Superantigens and Kawasaki disease Kawasaki disease (KD) is an acute illness of early childhood characterized by prolonged fever, diffuse mucosal inflammation, indurative edema of the hands and feet, polymorphous skin rash and nonsuppurative lymphadenopathy 1. Histopathological findings in KD patients indicate a panvasculitis with endothelial necrosis and infiltration of mononuclear cells into small and medium-sized blood vessels. Clinical symptoms of KD resemble scarlet fever and toxic shock syndrome that is induced by streptococcal or staphylococcal exotoxins. These bacterial toxins serve as 'superantigens' and suggest that KD may be caused by one or more superantigens. Peripheral blood macrophagesmonocytes, T cells and B cells are all changed during acute KD: there are changes in the number of cells, in the expression of activation markers and in cytokine production. The following changes occur. (1) Peripheral blood CD14 + macrophagemonocyte and CD23+CD14 + macrophage-monocyte counts increase during acute KD 2. (2) CD8+CDllb + T-cell and CD57+CD16 + natural killer (NK) cell counts decrease. (3) Soluble CD4 and CD8 levels in
Viral homologies with myelin basic protein The recent review article by K.W. Wucherpfennig and colleagues on T-cell recognition of myelin basic protein (MBP) in multiple sclerosis (MS) patients (Immunol. Today 1991, 12, 277-282) gave postulates for defining MS as a T-cell-mediated autoimmune disease and focussed on an immunodominant (84-102) peptide from MBP as one of the
P3AofCB3 MBP P3AofCB4
QGPPVYREFKISVAPETPPP II II I I DENPVVHFFKNIVTPRTPPP II I III QGPPVYRELKISV!PETPPP
IIII IIII
Fig. 1. The homology between MBP and P3 A of CB3 and CB4 is shown. Vertical lines: identical residues.
serum increase during acute KD, although the expression of HLA-DR on CD4 + and CD8 + T cells is not increased 3. (4) Peripheral blood CD23+CD19 + B-cell counts increase during the latter part of the acute stage 4. (5) Levels of spontaneous IgG and IgM synthesis in peripheral blood mononuclear cells increase, suggesting that peripheral blood B cells are strongly activated during acute KD s. (6) Levels of serum cytokines, such as tumor necrosis factor ~ (TNF-~x)6, interleukin 1 (IL-1) 7 and gamma-interferon 6, and the activity of IL-6 in serum 8 increase during the acute stage of KD. (7) This is accompanied by an increase in the levels of soluble IL-2 receptor in serum 6. (8) Peripheral blood mononuclear cells from acute KD patients spontaneously secrete high levels of TNF-~x and IL-1 (Ref. 9). (9) KD patients have many cytokines in serum during the acute stage, compared with anaphylactoid purpura (which shares some pathological findings with KD, such as vasculitis of small vessels) and to measles (which was examined as a representative acute febrile illness8). The results of these studies suggest that the immunological abnormalities observed in patients with KD are related to hyperreactive responses in immunocompetent cells. We suggest that these hyperreactive
1 Kawasaki, T., Kosaki, F., Osawa, S., Shigernatsu, I. and Yanagawa, S. (1974) Pediatrics 54, 271-276 2 Furukawa, S., Matsubara, T., Motohashi, T. et al. (1990) Clin. Immunol. Immunopathol. 56, 280-286 3 Furukawa, S., Matsubata, T., Tsuji, K. et al. Clin. Exp. Immunol. (in press) 4 Furukawa, S., Matsubata, T., Motohashi, T. et al. (1991) Int. Arch. Allergy Appl. Immunol. 95, 7-12 5 Leung, D.Y.M., Burns, J.C., Newburger, J.W. and Geha, R.S. (1987) J. Clin. Invest. 79, 468-472 6 Matsubara, T., Furukawa, S. and Yabuta, K. (1990) Clin. Immunol. Immunopathol. 56, 29-36 7 Maury, C.P.J., Salo, E. and Pelkonen, P. (1988) New Engl. J. Med. 318, 1670-1671 8 Furukawa, S., Matsubara, T., Yone, K. et al. Eur. J. Pediatr. (in press) 9 Leung, D.Y.M., Cortan, R.S., KurtJones, E. et aI. (1989) Lancet ii, 1298-1302
potential target autoantigens in MS1,2. Molecular mimicry between myelin proteins and viral proteins has been suggested as one possible cause of initiation or continuation of an autoimmune reaction in MS. We have thus searched for possible homologies between the MBP peptide and the National Biomedical Research Foundation protein sequence database using the FASTA program 3 in the University of Wisconsin Genetics Computer Group package 4 maintained at the Daresbury Laboratory. A high score was recorded with the P3 A region of the polyprotein of the Coxsackie virus B3 (strain Nancy) s and, to a lesser extent, with the same region of the Coxsackie virus B4 (strain Benschoten) 6. The P3 A-B region codes for a protein that is processed to give the protein
VPg which is attached to the 5' terminus of the viral RNA 6 and is involved in replication of viral RNA. The region of homology with MBP is the predicted amino-terminal portion of P3 A which may be part of the precursor VPg protein. The homology between MBP and P3 A of CB3 and CB4 is shown in Fig. 1. Only two amino acids of P3 A of CB4 differ from the sequence of P3 A of CB3 and they are underlined. The first amino acid of the peptide from CB3 is the amino acid at position 1429 in the sequence of the polyprotein of CB3. The predicted proteolytic cleavage site corresponding to the beginning of the P3 A protein is at position 1430 (Ref. 5). Jahnke and colleagues 7 reported other homologies among viral proteins from adenovirus 2, 5 and 7, respiratory syncytial virus and the
Immunology Today
464
responses during acute KD are compatible with those induced by superantigen.
Susumu Furukawa Tomoyo Matsubara Keijiro Yabuta Dept of Pediatrics, Juntendo University School of Medicine, Tokyo 113, Japan.
References
vo~ 12 No. 12 1991
same MBP region. Three years later, when the database was much larger, M,J. Weise and P.R. Carnegie8 found other homologies with this MBP region and viral proteins, i.e. the human T-cell leukemia virus II (HTLV II) gag polyprotein, the baboon endogenous gag polyprotein, the herpes simplex virus glycoprotein E and the hypothetical adenovirus 2 protein F-215 (Ref. 8). During our search, we also found a small homology with the L protein of measles virus (strain udem) (346364) 9. A T-ceil response to minor viral proteins, like P3 A, may be important in a protective immune response. For example, it has been shown that cytotoxic T cells (CTL) that recognize the immediate early protein of murine cytomegalovirus protect mice from lethal infection with this virus. Similarly CTL that recognize the reverse transcriptase and gag proteins of the human immuno-
N. et al. (1990) Science 248, 1016-1019 3 Pearson,W. and Lipman, D. (1988) Proc. Natl Acad. Sci. USA 85, 2444-2448 4 Devereux,J., Haeberli, P. and Smithies, O. (1984) Nucleic Acids Res. 12, 387-395 5 Linberg,A., Stalhandske,P. and Pettersson, U. (1987) Virology 156, 50-63 6 Jenkins, O., Booth, J., Miner, P. et al. (1987)J. Gen. Virol. 68, 1835-1848 7 Jahnke, U., Fisher, E. and Alvord, E. (1985) Science 229, 282-284 Dept of Biochemistry and 8 Weise,M.J. and Carnegie, P. (1988) Microbiology, St Andrews J. Neurochem. 51, 1267-1273 University, St Andrews, 9 Blumberg,B., Crowley,J., Fife KY16 9AL, UK. Silverman,J. et al. (1988) Virology 164, 487-497 The WellcomeTrust and the Multiple 10 Randall, R. and Souberbielle,B. Sclerosis Society provided support for (1990) in Control of Virus Diseases B.E. Souberbielle. (Dimmock,N.J. et al., eds), Cambridge UniversityPress References 11 Grist, N.R., Bell, E.J. and Assaeed, 10ta, K., Matsui, M., Milford, E. et F. (1978) Prog. Med. Virol. 24, al. (1990) Nature 346, 183-187 114-124 2 Wucherpfennig,K., Ota, K., Endo,
deficiency virus have been described (see Ref. 10 for a review). The aetiopathological relevance of the homologies between MBP and viral proteins reported here remains to be tested, although it is interesting that neurological diseases can be caused by Coxsackie viruses 11. This may complement the observations on MS patients described in the review article. Bernard E. Souberbielle Graham Kemp William C. Russell
On specific T-cell factors
Takemori and Tada observed about 90% antigen-specific suppression of IgG responses. I would like to Immunology is in a strange, schizophrenic state concerning some suggest that the reproducibility or simple questions that can readily be otherwise of their basic experiment settled experimentally. There have can reasonably be taken as an acid been many reports of specific T-cell test for the existence of specific T-cell factors but skepticism concerning factors. The experiment requires no the existence of these molecules special reagents or advanced techpersists. For example, Melchers1 niques, and should be readily reprorecently wrote that "... soluble fac- ducible with minimal expenditure of tors [are] antigen-unspecific stimu- time and effort by immunologists lators of antigen-specific responses" interested in knowing for themselves (Melchers' emphasis). Similarly, in a whether specific T-cell factors exist. Various immunologists make recent article on network theory, Varela and Coutinho 2 wrote that various demands concerning more "... V regions exist as cell-bound proof that they would like to see for lymphocyte receptors and as soluble the existence of specific T-cell facimmunoglobulin molecules". Specific tors. But the absence of whatever T-cell factors, if they exist, must additional proof they might demand have V regions, and any reference to is not proof of the nonexistence of them is conspicuous by its absence, the factors. The nonexistence of the especially in a network theory con- factors can be inferred only from text, where they have been ascribed a experiments in which immunologists fail to reproduce the basic central role 3,4. The most extensive and compel- findings. Specific T-cell factors play a key ling experimental evidence supporting the existence of specific T-cell role in a network theory of regulation that my colleagues and I have factors is for specific suppressor factors. An early, prototypical sup- developed3,4. The central problem of pressor T-cell factor experiment was theoretical immunology is to explain published in 1975 by Takemori and how T celts regulate B-cell responses. Tada s. The experiment included Our model explains in simple terms criss-cross specificity controls, and how specific T-cell factors can lead Immunology Today
465
to the observed helper and suppressor effects of T cells On B-cell immune responses. It accounts for the switch from IgM to IgG6. It also provides a basis for understanding a considerable amount of other regulatory phenomenology, including the roles of some nonspecific lymphokines, low-zone and high-zone tolerance, MHC restriction and the facts that helper T cells are CD4-bearing T cells while CD8 helper T cells are suppressor T cells. On the other hand, if the factors do not exist, this network theory is wrong. The theory has recently led to the formulation of a model of AIDS pathogenesis7. Geoffrey W. Hoffmann Depts of Microbiology and Physics, University of British Columbia, Vancouver, BC, Canada, V6T 1Z3.
References 1 Melchers, F. (1991) in Basel Institute for Immunology Annual Report, 1990, (Steinberg, C., ed.), p. 9, Basel Institute for Immunology 2 Varela, F. and Coutinho, A. (1991) Immunol. Today 12, 159-166 3 Hoffmann, G.W. (1978) in Theoretical Immunology (Bell, G.I., Perelson, A.S. and Pimbley,G.H., eds), pp. 571-602, Marcel Dekker
rot 12 No. 12 1991
Viral homologies with myelin basic protein The recent review article by K.W. Wucherpfennig and colleagues on T-cell recognition of myelin basic protein (MBP) in multiple sclerosis (MS) patients (Immunol. Today 1991, 12, 277-282) gave postulates for defining MS as a T-cell-mediated autoimmune disease and focussed on an immunodominant (84-102) peptide from MBP as one of the
P3AofCB3 MBP P3AofCB4
QGPPVYREFKISVAPETPPP II II I I DENPVVHFFKNIVTPRTPPP II I III QGPPVYRELKISV!PETPPP
IIII IIII
Fig. 1. The homology between MBP and P3 A of CB3 and CB4 is shown. Vertical lines: identical residues.
serum increase during acute KD, although the expression of HLA-DR on CD4 + and CD8 + T cells is not increased 3. (4) Peripheral blood CD23+CD19 + B-cell counts increase during the latter part of the acute stage 4. (5) Levels of spontaneous IgG and IgM synthesis in peripheral blood mononuclear cells increase, suggesting that peripheral blood B cells are strongly activated during acute KD s. (6) Levels of serum cytokines, such as tumor necrosis factor ~ (TNF-~x)6, interleukin 1 (IL-1) 7 and gamma-interferon 6, and the activity of IL-6 in serum 8 increase during the acute stage of KD. (7) This is accompanied by an increase in the levels of soluble IL-2 receptor in serum 6. (8) Peripheral blood mononuclear cells from acute KD patients spontaneously secrete high levels of TNF-~x and IL-1 (Ref. 9). (9) KD patients have many cytokines in serum during the acute stage, compared with anaphylactoid purpura (which shares some pathological findings with KD, such as vasculitis of small vessels) and to measles (which was examined as a representative acute febrile illness8). The results of these studies suggest that the immunological abnormalities observed in patients with KD are related to hyperreactive responses in immunocompetent cells. We suggest that these hyperreactive
1 Kawasaki, T., Kosaki, F., Osawa, S., Shigernatsu, I. and Yanagawa, S. (1974) Pediatrics 54, 271-276 2 Furukawa, S., Matsubara, T., Motohashi, T. et al. (1990) Clin. Immunol. Immunopathol. 56, 280-286 3 Furukawa, S., Matsubata, T., Tsuji, K. et al. Clin. Exp. Immunol. (in press) 4 Furukawa, S., Matsubata, T., Motohashi, T. et al. (1991) Int. Arch. Allergy Appl. Immunol. 95, 7-12 5 Leung, D.Y.M., Burns, J.C., Newburger, J.W. and Geha, R.S. (1987) J. Clin. Invest. 79, 468-472 6 Matsubara, T., Furukawa, S. and Yabuta, K. (1990) Clin. Immunol. Immunopathol. 56, 29-36 7 Maury, C.P.J., Salo, E. and Pelkonen, P. (1988) New Engl. J. Med. 318, 1670-1671 8 Furukawa, S., Matsubara, T., Yone, K. et al. Eur. J. Pediatr. (in press) 9 Leung, D.Y.M., Cortan, R.S., KurtJones, E. et aI. (1989) Lancet ii, 1298-1302
potential target autoantigens in MS1,2. Molecular mimicry between myelin proteins and viral proteins has been suggested as one possible cause of initiation or continuation of an autoimmune reaction in MS. We have thus searched for possible homologies between the MBP peptide and the National Biomedical Research Foundation protein sequence database using the FASTA program 3 in the University of Wisconsin Genetics Computer Group package 4 maintained at the Daresbury Laboratory. A high score was recorded with the P3 A region of the polyprotein of the Coxsackie virus B3 (strain Nancy) s and, to a lesser extent, with the same region of the Coxsackie virus B4 (strain Benschoten) 6. The P3 A-B region codes for a protein that is processed to give the protein
VPg which is attached to the 5' terminus of the viral RNA 6 and is involved in replication of viral RNA. The region of homology with MBP is the predicted amino-terminal portion of P3 A which may be part of the precursor VPg protein. The homology between MBP and P3 A of CB3 and CB4 is shown in Fig. 1. Only two amino acids of P3 A of CB4 differ from the sequence of P3 A of CB3 and they are underlined. The first amino acid of the peptide from CB3 is the amino acid at position 1429 in the sequence of the polyprotein of CB3. The predicted proteolytic cleavage site corresponding to the beginning of the P3 A protein is at position 1430 (Ref. 5). Jahnke and colleagues 7 reported other homologies among viral proteins from adenovirus 2, 5 and 7, respiratory syncytial virus and the
Immunology Today
464
responses during acute KD are compatible with those induced by superantigen.
Susumu Furukawa Tomoyo Matsubara Keijiro Yabuta Dept of Pediatrics, Juntendo University School of Medicine, Tokyo 113, Japan.
References
vo~ 12 No. 12 1991
same MBP region. Three years later, when the database was much larger, M,J. Weise and P.R. Carnegie8 found other homologies with this MBP region and viral proteins, i.e. the human T-cell leukemia virus II (HTLV II) gag polyprotein, the baboon endogenous gag polyprotein, the herpes simplex virus glycoprotein E and the hypothetical adenovirus 2 protein F-215 (Ref. 8). During our search, we also found a small homology with the L protein of measles virus (strain udem) (346364) 9. A T-ceil response to minor viral proteins, like P3 A, may be important in a protective immune response. For example, it has been shown that cytotoxic T cells (CTL) that recognize the immediate early protein of murine cytomegalovirus protect mice from lethal infection with this virus. Similarly CTL that recognize the reverse transcriptase and gag proteins of the human immuno-
N. et al. (1990) Science 248, 1016-1019 3 Pearson,W. and Lipman, D. (1988) Proc. Natl Acad. Sci. USA 85, 2444-2448 4 Devereux,J., Haeberli, P. and Smithies, O. (1984) Nucleic Acids Res. 12, 387-395 5 Linberg,A., Stalhandske,P. and Pettersson, U. (1987) Virology 156, 50-63 6 Jenkins, O., Booth, J., Miner, P. et al. (1987)J. Gen. Virol. 68, 1835-1848 7 Jahnke, U., Fisher, E. and Alvord, E. (1985) Science 229, 282-284 Dept of Biochemistry and 8 Weise,M.J. and Carnegie, P. (1988) Microbiology, St Andrews J. Neurochem. 51, 1267-1273 University, St Andrews, 9 Blumberg,B., Crowley,J., Fife KY16 9AL, UK. Silverman,J. et al. (1988) Virology 164, 487-497 The WellcomeTrust and the Multiple 10 Randall, R. and Souberbielle,B. Sclerosis Society provided support for (1990) in Control of Virus Diseases B.E. Souberbielle. (Dimmock,N.J. et al., eds), Cambridge UniversityPress References 11 Grist, N.R., Bell, E.J. and Assaeed, 10ta, K., Matsui, M., Milford, E. et F. (1978) Prog. Med. Virol. 24, al. (1990) Nature 346, 183-187 114-124 2 Wucherpfennig,K., Ota, K., Endo,
deficiency virus have been described (see Ref. 10 for a review). The aetiopathological relevance of the homologies between MBP and viral proteins reported here remains to be tested, although it is interesting that neurological diseases can be caused by Coxsackie viruses 11. This may complement the observations on MS patients described in the review article. Bernard E. Souberbielle Graham Kemp William C. Russell
On specific T-cell factors
Takemori and Tada observed about 90% antigen-specific suppression of IgG responses. I would like to Immunology is in a strange, schizophrenic state concerning some suggest that the reproducibility or simple questions that can readily be otherwise of their basic experiment settled experimentally. There have can reasonably be taken as an acid been many reports of specific T-cell test for the existence of specific T-cell factors but skepticism concerning factors. The experiment requires no the existence of these molecules special reagents or advanced techpersists. For example, Melchers1 niques, and should be readily reprorecently wrote that "... soluble fac- ducible with minimal expenditure of tors [are] antigen-unspecific stimu- time and effort by immunologists lators of antigen-specific responses" interested in knowing for themselves (Melchers' emphasis). Similarly, in a whether specific T-cell factors exist. Various immunologists make recent article on network theory, Varela and Coutinho 2 wrote that various demands concerning more "... V regions exist as cell-bound proof that they would like to see for lymphocyte receptors and as soluble the existence of specific T-cell facimmunoglobulin molecules". Specific tors. But the absence of whatever T-cell factors, if they exist, must additional proof they might demand have V regions, and any reference to is not proof of the nonexistence of them is conspicuous by its absence, the factors. The nonexistence of the especially in a network theory con- factors can be inferred only from text, where they have been ascribed a experiments in which immunologists fail to reproduce the basic central role 3,4. The most extensive and compel- findings. Specific T-cell factors play a key ling experimental evidence supporting the existence of specific T-cell role in a network theory of regulation that my colleagues and I have factors is for specific suppressor factors. An early, prototypical sup- developed3,4. The central problem of pressor T-cell factor experiment was theoretical immunology is to explain published in 1975 by Takemori and how T celts regulate B-cell responses. Tada s. The experiment included Our model explains in simple terms criss-cross specificity controls, and how specific T-cell factors can lead Immunology Today
465
to the observed helper and suppressor effects of T cells On B-cell immune responses. It accounts for the switch from IgM to IgG6. It also provides a basis for understanding a considerable amount of other regulatory phenomenology, including the roles of some nonspecific lymphokines, low-zone and high-zone tolerance, MHC restriction and the facts that helper T cells are CD4-bearing T cells while CD8 helper T cells are suppressor T cells. On the other hand, if the factors do not exist, this network theory is wrong. The theory has recently led to the formulation of a model of AIDS pathogenesis7. Geoffrey W. Hoffmann Depts of Microbiology and Physics, University of British Columbia, Vancouver, BC, Canada, V6T 1Z3.
References 1 Melchers, F. (1991) in Basel Institute for Immunology Annual Report, 1990, (Steinberg, C., ed.), p. 9, Basel Institute for Immunology 2 Varela, F. and Coutinho, A. (1991) Immunol. Today 12, 159-166 3 Hoffmann, G.W. (1978) in Theoretical Immunology (Bell, G.I., Perelson, A.S. and Pimbley,G.H., eds), pp. 571-602, Marcel Dekker
rot 12 No. 12 1991
