T cells can be activated during infection through cross-reactive epitopes. It seems that such T cells represent normal elements of the immune repertoire and that they need not cause disease. Nevertheless, there is evidence that anti-hsp immunity might contribute to autoimmune diseases under certain conditions. This is an attractive model for the #following reasons: the immune system frequently contacts microbial heat shock proteins; autologous heat shock proteins are Induced under stress situations, which occur in autoimmune lesions; and, because of their high conservation, heat shock proteins could represent a link between infection and autoimmunity. Increased heat shock protein expression has been observed in several cell types including B cells, T cells, macrophages, oligodendrocytes, Schwann cells and
Volume 1
Number 6
1991
,’
synovial cells [l-5]. Importantly, increased heat shock protein levels have been detected in the synovial lining and at the cartilage-pannus junction of rheumatoid joints as well as in oligodendrocytes in multiple sclerosis lesions [1,3]. Of course, increased heat shock protein expression does not necessarily imply increased inmune recognition of heat shock proteins, particularly because it has been thought that heat shock proteins are not expressed at the cell surface. Some reports, however, indicate surface expression of heat shock protein [4,5]. Moreover, increased levels of hsp-specific antibodies in different autoimmune diseases, such as rheumatoid arthritis and systemic lupus etythematosus, and recognition of stressed cells by hsp-reactive T cells have been described [1,4,5]. The predilection of a minor T-cell set - the y/S T lymphocytes - for heat shock protein is of particular interest. The y/S T cells recognize hsp-derived peptides in a conventional way, but additional interactions between heat shock protein on target cells and y/S T lymphocytes are likely [4,5]. Indeed, indirect evidence suggests that interactions of y/S T cells with B cells of lupus patients and with oligodendrocytes of multiple sclerosis patients involve heat shock protein [2,3]. But these Iindings, interesting as they are, remain circumstantial and further data are required to establish a definite role for hsp-reactive antibodies and y/S T cells in autoimmunity. Much stronger arguments have been raised for the in volvement of hsp-reactive conventional (oc/p> T cells in the experimental autoimmune disease models, adjuvant arthritis and insulin-dependent diabetes mellitus (IDDM) [6-91. In certain strains of rat, injection of complete Freund’s adjuvant (containing mycobacteria) causes the development of an inllammatory response in the joints which resembles rheumatoid arthritis of humans. Cloned T cells involved in arthritis crossreact with mycobacteria and cartilage proteoglycan. The very same T cells have been found to recognize mycobacterial hsp60 and, more precisely speaking, an epitope made up of hsp60 amino acid sequence 180-188, which has only minor sequence homology with the mammalian heat shock protein cognate [6]. But attempts to induce arthritis in rats using microbial hsp60, even in strong adjuvants, have failed. Rather, pretreatment with microbial hsp60 as well as with the synthetic peptide 180-188 protects rats from subsequent induction of arthritis with complete Freund’s adjuvant [9], Certain other experimental arthritis models can also be prevented by pretreatment with hsp60, whereas still others remain virtually una.IIected [9]. Pretreatment with mycobacterial hsp60 prevents -arthritis induced by
359
pristane, which does not contain any microbial components. Thus, we are left with the apparent paradox that a microbial protein prevents an autoimmune response by means of an epitope that is not common to the cognate host protein. In the so-called non-obese diabetic (NOD) mouse strain, the autoimmune disealse IDDM develops spontaneously. T cells that recognize mycobacterial hsp60 have been isolated from these mice [7]. Such T cells are present before clinical disease has fully developed. Upon adoptive transfer, they cause IDDM: even in congenic, naturally nonobese mice. After irradiation they become ‘attenuated, and cause resistance against IDDM after adoptive transfer. The T cells recognize an epitope that has been mapped to a stretch of 24 amino acids (437-460 of the human hsp60) and shares some homology (about SO%) with the mammalian hsp60 cognate [S]. Because administration of either the bacterial hsp60 or the synthetic peptide 437-460 comprising the mammalian sequence protects NOD mice against spontaneously developing diabetes, a true self-epitope that is cross-reactive is implicated in the causation of the disease. So, experimental autoimmune disease models strongly favour a central role for hsp60. What about corresponding diseases in humans? Not surprisingly, here the situation is not so clear. Arthritis is an inflammatory joint disease and several forms of arthritis involve T cells. Reactive arthritis frequently develops after gastrointestinal or urinary tract infections with various bacteria, such as Salmonella, Yersitza and CbZumyc&a.The disease is often self-limiting, which could be taken as an argument against true autoimmunity. T cells with specilicity for hsp60 have been isolated from the synovial fluids of reactive arthritis patients. One recent study described several T-cell clones with specificity for a unique epitope of mycobacterial hsp60, but in a more extensive study by the same group of scientists, arguments were raised against preferential T-cell recognition of mycobacterial hsp60 (summarized in [ lo]). Rather, it seems that various bacterial antigens other than heat shock protein are recognized. As it is likely that bacterial antigens are deposited in the joints of reactive arthritis patients, diierent bacterial antigens, some of them shared by various microbes, may be responsible for initiation of disease. Recent evidence for the importance of heat shock protein in reactive arm&is comes from a T-cell clone isolated from the synovial fluid of a patient suffering from Yersinia-induced reactive arthritis. Such T cells respond not only to Yersintiz antigens but also to the mycobacterial and human hsp60 cognates [ 111. They can be stimulated in vitro by a.utologous cells that have been heatshocked or which h(ave been obtained from the inflamed joints. This confirms the presence of true autoreactive T cells in lesions of reactive arthritis patients. T cells specific for hsp60 were initially thought to be in volved in the pathogenesis of chronic arthritis, but there is evidence to the contrary. When numerous T-cell clones isolated from the synovial fluid of chronic arthritis patients were challenged with a highly purified recombinant
360
hsp60 preparation, only one T-cell clone gave a positive response. When a distinction was made between juvenile and adult arthritis patients, however, an interesting picture arose [ 121. T cells from the synovial fluid of juvenile arthritis patients responded strongly to human and mycobacterial hsp60, whereas T cells from adult patients failed to give such a response [13j. Although the amino acid sequence of the responsible epitope remains to be defined, it seems to be a cross-reactive selfepitope. The symptoms of human IDDM result from the destruction of pancreatic p-cells by autoimmune mechanisms involving T lymphocytes. Several antigens have been inplicated as targets for these autoimmune mechanisms, with a major focus on a 64kD protein. The identity of this protein remained elusive for quite some time until two studies appeared. One implicated mammalian hspG0 [ 141. The other identified the enzyme glutamic acid decarboxylase as the central autoantigen [ 151. Even if hspG0 is expressed at increased levels in the l%cells of IDDM patients, it does not seem to be the major target of autoimmunity. Taken together, the data, though incompletely understood, point to several roles for heat shock protein in autoimmune disease. Perhaps in adult rheumatoid arthntis and in reactive arthritis, as well as in human IDDM, heat shock proteins perform some auxiliary function perpetuating the vicious circle after initiation by organ-specific antigens. In addition, as bacterial heat shock protein show partial sequence homology with many selfproteins, the contribution of cross-reactive epitopes from unrelated proteins deserves consideration. The finding in experimental systems that not only heat shock protein but also delined peptides prevent development of autoimmune disease, raises the hope that this field of experimentation is not only an intellectual exercise but may also eventually result in clinical applications.
References
1.
SHE: Immunol
KAUFMANN
sponse.
Heat shock proteins and Today 1990, 11:129136.
2.
RAJAGOPAIAN
3.
SELMQ K, BROSNAN CF, RA!BE CS: Colocahzation
the
immune
S, ZORDAN T, TSOKOS GC, DATA SK: Pathogenic anti-DNA autoantihody-inducing T helper cell lines from patients with active lupus nephritis isolation of CD4-8-T helper cell lines that express the y/6 T cell antigen receptor. Proc Nat1 Acud Sci USA 1990, 87:702&7024.
bearing y/6 T-cell receptor oligodendrocytes in multiple 1991, 8864526456. 4.
KAUFMANN
5.
MOUER
and heat sclerosis.
shock
of lymphocytes protein hsp65+
Proc Nat1 Acad Sci USA
SHE (ED): Heat shock proteins and the immune response. In Current Topics in Microbiology and Immunology 167. Berlin: Springer-Verlag, 1991.
G (ED.):
Heat-shock
proteins
and the immune Munksgaard,
Immunological Reviews 121. Copenhagen: 6.
re-
system. 1991.
VAN EDEN W, THOLE JE, VAN DER ZEE R, NOORDZIJ A, VAN E~DEN JD, HENSEN EJ, COHEN IR: Cloning of the mycobacterial epitope
recognized
by
T lymphocytes
h
adjuvant
arthritis.
Nature 1983, 331:171-173.
@ 1991 Current
Biology
7.
8.
EUU D, RESHEF T, BIRK OS, VAN DER ZEE R, WALKER MD, COHEN JR Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. PYOC Nat1 Acad Sci USA 1991, 88:3088-3091. E~u\s D,
MARKovrTs
D,
RESHEF T, VAN DER ZEE R, COHEN
12.
FEIGE U, COHEN
IR: The 65-kDa heat shock protein pathogenesis, prevention and therapy of autoimmune tis and diabetes melhtus in rats and mice. Sptinger Immunopathol 1991, 13:9?113.
13.
IR:
HILL GASTON JS: T-cell terial heat shock proteins in intIammatory Rev 1991, 121:113-‘135.
recognition arthritis.
in the arthriSevnin
LIFE PF, BA~SEY EOE,
of bacZmmuno~
11.
HERMANN E, LOHSE AW, VAN DER ZEE R, VAN EDEN W, MAVET %!I, PROBST P, PORALIA T, MF(ER ZUM BUSCHENFELDE K-H, FLEXHER
B: Synovial fluid-derived Yersinia-reactive T cells responding to human 65-kDa heat-shock protein and heat-stressed antigen-presenting cells. Eur J Immunol 1991, 21:2139-2143.
Volume 1
Number 6
1991
and
au1991,
DE GRAEFF-MEEDER ER, VAN DER ZEE R, ~JKERS GT, SCHUURMAI? H-J, KUIS W, BIJUMA JWJ, ZEGER~ BJM, VAN EDEN W: Recognition of human 60 kD heat shock protein by mononuclear cells
from patients 337:1368-1372. 14.
JONES DB,
with
HUNTER
a b cell antigen 336:583-585. 15.
10.
proteins Immunopatbol
13:81-98.
Induction and therapy of autoimmune diabetes in the nonobese diabetic (NDD/Lt) mouse by a 65-kDa heat shock protein. Proc Natl Acad Sci USA 1990, 87:15761580. 9.
RES P, T’uotk J, DE Vatas R: Heat-shock toimmunity in humans. Springer Semin
juvenile
chronic
NR, DUFF GW: of insulin-dependent
arthritis.
Lancet
1991,
Heat-shock protein diabetes. kmcet
65 as 1990,
BAEKESHOV S, JAN-AANSTOOT H, CHRISTGAU S, REETZ A, SOLIMENA M, CA.%XLHO M, FOLU F, RICER-OLESEN H, DE CAMILLI P: Iden-
tification of the 65 K autoantigen in insulin-dependent betes as the GABA-synthesizing enzyme ghnamic acid boxylase. Nature 1990, 347:151-156.
diadecar-
Stefan H.E. Kaufmann, Department of Immunology, University of Ulm, Albert-Einstein-Al& 11, D-7900 Ulm, Germany.
361
AUTOIMMUNITY
Heat shock proteins
and autoimmunity:
facts or fiction?
The evidence from animal models suggesting the involvement of heat shock proteins in autoimmune disease is supported by some, but not all, data from autoimmune disease patients. The immune system must be able specifically to respond to a plethora of fore&r invaders, leaving ‘self structures untouched. Although self-reactivity is normally sufficiently controlled, autoimmune diseases do occur. Some may be caused by previous infection: pathogenic microbes and the host are d.iIferent enough to allow their distinction at the molecular level, yet microbial epitopes can share such a high degnee of similaritywith host molecules that the immune system may eventually be fooled. The term ‘molecular mimicry has been coined to describe this possibility. Recent interest in this area has focused on a group of omnipresent highly conserved polypeptides, the heat shock proteins (hsp) [ 11. Many heat shock proteins perform important functions in normal cells, but most of them are produced at increased levels when cells are subjected to stress A particularly well studied member of the heat shock protein family is hsp60, which was originally cloned from mycobacteria and then found to exist in different organisms, including man. The human and bacterial cognates are highly similar and share more than 50% sequence homology; hence, there is potential for molecular mimicry The heat shock proteins pose particular problems for the immune system. They are the dominant antigens of many infectious agents [l], but their similarity to mammalian heat shock proteins demands that they should be ignored by the immune system to avoid autodestruction. Surprisingly, however, the immune response is directed not only against microbe-specifjc epitopes but also against those shared with the mammalian cognate. Some hsp-reactive T cells seem to recognize unprimed host cells, particularly after they have been stressed. These findings suggest that processing and presentation of self-hsp occurs; that T cells with specificity :for selfhsp exist; and that such T cells can be activated during infection through cross-reactive epitopes. It seems that such T cells represent normal elements of the immune repertoire and that they need not cause disease. Nevertheless, there is evidence that anti-hsp immunity might contribute to autoimmune diseases under certain conditions. This is an attractive model for the #following reasons: the immune system frequently contacts microbial heat shock proteins; autologous heat shock proteins are Induced under stress situations, which occur in autoimmune lesions; and, because of their high conservation, heat shock proteins could represent a link between infection and autoimmunity. Increased heat shock protein expression has been observed in several cell types including B cells, T cells, macrophages, oligodendrocytes, Schwann cells and
Volume 1
Number 6
1991
,’
synovial cells [l-5]. Importantly, increased heat shock protein levels have been detected in the synovial lining and at the cartilage-pannus junction of rheumatoid joints as well as in oligodendrocytes in multiple sclerosis lesions [1,3]. Of course, increased heat shock protein expression does not necessarily imply increased inmune recognition of heat shock proteins, particularly because it has been thought that heat shock proteins are not expressed at the cell surface. Some reports, however, indicate surface expression of heat shock protein [4,5]. Moreover, increased levels of hsp-specific antibodies in different autoimmune diseases, such as rheumatoid arthritis and systemic lupus etythematosus, and recognition of stressed cells by hsp-reactive T cells have been described [1,4,5]. The predilection of a minor T-cell set - the y/S T lymphocytes - for heat shock protein is of particular interest. The y/S T cells recognize hsp-derived peptides in a conventional way, but additional interactions between heat shock protein on target cells and y/S T lymphocytes are likely [4,5]. Indeed, indirect evidence suggests that interactions of y/S T cells with B cells of lupus patients and with oligodendrocytes of multiple sclerosis patients involve heat shock protein [2,3]. But these Iindings, interesting as they are, remain circumstantial and further data are required to establish a definite role for hsp-reactive antibodies and y/S T cells in autoimmunity. Much stronger arguments have been raised for the in volvement of hsp-reactive conventional (oc/p> T cells in the experimental autoimmune disease models, adjuvant arthritis and insulin-dependent diabetes mellitus (IDDM) [6-91. In certain strains of rat, injection of complete Freund’s adjuvant (containing mycobacteria) causes the development of an inllammatory response in the joints which resembles rheumatoid arthritis of humans. Cloned T cells involved in arthritis crossreact with mycobacteria and cartilage proteoglycan. The very same T cells have been found to recognize mycobacterial hsp60 and, more precisely speaking, an epitope made up of hsp60 amino acid sequence 180-188, which has only minor sequence homology with the mammalian heat shock protein cognate [6]. But attempts to induce arthritis in rats using microbial hsp60, even in strong adjuvants, have failed. Rather, pretreatment with microbial hsp60 as well as with the synthetic peptide 180-188 protects rats from subsequent induction of arthritis with complete Freund’s adjuvant [9], Certain other experimental arthritis models can also be prevented by pretreatment with hsp60, whereas still others remain virtually una.IIected [9]. Pretreatment with mycobacterial hsp60 prevents -arthritis induced by
359
pristane, which does not contain any microbial components. Thus, we are left with the apparent paradox that a microbial protein prevents an autoimmune response by means of an epitope that is not common to the cognate host protein. In the so-called non-obese diabetic (NOD) mouse strain, the autoimmune disealse IDDM develops spontaneously. T cells that recognize mycobacterial hsp60 have been isolated from these mice [7]. Such T cells are present before clinical disease has fully developed. Upon adoptive transfer, they cause IDDM: even in congenic, naturally nonobese mice. After irradiation they become ‘attenuated, and cause resistance against IDDM after adoptive transfer. The T cells recognize an epitope that has been mapped to a stretch of 24 amino acids (437-460 of the human hsp60) and shares some homology (about SO%) with the mammalian hsp60 cognate [S]. Because administration of either the bacterial hsp60 or the synthetic peptide 437-460 comprising the mammalian sequence protects NOD mice against spontaneously developing diabetes, a true self-epitope that is cross-reactive is implicated in the causation of the disease. So, experimental autoimmune disease models strongly favour a central role for hsp60. What about corresponding diseases in humans? Not surprisingly, here the situation is not so clear. Arthritis is an inflammatory joint disease and several forms of arthritis involve T cells. Reactive arthritis frequently develops after gastrointestinal or urinary tract infections with various bacteria, such as Salmonella, Yersitza and CbZumyc&a.The disease is often self-limiting, which could be taken as an argument against true autoimmunity. T cells with specilicity for hsp60 have been isolated from the synovial fluids of reactive arthritis patients. One recent study described several T-cell clones with specificity for a unique epitope of mycobacterial hsp60, but in a more extensive study by the same group of scientists, arguments were raised against preferential T-cell recognition of mycobacterial hsp60 (summarized in [ lo]). Rather, it seems that various bacterial antigens other than heat shock protein are recognized. As it is likely that bacterial antigens are deposited in the joints of reactive arthritis patients, diierent bacterial antigens, some of them shared by various microbes, may be responsible for initiation of disease. Recent evidence for the importance of heat shock protein in reactive arm&is comes from a T-cell clone isolated from the synovial fluid of a patient suffering from Yersinia-induced reactive arthritis. Such T cells respond not only to Yersintiz antigens but also to the mycobacterial and human hsp60 cognates [ 111. They can be stimulated in vitro by a.utologous cells that have been heatshocked or which h(ave been obtained from the inflamed joints. This confirms the presence of true autoreactive T cells in lesions of reactive arthritis patients. T cells specific for hsp60 were initially thought to be in volved in the pathogenesis of chronic arthritis, but there is evidence to the contrary. When numerous T-cell clones isolated from the synovial fluid of chronic arthritis patients were challenged with a highly purified recombinant
360
hsp60 preparation, only one T-cell clone gave a positive response. When a distinction was made between juvenile and adult arthritis patients, however, an interesting picture arose [ 121. T cells from the synovial fluid of juvenile arthritis patients responded strongly to human and mycobacterial hsp60, whereas T cells from adult patients failed to give such a response [13j. Although the amino acid sequence of the responsible epitope remains to be defined, it seems to be a cross-reactive selfepitope. The symptoms of human IDDM result from the destruction of pancreatic p-cells by autoimmune mechanisms involving T lymphocytes. Several antigens have been inplicated as targets for these autoimmune mechanisms, with a major focus on a 64kD protein. The identity of this protein remained elusive for quite some time until two studies appeared. One implicated mammalian hspG0 [ 141. The other identified the enzyme glutamic acid decarboxylase as the central autoantigen [ 151. Even if hspG0 is expressed at increased levels in the l%cells of IDDM patients, it does not seem to be the major target of autoimmunity. Taken together, the data, though incompletely understood, point to several roles for heat shock protein in autoimmune disease. Perhaps in adult rheumatoid arthntis and in reactive arthritis, as well as in human IDDM, heat shock proteins perform some auxiliary function perpetuating the vicious circle after initiation by organ-specific antigens. In addition, as bacterial heat shock protein show partial sequence homology with many selfproteins, the contribution of cross-reactive epitopes from unrelated proteins deserves consideration. The finding in experimental systems that not only heat shock protein but also delined peptides prevent development of autoimmune disease, raises the hope that this field of experimentation is not only an intellectual exercise but may also eventually result in clinical applications.
References
1.
SHE: Immunol
KAUFMANN
sponse.
Heat shock proteins and Today 1990, 11:129136.
2.
RAJAGOPAIAN
3.
SELMQ K, BROSNAN CF, RA!BE CS: Colocahzation
the
immune
S, ZORDAN T, TSOKOS GC, DATA SK: Pathogenic anti-DNA autoantihody-inducing T helper cell lines from patients with active lupus nephritis isolation of CD4-8-T helper cell lines that express the y/6 T cell antigen receptor. Proc Nat1 Acud Sci USA 1990, 87:702&7024.
bearing y/6 T-cell receptor oligodendrocytes in multiple 1991, 8864526456. 4.
KAUFMANN
5.
MOUER
and heat sclerosis.
shock
of lymphocytes protein hsp65+
Proc Nat1 Acad Sci USA
SHE (ED): Heat shock proteins and the immune response. In Current Topics in Microbiology and Immunology 167. Berlin: Springer-Verlag, 1991.
G (ED.):
Heat-shock
proteins
and the immune Munksgaard,
Immunological Reviews 121. Copenhagen: 6.
re-
system. 1991.
VAN EDEN W, THOLE JE, VAN DER ZEE R, NOORDZIJ A, VAN E~DEN JD, HENSEN EJ, COHEN IR: Cloning of the mycobacterial epitope
recognized
by
T lymphocytes
h
adjuvant
arthritis.
Nature 1983, 331:171-173.
@ 1991 Current
Biology
7.
8.
EUU D, RESHEF T, BIRK OS, VAN DER ZEE R, WALKER MD, COHEN JR Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. PYOC Nat1 Acad Sci USA 1991, 88:3088-3091. E~u\s D,
MARKovrTs
D,
RESHEF T, VAN DER ZEE R, COHEN
12.
FEIGE U, COHEN
IR: The 65-kDa heat shock protein pathogenesis, prevention and therapy of autoimmune tis and diabetes melhtus in rats and mice. Sptinger Immunopathol 1991, 13:9?113.
13.
IR:
HILL GASTON JS: T-cell terial heat shock proteins in intIammatory Rev 1991, 121:113-‘135.
recognition arthritis.
in the arthriSevnin
LIFE PF, BA~SEY EOE,
of bacZmmuno~
11.
HERMANN E, LOHSE AW, VAN DER ZEE R, VAN EDEN W, MAVET %!I, PROBST P, PORALIA T, MF(ER ZUM BUSCHENFELDE K-H, FLEXHER
B: Synovial fluid-derived Yersinia-reactive T cells responding to human 65-kDa heat-shock protein and heat-stressed antigen-presenting cells. Eur J Immunol 1991, 21:2139-2143.
Volume 1
Number 6
1991
and
au1991,
DE GRAEFF-MEEDER ER, VAN DER ZEE R, ~JKERS GT, SCHUURMAI? H-J, KUIS W, BIJUMA JWJ, ZEGER~ BJM, VAN EDEN W: Recognition of human 60 kD heat shock protein by mononuclear cells
from patients 337:1368-1372. 14.
JONES DB,
with
HUNTER
a b cell antigen 336:583-585. 15.
10.
proteins Immunopatbol
13:81-98.
Induction and therapy of autoimmune diabetes in the nonobese diabetic (NDD/Lt) mouse by a 65-kDa heat shock protein. Proc Natl Acad Sci USA 1990, 87:15761580. 9.
RES P, T’uotk J, DE Vatas R: Heat-shock toimmunity in humans. Springer Semin
juvenile
chronic
NR, DUFF GW: of insulin-dependent
arthritis.
Lancet
1991,
Heat-shock protein diabetes. kmcet
65 as 1990,
BAEKESHOV S, JAN-AANSTOOT H, CHRISTGAU S, REETZ A, SOLIMENA M, CA.%XLHO M, FOLU F, RICER-OLESEN H, DE CAMILLI P: Iden-
tification of the 65 K autoantigen in insulin-dependent betes as the GABA-synthesizing enzyme ghnamic acid boxylase. Nature 1990, 347:151-156.
diadecar-
Stefan H.E. Kaufmann, Department of Immunology, University of Ulm, Albert-Einstein-Al& 11, D-7900 Ulm, Germany.
361