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Determinant spreading: implications in allergic disorders
kaleidoscope lette:s Histamine modulates the acute phase response at multiple points In a recent article, H. Baumann and J. G_,u!die provided a comprehensive and outstanding review on the regulation of the acute phase response ~. However, a description of the complexity of the regulatory molecules should be completed by mentioning the significant effectiveness of histamine in the acute phase reaction. Histamine, in addition to its abundantly characterized physiological and pathological activities !e.g. gastric acid production, vaso dilation, smooth muscle contraction, neurotransmission), interferes with the pr~-duction of so-called "inflammatory cytokines'. Physiological concentratmns i 10--1O0 nM) of histamine either inhibits or enhances the gene expression and biosynthesis of inflammatory cytokines such as tumor necrosis factor (TNF-a) (Ref. 2), or interleukin 1 (IL-1) (Ref. 3) and IL-6 (Ref. 4), respectively. Moreover, cell-specific regulation of expression of the IL-6 receptor by histamine has been described on hepatoc~tes, as well as on other cellss. The action of histamine, and its agonists, o,1 the regulation of the acute pka~o response involves a direct (mostly pre-tran., lationai) influence on the production of acute phase proteins 6 and complement factors 7,8. The effect of histamine is preceded by its attachment to histamine receptors HI, H2 or H3, on the plasma membrane, and these reveal a varied pattern ot expression. The consequences of histamine binding depends on the receptor type involved in the action (generally, H1 mediates enhancing effects and H2 mediates inhibitory effects). Since map4 cells possess histamine receptors o¢ different kinds, the net outcome of the response depends on the actuai ratio of the histamine receptors on the given ceil. It has been shown that pre-activation of cells by IL-1 or interferon ~/(IFN-~/) can modify the relative expression of each of the histamine receptors 9, and therefore the overall effect of histamine. Histamine occurs in all body fluids and is produced mainly by
mast cells and basophils by decarboxylation of histidine by histidine decarboxylase (HDC)(Ref. 10). Recently, it was demonstrated that many other cells (e.g. hematopoietic precursor cells, glial cells, T cell~ and macrophages) are capable of expressing HDC, and may therefore generate histamine ~*. Interestingle; HDC expression is regulated by several cytokines that are also involved in the acute phase response, such as IL-1, fiN--/ and TNF-~ (Refs 12,13). By confirming the ubiquitous tissue expression of histamine, these findings suggest not only that local histamine levels depend on in situ inflammatory events, but also that histamine mtdiates a modulatory role in the reguietion of the acute phase response. Andrfis Falus w~v, ,,[ Btology, $emmehveis Medical Unwersity, 4 NaD, varad Square, 089 Budapest, Hungary.
Determinant spreading: •AI.zzj[.,~,~.~.,~w.i~.a, _ ' m n l l ~ a t ~ n cl z o , ~n ~11~.;~ JiJ.Z ~.~.Jl.ll,.JL ~ l ~ . ,
disorders 1 read the review by Lehmann a~d others ~ with interest and should like to comment and add to the topic of determinant spreading. Our research interests have mainly fc,cused on parallel issues in the context of allergy. Allergic disorders may be cot sidered similar to those of some autoimmune conditions, in that they represent aberrant immune responses involving elevated synthesis of certain immunoglobulin (Ig)isotypes. Recent studies with allergens have revealed (1) the m'~ltiplicity of epitopes on allergenic molecules2-4; ' ' ~ the extensive crossreactivities among different groups of a!iergens at the level of B- and T-cell epitopes z,s. Analysis of the primary structures ot allergens has also suggested the possibility of certain antigenic motifs6. In practice, it is commonplace to find that
Immunology Today 5 9 6
References 1 Baulnann, H. and Gauldie, J. (1994) lmmunoi. Today 15, 74-80 2 Vannier, E., Miller, L.C. and Dinarello, C.A. ( 199 ! ) ]. Exp. Med. 174, 281-284 30kamoto, H. and Nakano, K. (1990) Immunology 69, 162-165 4 Falus, A. (1993) Immunology 78, 193-196 5 Merdtey, K., Falus, A., Taga, T. and Kishimoto, T. (1991) Agents Actions 33, 189-191 6 Rokita, H., Falus, A., Bir6, J. Smolen,J., Kordula, T. and Stalinska, K. (1992) Scand. J. l.nmunol. 35, 681-685 7 Lappin, D. and Whaley, K. (1980) Clin. Exp. Immunol. 41,497-501 8 0 o i , Y.M. (1982)J. Immunoi. 129, 200-205 9 Falus, A. Walcz, E., Brozik, M. et al. (1989) Scan~. j. Immunol. 30, 241-248 10 RangacL~fi, P.K (1992) A:::. J. F.~ysiol. 262, G1-G13 11 Aoi, R., Nakashima, I., Kitamura, Y., Asai, H. and ~hkano, K. (1989) Immunology 66, 219-223 12 Endo, Y. (1989) Block. re. PbarmacG!. 38, 1287-1292 13 Okada, E, Sugie, I. and Aisaka, K. (1993) Lyrnpbokine Cytokine Res. 12, 87-91
some individuals with allergies to one group of antigens progressively become allergic to other crossreactive antigens. It is likely that progression to a chronic allergic phase may be due to the determinant spreading, resulting in the involvement of a large variety of crossreactive allergens and/or their epitopes. An example of crossreactive T-cell epitopes is illustrated in Fig. 1. The sit,ation is particularly complex for approximately half of the allergic pop,'lation, who may be sensitized to a diverse repertoire of aeroaiiergens. The total number of determinants on major allergens ha~ been estimated to be approximately 200, of which at least 50 may be considered crossreactive. Despite the above implications, studies on the T-cell receptor (TCR) gene usage of hun'an T-cell clones specific to mite and grass allergens, isolated from the same individual within an interval of several years, have suggested limited usage of TCR Va al~d/or VI3 geness,7.
vol 15 No. 12 1994
kaleidoscope letters Shvam S. Mohapatra (a) Bluegrass Ryegrass Ragweed
~C~E
S S E I C S K K C G K
(b) Bluegrass Redtop Smooth Brome Birch Tree
:~Ly2E [AAE !A A F. !P A A E
L L L L
iV KI~YIT . . v F. I ~.T T A.- L - K. - ] ( A
I T L K K N G D
H G S N E WL__-A
QV QV QV QV
I I I I
DK V DA DKVDF D K-A-D A D K A D A
Fig. 1. Comparison of amino acid sequences of T-cell epitopes of (a1 different antLgens of plant pollens and (b) similar antigens of diffi'rent plant pollens. The boxed areas indicate similarities among sequences. The sequences have been al(~ned to sbou, maximal similarity The following residues are co,2sidered similar: F and W E and L. Modified data reproduced from Refs 5.10.
Moreover, the dominant T-cell clones prevail in the immune system throughout this time span, implying 'in vivo clonal dominance'. Furthermore, another important finding consistent with this is the recent demonstration that it is possible to modulate both de novo and established allergenspecific humoral immune responses with TCR peptides s. These latter studies were performed in a munne model using ovalbumin as an allergen. In another study, tolerization with two dominant peptides of a cat allergen, Feld 1, led to the induction of tolerance to the native allergen ~. Clearly, these studies need to be extended with respect to ~nnlwi~ nf qneciflc T-cell rnler~nce to diverse allergens in mice and ether outbred animal species, and in humans. Nevertheless, it may be
inferred from these studies that, despite the possibility of spreading, immunodominance appears to be critical to the resulting immune response (or tolerance). However, in terms of mechanism, the studies by Lehmann et al. have raised several very pertinent questions. For instance: (1) does determinant-shift shape the repertoire-shift or vice versa? (2) how dynamic is the T-cell repertoire, and how much of this is due to determinant spreading? and (3) does the magnitude of spreading affect the induction of tolerance to the antigen(s)in question? These questions need to be thoroughly addressed in order to validate the nr, renrml nf T-cell ~ndlnr TCR nentides for immunotherapeutic treatment of autoimmune and allergic disorders.
Exogenous antigen control of autoreactive T-cell MHC specificity
and Hendrix 2, demonstrated that: (1) peptide binding inhibits aggregation of invariant chain (Ii)-free MHC class II molecules; and (2) excess exogenous antigen promotes increased formation of stable MHC class II dimers, and upregulates their surface expression. Several studies indicate that stimulation with exogenous antigen greatly enhances the ability to obtain and clone autoreactive T cells;. It has been demonstrated that, for autoreactive T-cell clones derived from priming with antigens under specific MHC class II control, MHC specificity was skewed towards the same class II molecule restricting the conventional antigen response 4`s. Thus,
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I would like to comment on a possible explanation for a longstanding and puzzling observation concerning the major histocompatibility complex (MHC) specificity of autoreactive T cells. It has been shown that autoreactive T cells isolated in vitro, following responses to conventional foreign antigens, are induced by, and restricted to, the same MHC class II specificity that restricts the response to foreign antigen. The combined studies of Cermam and Rinker l, and Germain
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;,.,,,.,,otogy Tod~:,
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597
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r'-l-
Dept ,,llm,um,,l,,g)~ University ,f.~|anit,,ha, Winmpeg, Manitoba, Gmada R3E OWL
References 1 Lehmann, P.V., Sercarz, E.E., Forsthuber, T., Da.van, CM. and Gammon, G. ( 1993 }lmmunol. Tod,n' 14, 203-208 2 Mohapatra, S.S. (1994) Clm. Rev Allergy 12, 3-22 3 Ebner, C., Szepfalusi, Z., Ferreira, E et al. ;1993)J. lmmunol. 150, 1047-1054 4 Spiegelberg, H.L., Beck, L., Stevenson, D.D. ar,d Ishioka, G.Y. (1994) J. hnmunol. 152, 4706-4711 5 M',hapatra. S.S., Mohapatra, S., Yang, M., Parronchi, E, Maggi, E. and Romagnani, S. (1994) lmmunoh)gy 80, 15-20 6 Mohapatra, S.S. (1993)in Molecular Biology and hnmunology of Allergens
(Kraft, D. and Sehon, A., eds), pp. 69-81, CRC Press 7 Wedderburn. L., O'Hehir, R., Hewitt, C.R.A., Lamb, J. and Owen, M.J. i 1993) Proc. Natl Acad. Sci. USA 90, 8214-8218 8 Mohapatra, S., Chen, Y., Takata, M, *lohapatra, S.S. and Sehon, A.H. (1993) J. Immunol. 15 I, 688-698 9 Briner,Z, Kuo, M-C., Keating, K.M., Rogers, B.L. and Greenstein, J.L. (1993) Proc. Natl Acad. Sci. USA 90, 760P,-7612 10 Mohapatra, S.S. {!992)in n! . . . . . . . . l-I]tlFIlltlglLI
: _
A It . . . . l~.llffT~.)'
n . . . . . . 1_ IXCSC~.II LIJ
Foundation Awards Book (Debelic, M.,
ed.), pp. 5-15, Pharmacia Allergy Research Foundation
in murine responses, I-E-specific autareactive T cells were detected at much higher frequency in populations primed with the I-E-restricted antigen GL+ (a random copolymer of glutamic acid, lysine and phenylalanine) than in populations primed with keyhole limpet hemocyanin (KLH), which is mainly I-A restricted 4. In a guinea-pig model, autoreactive (2)<13)F I T-cell colonies were isolated from syngeneic mixed lymphocyte reactions (MLRs)induced with (2× 13)FI antigenpresenting cells (APCs), and were found to contain roughly comparable numbers of MHC class IIrestricted T cells specific for strain 2 or for strain 13. However, if
v,,£ is N,,. ;2 ;9~4
mast cells and basophils by decarboxylation of histidine by histidine decarboxylase (HDC)(Ref. 10). Recently, it was demonstrated that many other cells (e.g. hematopoietic precursor cells, glial cells, T cell~ and macrophages) are capable of expressing HDC, and may therefore generate histamine ~*. Interestingle; HDC expression is regulated by several cytokines that are also involved in the acute phase response, such as IL-1, fiN--/ and TNF-~ (Refs 12,13). By confirming the ubiquitous tissue expression of histamine, these findings suggest not only that local histamine levels depend on in situ inflammatory events, but also that histamine mtdiates a modulatory role in the reguietion of the acute phase response. Andrfis Falus w~v, ,,[ Btology, $emmehveis Medical Unwersity, 4 NaD, varad Square, 089 Budapest, Hungary.
Determinant spreading: •AI.zzj[.,~,~.~.,~w.i~.a, _ ' m n l l ~ a t ~ n cl z o , ~n ~11~.;~ JiJ.Z ~.~.Jl.ll,.JL ~ l ~ . ,
disorders 1 read the review by Lehmann a~d others ~ with interest and should like to comment and add to the topic of determinant spreading. Our research interests have mainly fc,cused on parallel issues in the context of allergy. Allergic disorders may be cot sidered similar to those of some autoimmune conditions, in that they represent aberrant immune responses involving elevated synthesis of certain immunoglobulin (Ig)isotypes. Recent studies with allergens have revealed (1) the m'~ltiplicity of epitopes on allergenic molecules2-4; ' ' ~ the extensive crossreactivities among different groups of a!iergens at the level of B- and T-cell epitopes z,s. Analysis of the primary structures ot allergens has also suggested the possibility of certain antigenic motifs6. In practice, it is commonplace to find that
Immunology Today 5 9 6
References 1 Baulnann, H. and Gauldie, J. (1994) lmmunoi. Today 15, 74-80 2 Vannier, E., Miller, L.C. and Dinarello, C.A. ( 199 ! ) ]. Exp. Med. 174, 281-284 30kamoto, H. and Nakano, K. (1990) Immunology 69, 162-165 4 Falus, A. (1993) Immunology 78, 193-196 5 Merdtey, K., Falus, A., Taga, T. and Kishimoto, T. (1991) Agents Actions 33, 189-191 6 Rokita, H., Falus, A., Bir6, J. Smolen,J., Kordula, T. and Stalinska, K. (1992) Scand. J. l.nmunol. 35, 681-685 7 Lappin, D. and Whaley, K. (1980) Clin. Exp. Immunol. 41,497-501 8 0 o i , Y.M. (1982)J. Immunoi. 129, 200-205 9 Falus, A. Walcz, E., Brozik, M. et al. (1989) Scan~. j. Immunol. 30, 241-248 10 RangacL~fi, P.K (1992) A:::. J. F.~ysiol. 262, G1-G13 11 Aoi, R., Nakashima, I., Kitamura, Y., Asai, H. and ~hkano, K. (1989) Immunology 66, 219-223 12 Endo, Y. (1989) Block. re. PbarmacG!. 38, 1287-1292 13 Okada, E, Sugie, I. and Aisaka, K. (1993) Lyrnpbokine Cytokine Res. 12, 87-91
some individuals with allergies to one group of antigens progressively become allergic to other crossreactive antigens. It is likely that progression to a chronic allergic phase may be due to the determinant spreading, resulting in the involvement of a large variety of crossreactive allergens and/or their epitopes. An example of crossreactive T-cell epitopes is illustrated in Fig. 1. The sit,ation is particularly complex for approximately half of the allergic pop,'lation, who may be sensitized to a diverse repertoire of aeroaiiergens. The total number of determinants on major allergens ha~ been estimated to be approximately 200, of which at least 50 may be considered crossreactive. Despite the above implications, studies on the T-cell receptor (TCR) gene usage of hun'an T-cell clones specific to mite and grass allergens, isolated from the same individual within an interval of several years, have suggested limited usage of TCR Va al~d/or VI3 geness,7.
vol 15 No. 12 1994
kaleidoscope letters Shvam S. Mohapatra (a) Bluegrass Ryegrass Ragweed
~C~E
S S E I C S K K C G K
(b) Bluegrass Redtop Smooth Brome Birch Tree
:~Ly2E [AAE !A A F. !P A A E
L L L L
iV KI~YIT . . v F. I ~.T T A.- L - K. - ] ( A
I T L K K N G D
H G S N E WL__-A
QV QV QV QV
I I I I
DK V DA DKVDF D K-A-D A D K A D A
Fig. 1. Comparison of amino acid sequences of T-cell epitopes of (a1 different antLgens of plant pollens and (b) similar antigens of diffi'rent plant pollens. The boxed areas indicate similarities among sequences. The sequences have been al(~ned to sbou, maximal similarity The following residues are co,2sidered similar: F and W E and L. Modified data reproduced from Refs 5.10.
Moreover, the dominant T-cell clones prevail in the immune system throughout this time span, implying 'in vivo clonal dominance'. Furthermore, another important finding consistent with this is the recent demonstration that it is possible to modulate both de novo and established allergenspecific humoral immune responses with TCR peptides s. These latter studies were performed in a munne model using ovalbumin as an allergen. In another study, tolerization with two dominant peptides of a cat allergen, Feld 1, led to the induction of tolerance to the native allergen ~. Clearly, these studies need to be extended with respect to ~nnlwi~ nf qneciflc T-cell rnler~nce to diverse allergens in mice and ether outbred animal species, and in humans. Nevertheless, it may be
inferred from these studies that, despite the possibility of spreading, immunodominance appears to be critical to the resulting immune response (or tolerance). However, in terms of mechanism, the studies by Lehmann et al. have raised several very pertinent questions. For instance: (1) does determinant-shift shape the repertoire-shift or vice versa? (2) how dynamic is the T-cell repertoire, and how much of this is due to determinant spreading? and (3) does the magnitude of spreading affect the induction of tolerance to the antigen(s)in question? These questions need to be thoroughly addressed in order to validate the nr, renrml nf T-cell ~ndlnr TCR nentides for immunotherapeutic treatment of autoimmune and allergic disorders.
Exogenous antigen control of autoreactive T-cell MHC specificity
and Hendrix 2, demonstrated that: (1) peptide binding inhibits aggregation of invariant chain (Ii)-free MHC class II molecules; and (2) excess exogenous antigen promotes increased formation of stable MHC class II dimers, and upregulates their surface expression. Several studies indicate that stimulation with exogenous antigen greatly enhances the ability to obtain and clone autoreactive T cells;. It has been demonstrated that, for autoreactive T-cell clones derived from priming with antigens under specific MHC class II control, MHC specificity was skewed towards the same class II molecule restricting the conventional antigen response 4`s. Thus,
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I would like to comment on a possible explanation for a longstanding and puzzling observation concerning the major histocompatibility complex (MHC) specificity of autoreactive T cells. It has been shown that autoreactive T cells isolated in vitro, following responses to conventional foreign antigens, are induced by, and restricted to, the same MHC class II specificity that restricts the response to foreign antigen. The combined studies of Cermam and Rinker l, and Germain
v
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;,.,,,.,,otogy Tod~:,
.
.
.
.
.
.
597
.
.
.
.
.
.
.
.
.
.
r'-l-
Dept ,,llm,um,,l,,g)~ University ,f.~|anit,,ha, Winmpeg, Manitoba, Gmada R3E OWL
References 1 Lehmann, P.V., Sercarz, E.E., Forsthuber, T., Da.van, CM. and Gammon, G. ( 1993 }lmmunol. Tod,n' 14, 203-208 2 Mohapatra, S.S. (1994) Clm. Rev Allergy 12, 3-22 3 Ebner, C., Szepfalusi, Z., Ferreira, E et al. ;1993)J. lmmunol. 150, 1047-1054 4 Spiegelberg, H.L., Beck, L., Stevenson, D.D. ar,d Ishioka, G.Y. (1994) J. hnmunol. 152, 4706-4711 5 M',hapatra. S.S., Mohapatra, S., Yang, M., Parronchi, E, Maggi, E. and Romagnani, S. (1994) lmmunoh)gy 80, 15-20 6 Mohapatra, S.S. (1993)in Molecular Biology and hnmunology of Allergens
(Kraft, D. and Sehon, A., eds), pp. 69-81, CRC Press 7 Wedderburn. L., O'Hehir, R., Hewitt, C.R.A., Lamb, J. and Owen, M.J. i 1993) Proc. Natl Acad. Sci. USA 90, 8214-8218 8 Mohapatra, S., Chen, Y., Takata, M, *lohapatra, S.S. and Sehon, A.H. (1993) J. Immunol. 15 I, 688-698 9 Briner,Z, Kuo, M-C., Keating, K.M., Rogers, B.L. and Greenstein, J.L. (1993) Proc. Natl Acad. Sci. USA 90, 760P,-7612 10 Mohapatra, S.S. {!992)in n! . . . . . . . . l-I]tlFIlltlglLI
: _
A It . . . . l~.llffT~.)'
n . . . . . . 1_ IXCSC~.II LIJ
Foundation Awards Book (Debelic, M.,
ed.), pp. 5-15, Pharmacia Allergy Research Foundation
in murine responses, I-E-specific autareactive T cells were detected at much higher frequency in populations primed with the I-E-restricted antigen GL+ (a random copolymer of glutamic acid, lysine and phenylalanine) than in populations primed with keyhole limpet hemocyanin (KLH), which is mainly I-A restricted 4. In a guinea-pig model, autoreactive (2)<13)F I T-cell colonies were isolated from syngeneic mixed lymphocyte reactions (MLRs)induced with (2× 13)FI antigenpresenting cells (APCs), and were found to contain roughly comparable numbers of MHC class IIrestricted T cells specific for strain 2 or for strain 13. However, if
v,,£ is N,,. ;2 ;9~4