156
immt~nology lo@', A~g~.rl 198/
cigarette smoke is due to oxidation reactions 9. The report indicates that inactivation of %-antitrypsin depended in part on O> H 2 0 2 and myeloperoxidase. Monocytes and leucocytes from patients with chronic granulomatous disease, in whom the generation of O 2 and H 2 0 2 are depressed, did not inactivate the antiprotease after exposure to PMA. The effect of cigarette smoke on alveolar macrophage activity suggests that these cells produce reactive oxygen species which should result in enhanced inactivation References 1 Morse, J. O. (1978) .N. Eng/. J. Med. 299, 1045-1048; 1099-1105 2 ,Janoff, A., White, R., Carp, H., tfarel, S., Dearing, R. and Lee, D. (1979) Am.J. l°ntaol. 97, 111-136 3 Merrill, W. W., Naegel, G. P., Matthay, R. A. and Reynolds, tl. Y. (1980),7. C/in. Irtve.~/.65,268-276 4 Gadek, J. E., Hunninghake, G. W., Zimmerman, R. L. and Crystal, R. G. (1980) Am. Re¢~.Re.@r. Dis. 121,723-733
of antiproteases leading to increased destruction of alveolar connective tissue. It appears from these studies that alveolar macrophages and leucocytes are largely responsible for the generation of emphysema. Exposure to cigarette smoke has a profound effect on t h e hemostatic mechanisms of the lung leading to emphysema. BRUCE
S. Z ' W 1 L L I N G
Depar/ment ~!fMicrobiology, Od/ege ~!/"Biologica! Sciences and Comprehens'iz,e Caneer (>,let, The Ohir; S/ale University, Odumbus, OH d3210, U.S.A.
5 Hunninghake, G. W., Davidson,j. M., Rennard, S., Szapiel, S., Gadek,.J.E. and Crystal, R. G. (19811 Science 212, 925-927 6 Janoff, A., Carp. H., Lee, 1). K. and Drew, R. T. (19791 Science 206, 1313-1314 7 Gadek, J. E., Fellis, G. A. and Crystal, R. G. (1979) &ience 206, 1315 1316 8 Carp, It. andJanoff, A. (19801,7. (Yi,. I, vesl. 66, 987-995 9 Carp, H. andJanoff, A. (1978) Am. Rev. Respir. Dis 118,617-621
) The regulation of gastrointestinal immune responses Warren Strober, Lee K. Richman and Charles O. Elson hnmunophysiology Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20205, U.S.A. The antigenic environment of the mucosal i m m u n e system differs from that of the systemic i m m u n e system. The mucosae are in constant contact with a myriad of substances that have readily demonstrable i m m u n o s t i m u l a t o r y or i m m u n o m o d u l a t o r y properties and within such an environment lymphoid tissue could conceivably undergo excessive stimulation. As a result responses to potentially pathogenic stimuli might be pre-empted by responses to an overwhelming array of inconsequential materials. For this reason it would not be surprising to find that the mucosal i m m u n e system had regulatory mechanisms allowing it to react selectively to m a n y or most substances found in the mucosal environment. It is reasonable to suppose that such mechanisms would be mediated by cellular components that differ qualitatively a n d / o r quantitatively from those found elsewhere in the i m m u n e system (see Fig. i ). In the following review, we will discuss mucosal i m m u n e responses from an i m m u n o r e g u l a t o r y viewpoint. We shall first consider studies ,in which ¢ Else~i(J/North I lolland Biomcdica~ Press 1981 0167
4919/81/[)0110
11(1(10/.~112,30
antigen feeding fails to result in i m m u n i z a t i o n and, instead, induces unresponsiveness (tolerance) to subsequent challenge with the antigen. We shall then consider studies in which antigen feeding results in immunization as well as priming of the animal for secondary antibody responses. Finally, we will discuss studies of a mechanism by which the mucosal i m m u n e system can compartmentalize its regulation of a response, so that simultaneous e n h a n c e m e n t and suppression can be obtained, depending on the Ig class of the induced responses. Such a mechanism is indicative of the complexity of mucosal i m m u n o r e g u l a t i o n and provides evidence that regulation in this area may have several unique features. M e c h a n i s m s of oral u n r e s p o n s i v e n e s s (tolerance) Suppre.rsiorz of oral res~Jm~.sesby 13 cells or B-cell products
Oral unresponsiveness was first studied within the context of modern immunology by Chase in 1946, although related observations were made as early as the mid-nineteenth century ~. Chase showed that after
mmmmdogy/oday, .4e~gen//-()~/
~..)/"~-~
157
~$YSTEMIC
_ _ _ cc LYMPH NODE
Fig. 1. Diagrammatic representation of antigenic stimulation occurring in the mucosal immune system. The gut lumen is filled with antigenic material (A) which gains entry to organized gut lymphoid tissues such as tl']e Peyer's patches, tlere the encounter B ceils as well as regulatory T cells which can migrate to draining lymphoid tissues (mesenteric lymph node) and then to the systemic and mucosal circulations. Both helper and suppressor T cells may be stimulated in the Payer's patch and this may account for the fact that both responsiveness and unresponsivenesscan followantigen feeding.
guinea pigs were fed with a chemically simple skinsensitizing substance, dinitrochlorobenzene (DNCB), they did not show contact s e n s i t i z a t i o n with this material. This p h e n o m e n o n has been recently reinvestigated by Asherson e! a/., who studied the e q u i v a l e n t u n r e s p o n s i v e n e s s which follows oral challenge of rats with the skin-sensitizing agents oxazalone and picryl chloridC. These investigators showed, in cell-transfer studies, that unresponsiveness was associated with the development of (1) suppressor B cells capable of suppressing skin reactivity in recipient animals which had been transferred in suspensions of lymph-node or spleen cells obtained from skin-sensitized animals; and (2) suppressor T cells capable of suppressing DNA proliferation of lymph-node cells of recipient animals and which were present in the recipients as a result of prior skin sensitization. In other studies, Asherson et a[. observed that the suppressor B cells are not only associated with the unresponsive states we have mentioned but also with responsive states, e.g. responsiveness in animals receiving topical applications of contactant 3. O n e interpretation of this data is that, after oral exposure to c o n t a c t a n t , suppressor B cells are generated early in the response and in large enough numbers to prevent any observable i m m u n e response at all, whereas after topical application of contactant the suppressor B cells occur late in the response and in lower numbers, so that an i m m u n e response does
develop but is eventually shut off. An alternative explanation, based on the fact that suppressor B cells occur during states of both responsiveness and unresponsiveness, is that the suppressor B cells are not involved in oral tolerance to contactants; in this case, the suppressor T cells or other suppressor components (as discussed below) might be important factors. Assuming that suppressor B cells do play a role in oral unresponsiveness, several mechanisms of suppression are possible. In the first place, it is well known that antibody to stimulating antigen may cause immunosuppression4, so suppressor B cells might act by producing antibodies that have suppressor effects. There is some support for this explanation in the observation that mice orally immunized with sheep red blood cells (SRBC) develop serum suppressor factors which, at least in part, react with i m m u n i z i n g antigen. In the relevant studies, mice were given SRBC by intragastric i n t u b a t i o n and cells and serum from such animals were examined for suppressor capabilityL Feeding with SRBC, unlike contactants (mentioned above) or soluble proteins (mentioned below), induced no suppressor cells in the spleen of recipient animals but their serum contained a substance which suppressed the responses of both unfed animals subsequently i m m u n i z e d with SRBC irz ~,i~o and virgin cells cultured with SRBC zr~ vilro. This suppressor capability was antigen-specific and nonH-2 restricted; in addition, it was absorbed by staphylococcal protein A or ~Sephadex' coated with anti-mouse-lg, whereas absorption with i m m u n i z i n g antigen (SRBC) was succ'essful only some of the time 5. A. B. +660
+100
uJ
-100
DIgM [ ] IgG [] IgA
+100
uJ
(,.9
-100
Fig. 2. Differential immunoregulatory effects on IgM/IgG and IgA responses mediated by Peyer's patch T cells (polyclonal system). In this experiment Concanavalin A-pulsed T cells were added to an indicator culture consisting of spleen cells or Peyer's patches cells stimulated with I,PS. It is seen that the addition of pulsed T ceils leads to suppression of lgM/IgG synthesis, but enhancement of lgA synthesis. This is the critical observation that indicates that separate, class-specific T cells regulate IgM/lg(/ and lgA synthesis. In comparison with the spleen, Peyer's patch is enriched for IgA specifc helper '1' cells.
imm~mr;/
immt~nology lo@', A~g~.rl 198/
cigarette smoke is due to oxidation reactions 9. The report indicates that inactivation of %-antitrypsin depended in part on O> H 2 0 2 and myeloperoxidase. Monocytes and leucocytes from patients with chronic granulomatous disease, in whom the generation of O 2 and H 2 0 2 are depressed, did not inactivate the antiprotease after exposure to PMA. The effect of cigarette smoke on alveolar macrophage activity suggests that these cells produce reactive oxygen species which should result in enhanced inactivation References 1 Morse, J. O. (1978) .N. Eng/. J. Med. 299, 1045-1048; 1099-1105 2 ,Janoff, A., White, R., Carp, H., tfarel, S., Dearing, R. and Lee, D. (1979) Am.J. l°ntaol. 97, 111-136 3 Merrill, W. W., Naegel, G. P., Matthay, R. A. and Reynolds, tl. Y. (1980),7. C/in. Irtve.~/.65,268-276 4 Gadek, J. E., Hunninghake, G. W., Zimmerman, R. L. and Crystal, R. G. (1980) Am. Re¢~.Re.@r. Dis. 121,723-733
of antiproteases leading to increased destruction of alveolar connective tissue. It appears from these studies that alveolar macrophages and leucocytes are largely responsible for the generation of emphysema. Exposure to cigarette smoke has a profound effect on t h e hemostatic mechanisms of the lung leading to emphysema. BRUCE
S. Z ' W 1 L L I N G
Depar/ment ~!fMicrobiology, Od/ege ~!/"Biologica! Sciences and Comprehens'iz,e Caneer (>,let, The Ohir; S/ale University, Odumbus, OH d3210, U.S.A.
5 Hunninghake, G. W., Davidson,j. M., Rennard, S., Szapiel, S., Gadek,.J.E. and Crystal, R. G. (19811 Science 212, 925-927 6 Janoff, A., Carp. H., Lee, 1). K. and Drew, R. T. (19791 Science 206, 1313-1314 7 Gadek, J. E., Fellis, G. A. and Crystal, R. G. (1979) &ience 206, 1315 1316 8 Carp, It. andJanoff, A. (19801,7. (Yi,. I, vesl. 66, 987-995 9 Carp, H. andJanoff, A. (1978) Am. Rev. Respir. Dis 118,617-621
) The regulation of gastrointestinal immune responses Warren Strober, Lee K. Richman and Charles O. Elson hnmunophysiology Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20205, U.S.A. The antigenic environment of the mucosal i m m u n e system differs from that of the systemic i m m u n e system. The mucosae are in constant contact with a myriad of substances that have readily demonstrable i m m u n o s t i m u l a t o r y or i m m u n o m o d u l a t o r y properties and within such an environment lymphoid tissue could conceivably undergo excessive stimulation. As a result responses to potentially pathogenic stimuli might be pre-empted by responses to an overwhelming array of inconsequential materials. For this reason it would not be surprising to find that the mucosal i m m u n e system had regulatory mechanisms allowing it to react selectively to m a n y or most substances found in the mucosal environment. It is reasonable to suppose that such mechanisms would be mediated by cellular components that differ qualitatively a n d / o r quantitatively from those found elsewhere in the i m m u n e system (see Fig. i ). In the following review, we will discuss mucosal i m m u n e responses from an i m m u n o r e g u l a t o r y viewpoint. We shall first consider studies ,in which ¢ Else~i(J/North I lolland Biomcdica~ Press 1981 0167
4919/81/[)0110
11(1(10/.~112,30
antigen feeding fails to result in i m m u n i z a t i o n and, instead, induces unresponsiveness (tolerance) to subsequent challenge with the antigen. We shall then consider studies in which antigen feeding results in immunization as well as priming of the animal for secondary antibody responses. Finally, we will discuss studies of a mechanism by which the mucosal i m m u n e system can compartmentalize its regulation of a response, so that simultaneous e n h a n c e m e n t and suppression can be obtained, depending on the Ig class of the induced responses. Such a mechanism is indicative of the complexity of mucosal i m m u n o r e g u l a t i o n and provides evidence that regulation in this area may have several unique features. M e c h a n i s m s of oral u n r e s p o n s i v e n e s s (tolerance) Suppre.rsiorz of oral res~Jm~.sesby 13 cells or B-cell products
Oral unresponsiveness was first studied within the context of modern immunology by Chase in 1946, although related observations were made as early as the mid-nineteenth century ~. Chase showed that after
mmmmdogy/oday, .4e~gen//-()~/
~..)/"~-~
157
~$YSTEMIC
_ _ _ cc LYMPH NODE
Fig. 1. Diagrammatic representation of antigenic stimulation occurring in the mucosal immune system. The gut lumen is filled with antigenic material (A) which gains entry to organized gut lymphoid tissues such as tl']e Peyer's patches, tlere the encounter B ceils as well as regulatory T cells which can migrate to draining lymphoid tissues (mesenteric lymph node) and then to the systemic and mucosal circulations. Both helper and suppressor T cells may be stimulated in the Payer's patch and this may account for the fact that both responsiveness and unresponsivenesscan followantigen feeding.
guinea pigs were fed with a chemically simple skinsensitizing substance, dinitrochlorobenzene (DNCB), they did not show contact s e n s i t i z a t i o n with this material. This p h e n o m e n o n has been recently reinvestigated by Asherson e! a/., who studied the e q u i v a l e n t u n r e s p o n s i v e n e s s which follows oral challenge of rats with the skin-sensitizing agents oxazalone and picryl chloridC. These investigators showed, in cell-transfer studies, that unresponsiveness was associated with the development of (1) suppressor B cells capable of suppressing skin reactivity in recipient animals which had been transferred in suspensions of lymph-node or spleen cells obtained from skin-sensitized animals; and (2) suppressor T cells capable of suppressing DNA proliferation of lymph-node cells of recipient animals and which were present in the recipients as a result of prior skin sensitization. In other studies, Asherson et a[. observed that the suppressor B cells are not only associated with the unresponsive states we have mentioned but also with responsive states, e.g. responsiveness in animals receiving topical applications of contactant 3. O n e interpretation of this data is that, after oral exposure to c o n t a c t a n t , suppressor B cells are generated early in the response and in large enough numbers to prevent any observable i m m u n e response at all, whereas after topical application of contactant the suppressor B cells occur late in the response and in lower numbers, so that an i m m u n e response does
develop but is eventually shut off. An alternative explanation, based on the fact that suppressor B cells occur during states of both responsiveness and unresponsiveness, is that the suppressor B cells are not involved in oral tolerance to contactants; in this case, the suppressor T cells or other suppressor components (as discussed below) might be important factors. Assuming that suppressor B cells do play a role in oral unresponsiveness, several mechanisms of suppression are possible. In the first place, it is well known that antibody to stimulating antigen may cause immunosuppression4, so suppressor B cells might act by producing antibodies that have suppressor effects. There is some support for this explanation in the observation that mice orally immunized with sheep red blood cells (SRBC) develop serum suppressor factors which, at least in part, react with i m m u n i z i n g antigen. In the relevant studies, mice were given SRBC by intragastric i n t u b a t i o n and cells and serum from such animals were examined for suppressor capabilityL Feeding with SRBC, unlike contactants (mentioned above) or soluble proteins (mentioned below), induced no suppressor cells in the spleen of recipient animals but their serum contained a substance which suppressed the responses of both unfed animals subsequently i m m u n i z e d with SRBC irz ~,i~o and virgin cells cultured with SRBC zr~ vilro. This suppressor capability was antigen-specific and nonH-2 restricted; in addition, it was absorbed by staphylococcal protein A or ~Sephadex' coated with anti-mouse-lg, whereas absorption with i m m u n i z i n g antigen (SRBC) was succ'essful only some of the time 5. A. B. +660
+100
uJ
-100
DIgM [ ] IgG [] IgA
+100
uJ
(,.9
-100
Fig. 2. Differential immunoregulatory effects on IgM/IgG and IgA responses mediated by Peyer's patch T cells (polyclonal system). In this experiment Concanavalin A-pulsed T cells were added to an indicator culture consisting of spleen cells or Peyer's patches cells stimulated with I,PS. It is seen that the addition of pulsed T ceils leads to suppression of lgM/IgG synthesis, but enhancement of lgA synthesis. This is the critical observation that indicates that separate, class-specific T cells regulate IgM/lg(/ and lgA synthesis. In comparison with the spleen, Peyer's patch is enriched for IgA specifc helper '1' cells.
imm~mr;/
