Imn~unology Today, voL 8, No. 12, 1987
lnterferons _
and rheumatoid arthritis: insight into interferon biology?
Recent dinical studies indicate that gamma-interferon (IFN-~/) has some efficacy in the treatment of rheumatoid 1-7 and psoriatic arthritis 8. These investigations include a double blind, multicenter, placebocontrolled trial using patients with classical or definite rheumatoid arthritis 6. Although some patients have been successfully treated for more than a year, long-term disease modification has yet to be assessed. In light of the postulated roles for IFN-% this particular therapeutic application poses an interesting dilemma to immunologists. IFN-~/is a type U interferon, distinguished from type I interferons (a and 13)by its ability to activate monocytes and to induce expression of class U histocompatibility antigens (for review see Refs 9,10). Increased class II antigen expression could be expected to enhance antigen presentation and possibly exacerbate a hyperimmune condition. Consequently it has been proposed that the immune-activating lymphokines may have deleterious effects in autoimmune disease~1.~2. How can one reconcile this viewpoint with the clinical results? IFN--y has a number of actions in addition to the classically characterized antiviral and macrophage-activation properties, and here I will attempt to spotlight those aspects that may be relevant to the application of IFN--y in rheumatoid arthritis. Monocytes are central to the inflammatory response due to their production of pro-inflammatory substances such as interleukin 1(IL-1), tumor necrosis factor and eicosanoids, as well as to their ability to release a number of counteracting agents (IL-1 inhibitors, C1 esterase inhibitor, etc.). Interferons have regulatory activities e- - Ts ~. .d. . . l y i...,nn~..=n.,tto +,v~ ~~e. '"I 1983, P. DoreI.i II Duffy and co-workers demonstrated that type I interferons could dramatically inhibit prostaglandin release from human peripheral monoc/tes 13, a result subsequently confirmed by others ~4. Boraschi e t al. using mouse macrophages~ have expanded this observation to show that levels of metabolites in the lipooxygenase and cyclooxygenase timbs of the eicosanoid pathway as well as that of arachidonic acid itself, are modulated by interferons ~6. Recently, this modulatory effect has been examined in the context of IL-1 action and indeed both interferon types can inhibit IL-l-induced prostaglandin release from human peripheral monocytes ~7. In all these studies, the effects of interferon were manifested rapidly and at low concentrations. In vivo, the inhibitory effect of type I interferon in the carrageenan-induced pleurisy inflammation model is, and of both types I and II interferons on lipopolysaccharide-induced footpad swelling 19 may result from modification of monocyte eicosanoid metabolism. The apparent anti-inflammatory effect of interferons on monocytes may be directly relevant to the arthritis case. The regulation of eicosanoid metabolism in monocytes by interferon may be indicative of a broader phenomenon. First, IL-1 induces bone resorption via osteo372
Departmentof CellBiologyand Immunology,BiogenResearchCorp., 14 CambridgeCenter,Cambridge,MA 02~42, USA
Jefl Br0wning clast activation in an apparently prostaglandin-mediated process. IFN-~/can effectively block this resorption process in vitro zo as well as the production of prostaglandin by calvariae zl . Second, interferons appear to be involved in the control of collagen synthesis. Natural IL-1 induces the synthesis of type IV collagen in mammary epithelial cells, and monocyte supernatents could also increase collagen types I and III synthesis in cultured synovial fibroblasts. Recent studies suggest that transforming growth factor-~ (TGF-13)is a more likely candidate for the factor responsible for inducing collagen synthesis in mesenchymal and epithelial tissues22 and bone resorption in clavariae23. Interferons can inhibit in-vitro types I and III collagen synthesis by both synovial and normal dipoloid fibroblasts as well as type Ucollagen synthesis by cultured chondrocytes24, zs. Interestingly, a mini-pump inserted into a rat resulted in the eventual formation of collagen 'scar' around the pump; inclusion of murine IFN-~f in the solution released prevented scar formation, implying that this process is affected by IFN-~ in vivo26. Moreover, in those cells in which collagen synthesis was regulated by TGF-13, fibronectin production was also increased by this factor 22, while in endothelial cell cultures, the maintenance of fibronectin on the substrate was inhibited by IFN-~/(Ref. 27). These results prompt speculations that the synthesis of extracellular matrix/ connective tissue may be reQulated bv TGF-B (or !1_-! and fibroblast growth factor?) and interferons at the level of collagen and fibronectin synthesis, while matrix degradation may be controlled by IL-1. By affecting bone resorption as well as lessening the extent of fibrosis or scarring associated with aberrant matrix repair, the interferons may have therapeutic effects in some subsets of arthritis. Interferons may have beneficial effects in rheumatoid arthritis due to their involvement in two additional areas. Recent work on the regulation of B cells by B-cell stimulating factor-1 (interleukin 4) has revealed rather surprisingly that IFN-~ blocks the effects of IL-4 on B-cell proliferation, the secretion of IgG 1 and IgG3 antibodies, the response to polyclonal type antigens and the induction of class II antigen on B cells28.29. Whether there is a role for leukotrienes or prostaglandins in these phenomena remains to be clarified but there are several indications of eicosanoid involvement30. 31. The effective inhibition by IFN-~/of Epstein-Barr virus-induced B-cell proliferation and subsequent IgM production may be a esult of this regulatory activity 3z, and may explain the nerapeutic effect of IFN-~ on rheumatoid arthritis 32. Presumably a dampening of the humoral arm of the immune system and decreased rheumatoid factor levels would be desirable in the therapy of an autoimmune condition. Possibly complementary to these observations are reports by several groups that peripheral lymphocytes from rheumatoid arthritis patients are relatively unresponsive to lectin stimulation33. 34. These patients appear
~
( ~ 1987. Elsevier Publications, Cambridge
0167 - 4919187/$02.00
Immunology Today, vol. 8, No. 12, 1987 i
i
to have defective IL-1 regulation, which in turn leads to Table1. Thepossibleinvolvementof eicosanoidsin theeffectsof interferon depressed IL-2 and IFN-~/ production by their lymphocytes 33. It is possible that exogenous IFN-~y supEffectsof IFNs Roleof eic0sanoids plied in this context reconstitutes some aspect of the immune system in a therapeutically beneficial manner. Typel(odl3) TypeII (~/) Ref.a While many of these actions of interferon may be helpful, there are many that should exacerbate the Classicala~ons of interferons disease, besides the enhancement of class II antigen Antiviral Active Active 39 Cyciooxygenase inhibit~ 40 expression mentioned above. IFN-~/ can increase the suppress the antiviral proliferation of synovial fibroblasts in culture3S; if hyperstate plasia of the synovial lining is a fundamental aspect of Anti-proliferative Poody Active 39 rheumatoid disease, then this enhancing activity should effects active be detrimental. Interferons may play an active role in the Macr0phage Inactive Active 39 Pr0staglandinsantagonize regulation of endothelial lining and the infiltration of activation interferon-inducedmonoleucocytes through this barrier although how manipulacytecytotoxicactivity tion at this level affects inflammatory events is still ClassI antigen Poorly Active 42 unclear. The macrophage-activating property of IFN-~/ expression active can lead to enhanced oxygen radical formation as well as ClassII antigen Inactive Active 42 Indomethacinprolongs 43. the production of II.-1 and tumor necrosis factor. But at expression interfer0n-inducedantigen 44 this stage, it is difficult to assess the effects of interferons expressionin vitro on the balance between pro-inflammatory and antiinflammatory mediator production. In this sense it is Inhibitoryactionsof interferons interesting that interferon induces the synthesis by MacrophagePGE Active Active 15.17 monocytes of C1 esterase inhibitor - an activity which release could result in a potent anti-inflammatory effect 36. Collagen Active Active 45 The diversity of the effects mediated by interferons synthesis 21 suggests that they influence fundamental aspects of cell PGErmediated Boneresorption Inactive Active 20 Complex;PGEsenhance regulation, and the control of eicosanoid metabolism 30, IL-4action ? Active 29 31 earlyphaseof B-cell may be one such action. Eicosanoid metabolism is limited on Bcells activationandinhibit by the supply of free arachidonic acid, and the enzyme latersteps phospholipase A2 is a control point for these pathways. Boraschi et al. suggested that the inhibitory effects of Epstein-Barrvirus- Poorly Active 32 interferon on prostanoid release from murine macinducedB-cell active rophages was at the level of phospholipase A2 (Ref. 15). proliferation Inductionof C1 Poorly Active 36 The effects of interferon on eicosanoid metabolism may be complex, ranging from direct modulation to more inhibitorsynthesis~' active secondary effects stemming from interferon-induced ~l'l'~r~;~e " .-,-,11 . - , , . - I ; - - , - ............ in ~,, ~y~,,,,~. The obsercation that contrary aRelativeactivities are usuallybased on equal antiviral units despite the lower to the monocyte case, natural type I interferons can specific activity of IFN-~as an antiviralagent. For this reasonthe relativepotency elevate prostaglandin synthesis in fibroblasts underlines may not be validwhen consideredon a molarbasis. this complexity 37. Several diverse actions may result from blnhibitonjin the sensethat interferonswould inhibitthe complementcascade. modulation of eicosanoid metabolism. In such a model, interferon would exert a highly pleiotropic influence, depending on the specific cell type and the role of more classical macrophage-activating and MHCleukotrienes and prostaglandins in that system. A limited regulating functions of interferon towards the inhibitory synopsis of the various activities of interferons and the putative involvement of eicosanoid metabolism in these aspects outlined above. Interferons may not only be phenomena is outlined in Table 1. The efficacy of type I directly anti-inflammatory, but may also be disease modversus type II interferon in these different in-vitro assay ifying by affecting the balance between tissue destruction and remodelling and through the regulation of systems clearly varies. The question of the relative poB-cell function. Further clinical experimentation should tency of types I and II interferons in the treatment of provide a clearer definition of interferon's actions. But a rheumatoid arthritis may eventually help to elucidate the better understanding of these phenomena will probably mode of action. In one small study, leukocyte interferon require an improved appreciation of the properties of (type I) was effective in the treatment of rheumatoid interferon and the nature of the disease itself. arthritis 38. But mechanistic implications based on t~'"se studies may be obfuscated by pharmacokinetic di,~erences between the various interferon types, as well as by References the relative distribution of type I and type II receptors on 10bert, H-J. and Hofschnieder, P.H.(1985)Dtsch. Med. the relevant cell types. Wochenschr. 100, 1766-1769 The evaluation of the in-vivo role of a complex cyto20bert, H-J. (1986) J. Interferon Res. 6 (Suppl. 1), 37 kine such as an interferon has been a particularly difficult 3 Lemmel, E.-M., Franke, M., Gaus,W. etaL (1986)Arthritis hurdle for the immunologist. Typically, vision is clouded Rheum. 29 (Suppl. $79) (Abstract) by myriad reports describing various in-vitro experiments, 4 Lemmel, E.M., Franke, M., Gaus,W. etal. (1987) RheumatoL and the question of which activities are relevant in-vivo is Int. 7, 127-132 $ Wolfe, F., Cathey, M.A., Hawley,D.J. and Schindler,J. (1986) difficult to answer. In the case of rheumatoid arthritis, 373 Arthritis Rheum. 29 (Suppl. $18) (Abstract) the clinical results suggest a shift in emphasis from the
-re 'ie vs
ImmunologyToday,vol. 8, No. 12, 1987 l .
.
.
.
i
' imm,
,i
,
,
HH,,,
,
--
,,
ti Cannon. G,W.. Schindler, J,D,. Emkey. R.D. eta/. (1987) Arthn'bs Rheum. 30 (Suppl. 518) (Abstract) 7 Seitz, M,, Manz, G, and Franke, M. (1986)Z. Rheumatol. 45, 93-99 11Fierlbeck. G. and Rassner, G. (1986) Dtsch. Med. ~ r . 111, 1313-1316 9 Peska,S., Langer, J., Zoon, K.C. and Samuel, C.E. (1987) Annu. Rev./mmuno/. 56, 727-777 10 Bonnem, E.M. and Oldham, R.K. (1987) J. Biol. Response 6, 275-301 11 Rosenbach,T,O., Moshonov, S., Zor, U. and Yaron, M. (1984) Clin. Rheumato/. 3, 361-364 12 Rosenberg,Y J,, Steinberg, A.D. and Santoro, T.J. (1984)
Immunol. Today 5, 64-67 13 Dore-Duffy, P., Perry, W. and Kuo, H-H. (1983) Cell
Immunol. 79, 232-239 14 Rachmilewitz, D.. Karmeli, F. and Panet, A. (1985) J,/nterferon Res. 5, 629--635 1$ Bo~aschi,D, Censini, S., Bartalini. M. and Tagliabue, A. (1985)J. Immunol. 135, 502-505 tG Boraschi, D., Censini, S., Bartalini, M. eta/. (1987) J. Irnmunol. 138, 4341-4346 17 Browning, J and Ribolini, A. (1987)J. Immunol. 138, 2857-2863 111Ghiara, P., Bartalini, M., Tagliabue, A. and Boraschi, D. (1986) C//n. E~. Immunol. 66, 606-614 19 Heremans,J., Dijkmans, R., Sobis, H., Vandekerckhove, F. and Billiau,A. (1987)J. Immunol. 138, 4175-4179 20 Gowen, M.,Nedwin, G.E. and Mundy, G.R. (1986) J. Bone Mineral Res. 1,469-474 21 Hoffmann, O., Klaushofer, K., Gleispach, H. eta/. (1987) Biochem. Biophys. Re_s.Comm. 143, 38-43 22 Ignotz, R.A., Endo, T. and Massague, J. (1987) J. Biol. Chem. 262, 6443-6446 23 Centrella, M., McCarthy, T.I.. and Canalis, E. (1987) J. Biol. Chem. 262, 2869-2874 24 Freundlich, B., Bomalaski, J.S., Neilson, E.and Jimenez, S.A. (1986) Immunol. Today 7, 303-306 23 Goldring, M.B., Sandell, L.J., Stephanson, M. L. and Krane, S.M. (1986)J. Biol. Chem. 261,9049-9056
26 Granstein, R.D., Murphy, G.F., Margolis, R.J., Byrne, M.H. and Amento, E.P.(1987) J. C/in. Invest. 79, 1254-1258 27 Stolpen, A.H., Guinan, E.C., Fiers, W. and Pober, J.S. (1986) Am. J Pathol. 123, 16-24 Coffman, R.L. and Carty, J. (1986)J. Immunol. 136, 949-954 Mond, J.J., Carmen, J., Sarma, C., Ohara, J. and Finkelman, F.D. (1986) J. Immunol. 137, 3534-3537 Goodman, M. (1986)J. Immunol. 137, 3753-3757 31 Straite, N.G. and Panayi, G.S. (1984) lmmunol. Today5, 175-177 Lotz, M., Tsoukas, C.D., Curd, J.G., Carson, D.A. and Vaughan, J.H. (1987) J. Rheurnatol. 14, 42-45 33 Lotz, M., Tsoukas, C.D., Robinson, C.A. eta/. (1986) J. C/in. Invest. 78, 713-721 34 Malaise, M.G. and Franchimont, P. (1987) Arthritis Rheum. 30, 230--231 35 Brinkerhoff, C.E. and Guyre, P.M. (1985) J. Immunol. 134, 3142-3146 ]6 Hamilton, A.O., Jones, L., Morrison, L. and Whaley, K. (1987) Biochem. J, 242, 809--815 37 Fuse,A., Mahmud, I. and Kuwata, T. (1982) CancerRes. 42, 3209-3214 ]6 Peddinani, M.V., Savery, F. and Hang, L. (1986) C/in. Ther. 9, 39-42 Trinchieri, G. and Perussia,B. (1985)Immunol. Today6, 131-136 Pottathil, R., Chandrabose, K.A., Cuatrecasas, P. and Long, D.J. (1980) Proc. Natl Acad. Sci. USA 77, 5437-5440 41 Russell,S.W. and Pace,J.L. (1984)Mol. Immunol. 21, 249--254 42 Revel, M. and Chebath, J. (1986) Trends Biochem. Sci. 11, 166-170
43 Papiernik, M., Dombret, H., Stefanos, S. and Wietzerbin, J. (1986) Eur. J. Immunol. 16, 296-300 44 Piacibello, W., Rubin, B.Y. and Broxmeyer, H.E. (1986)Exp. Hematol. 14, 44-50 45 Duncan, M.R. and Berman, B. (1985)J. Exp. Med. 162, 516-527
genetic origin of autoantibodies Aut~'mmune disease appears to be a consequence of the generation of serf-reactive antibodies. The relationship between these autoantibodies and antibodies directed against exogenous antigens has fostered much recent work, especially on the murine models of systemic lupus erythematosus and rheumatoid arthritis, as Reinhard Kofler and his colleagues review here. While the complexities surrounding the origin of serf-specific antibodies are still to be completely unravelled, it appears that lupus autoantibody expression may not result from defects in !g germline genes nor in mechanisms generating antibody repertoires (variable region gene selection, rearrangement, somatic mutation) but follows the same general prindples governing responses to foreign ant~ens. A characteristic feature of the immune system is its ability to recognize, and interact with, essentially any antigen. However, this enormous recognition potential includes
374
1Depertmentof Immunology,ScrippsClinicand ResearchFoundation, la Jolla, CA 92037, USA; and 2Institutefor Generaland Experimental Pathology, Universityof Innsbruck,Austria,
R. KoA~1,2,F.J. DixonI and A.N. lheofilopoulos possible interactions with self components, some of which appear to be essential for the regulation of immune functions ~, whereas others can be pathogenic, particularly if expressed at high levels. Pathogenic expression of self reactivity may result from abnormalities in the generation of the 1"- and B-cell receptor :epertoire. Alternatively, such autoreactive receptors may represent normal components of the immune system that, under physiologic conditions, remain unstimulated or suppressed. Corresponding possibilities can be distinguished by defining the genetic origin of, and somatic mechanisms generating, the B- and T-cell receptors responsible for anti-self responses. Of particular importance to etiology and therapy is whether the autoimmune receptor germline gene repertoire is abnormal, whether anti-self receptors are encoded by unique gene segments, whether the anti-self response is genetically, structurally and/or idiotypically restricted, and to what extent somatic events contribute to the generation of self specificitieso (~ 1987,
Elsevier Publications.
Cambridge
0167-4919/871502.00
lnterferons _
and rheumatoid arthritis: insight into interferon biology?
Recent dinical studies indicate that gamma-interferon (IFN-~/) has some efficacy in the treatment of rheumatoid 1-7 and psoriatic arthritis 8. These investigations include a double blind, multicenter, placebocontrolled trial using patients with classical or definite rheumatoid arthritis 6. Although some patients have been successfully treated for more than a year, long-term disease modification has yet to be assessed. In light of the postulated roles for IFN-% this particular therapeutic application poses an interesting dilemma to immunologists. IFN-~/is a type U interferon, distinguished from type I interferons (a and 13)by its ability to activate monocytes and to induce expression of class U histocompatibility antigens (for review see Refs 9,10). Increased class II antigen expression could be expected to enhance antigen presentation and possibly exacerbate a hyperimmune condition. Consequently it has been proposed that the immune-activating lymphokines may have deleterious effects in autoimmune disease~1.~2. How can one reconcile this viewpoint with the clinical results? IFN--y has a number of actions in addition to the classically characterized antiviral and macrophage-activation properties, and here I will attempt to spotlight those aspects that may be relevant to the application of IFN--y in rheumatoid arthritis. Monocytes are central to the inflammatory response due to their production of pro-inflammatory substances such as interleukin 1(IL-1), tumor necrosis factor and eicosanoids, as well as to their ability to release a number of counteracting agents (IL-1 inhibitors, C1 esterase inhibitor, etc.). Interferons have regulatory activities e- - Ts ~. .d. . . l y i...,nn~..=n.,tto +,v~ ~~e. '"I 1983, P. DoreI.i II Duffy and co-workers demonstrated that type I interferons could dramatically inhibit prostaglandin release from human peripheral monoc/tes 13, a result subsequently confirmed by others ~4. Boraschi e t al. using mouse macrophages~ have expanded this observation to show that levels of metabolites in the lipooxygenase and cyclooxygenase timbs of the eicosanoid pathway as well as that of arachidonic acid itself, are modulated by interferons ~6. Recently, this modulatory effect has been examined in the context of IL-1 action and indeed both interferon types can inhibit IL-l-induced prostaglandin release from human peripheral monocytes ~7. In all these studies, the effects of interferon were manifested rapidly and at low concentrations. In vivo, the inhibitory effect of type I interferon in the carrageenan-induced pleurisy inflammation model is, and of both types I and II interferons on lipopolysaccharide-induced footpad swelling 19 may result from modification of monocyte eicosanoid metabolism. The apparent anti-inflammatory effect of interferons on monocytes may be directly relevant to the arthritis case. The regulation of eicosanoid metabolism in monocytes by interferon may be indicative of a broader phenomenon. First, IL-1 induces bone resorption via osteo372
Departmentof CellBiologyand Immunology,BiogenResearchCorp., 14 CambridgeCenter,Cambridge,MA 02~42, USA
Jefl Br0wning clast activation in an apparently prostaglandin-mediated process. IFN-~/can effectively block this resorption process in vitro zo as well as the production of prostaglandin by calvariae zl . Second, interferons appear to be involved in the control of collagen synthesis. Natural IL-1 induces the synthesis of type IV collagen in mammary epithelial cells, and monocyte supernatents could also increase collagen types I and III synthesis in cultured synovial fibroblasts. Recent studies suggest that transforming growth factor-~ (TGF-13)is a more likely candidate for the factor responsible for inducing collagen synthesis in mesenchymal and epithelial tissues22 and bone resorption in clavariae23. Interferons can inhibit in-vitro types I and III collagen synthesis by both synovial and normal dipoloid fibroblasts as well as type Ucollagen synthesis by cultured chondrocytes24, zs. Interestingly, a mini-pump inserted into a rat resulted in the eventual formation of collagen 'scar' around the pump; inclusion of murine IFN-~f in the solution released prevented scar formation, implying that this process is affected by IFN-~ in vivo26. Moreover, in those cells in which collagen synthesis was regulated by TGF-13, fibronectin production was also increased by this factor 22, while in endothelial cell cultures, the maintenance of fibronectin on the substrate was inhibited by IFN-~/(Ref. 27). These results prompt speculations that the synthesis of extracellular matrix/ connective tissue may be reQulated bv TGF-B (or !1_-! and fibroblast growth factor?) and interferons at the level of collagen and fibronectin synthesis, while matrix degradation may be controlled by IL-1. By affecting bone resorption as well as lessening the extent of fibrosis or scarring associated with aberrant matrix repair, the interferons may have therapeutic effects in some subsets of arthritis. Interferons may have beneficial effects in rheumatoid arthritis due to their involvement in two additional areas. Recent work on the regulation of B cells by B-cell stimulating factor-1 (interleukin 4) has revealed rather surprisingly that IFN-~ blocks the effects of IL-4 on B-cell proliferation, the secretion of IgG 1 and IgG3 antibodies, the response to polyclonal type antigens and the induction of class II antigen on B cells28.29. Whether there is a role for leukotrienes or prostaglandins in these phenomena remains to be clarified but there are several indications of eicosanoid involvement30. 31. The effective inhibition by IFN-~/of Epstein-Barr virus-induced B-cell proliferation and subsequent IgM production may be a esult of this regulatory activity 3z, and may explain the nerapeutic effect of IFN-~ on rheumatoid arthritis 32. Presumably a dampening of the humoral arm of the immune system and decreased rheumatoid factor levels would be desirable in the therapy of an autoimmune condition. Possibly complementary to these observations are reports by several groups that peripheral lymphocytes from rheumatoid arthritis patients are relatively unresponsive to lectin stimulation33. 34. These patients appear
~
( ~ 1987. Elsevier Publications, Cambridge
0167 - 4919187/$02.00
Immunology Today, vol. 8, No. 12, 1987 i
i
to have defective IL-1 regulation, which in turn leads to Table1. Thepossibleinvolvementof eicosanoidsin theeffectsof interferon depressed IL-2 and IFN-~/ production by their lymphocytes 33. It is possible that exogenous IFN-~y supEffectsof IFNs Roleof eic0sanoids plied in this context reconstitutes some aspect of the immune system in a therapeutically beneficial manner. Typel(odl3) TypeII (~/) Ref.a While many of these actions of interferon may be helpful, there are many that should exacerbate the Classicala~ons of interferons disease, besides the enhancement of class II antigen Antiviral Active Active 39 Cyciooxygenase inhibit~ 40 expression mentioned above. IFN-~/ can increase the suppress the antiviral proliferation of synovial fibroblasts in culture3S; if hyperstate plasia of the synovial lining is a fundamental aspect of Anti-proliferative Poody Active 39 rheumatoid disease, then this enhancing activity should effects active be detrimental. Interferons may play an active role in the Macr0phage Inactive Active 39 Pr0staglandinsantagonize regulation of endothelial lining and the infiltration of activation interferon-inducedmonoleucocytes through this barrier although how manipulacytecytotoxicactivity tion at this level affects inflammatory events is still ClassI antigen Poorly Active 42 unclear. The macrophage-activating property of IFN-~/ expression active can lead to enhanced oxygen radical formation as well as ClassII antigen Inactive Active 42 Indomethacinprolongs 43. the production of II.-1 and tumor necrosis factor. But at expression interfer0n-inducedantigen 44 this stage, it is difficult to assess the effects of interferons expressionin vitro on the balance between pro-inflammatory and antiinflammatory mediator production. In this sense it is Inhibitoryactionsof interferons interesting that interferon induces the synthesis by MacrophagePGE Active Active 15.17 monocytes of C1 esterase inhibitor - an activity which release could result in a potent anti-inflammatory effect 36. Collagen Active Active 45 The diversity of the effects mediated by interferons synthesis 21 suggests that they influence fundamental aspects of cell PGErmediated Boneresorption Inactive Active 20 Complex;PGEsenhance regulation, and the control of eicosanoid metabolism 30, IL-4action ? Active 29 31 earlyphaseof B-cell may be one such action. Eicosanoid metabolism is limited on Bcells activationandinhibit by the supply of free arachidonic acid, and the enzyme latersteps phospholipase A2 is a control point for these pathways. Boraschi et al. suggested that the inhibitory effects of Epstein-Barrvirus- Poorly Active 32 interferon on prostanoid release from murine macinducedB-cell active rophages was at the level of phospholipase A2 (Ref. 15). proliferation Inductionof C1 Poorly Active 36 The effects of interferon on eicosanoid metabolism may be complex, ranging from direct modulation to more inhibitorsynthesis~' active secondary effects stemming from interferon-induced ~l'l'~r~;~e " .-,-,11 . - , , . - I ; - - , - ............ in ~,, ~y~,,,,~. The obsercation that contrary aRelativeactivities are usuallybased on equal antiviral units despite the lower to the monocyte case, natural type I interferons can specific activity of IFN-~as an antiviralagent. For this reasonthe relativepotency elevate prostaglandin synthesis in fibroblasts underlines may not be validwhen consideredon a molarbasis. this complexity 37. Several diverse actions may result from blnhibitonjin the sensethat interferonswould inhibitthe complementcascade. modulation of eicosanoid metabolism. In such a model, interferon would exert a highly pleiotropic influence, depending on the specific cell type and the role of more classical macrophage-activating and MHCleukotrienes and prostaglandins in that system. A limited regulating functions of interferon towards the inhibitory synopsis of the various activities of interferons and the putative involvement of eicosanoid metabolism in these aspects outlined above. Interferons may not only be phenomena is outlined in Table 1. The efficacy of type I directly anti-inflammatory, but may also be disease modversus type II interferon in these different in-vitro assay ifying by affecting the balance between tissue destruction and remodelling and through the regulation of systems clearly varies. The question of the relative poB-cell function. Further clinical experimentation should tency of types I and II interferons in the treatment of provide a clearer definition of interferon's actions. But a rheumatoid arthritis may eventually help to elucidate the better understanding of these phenomena will probably mode of action. In one small study, leukocyte interferon require an improved appreciation of the properties of (type I) was effective in the treatment of rheumatoid interferon and the nature of the disease itself. arthritis 38. But mechanistic implications based on t~'"se studies may be obfuscated by pharmacokinetic di,~erences between the various interferon types, as well as by References the relative distribution of type I and type II receptors on 10bert, H-J. and Hofschnieder, P.H.(1985)Dtsch. Med. the relevant cell types. Wochenschr. 100, 1766-1769 The evaluation of the in-vivo role of a complex cyto20bert, H-J. (1986) J. Interferon Res. 6 (Suppl. 1), 37 kine such as an interferon has been a particularly difficult 3 Lemmel, E.-M., Franke, M., Gaus,W. etaL (1986)Arthritis hurdle for the immunologist. Typically, vision is clouded Rheum. 29 (Suppl. $79) (Abstract) by myriad reports describing various in-vitro experiments, 4 Lemmel, E.M., Franke, M., Gaus,W. etal. (1987) RheumatoL and the question of which activities are relevant in-vivo is Int. 7, 127-132 $ Wolfe, F., Cathey, M.A., Hawley,D.J. and Schindler,J. (1986) difficult to answer. In the case of rheumatoid arthritis, 373 Arthritis Rheum. 29 (Suppl. $18) (Abstract) the clinical results suggest a shift in emphasis from the
-re 'ie vs
ImmunologyToday,vol. 8, No. 12, 1987 l .
.
.
.
i
' imm,
,i
,
,
HH,,,
,
--
,,
ti Cannon. G,W.. Schindler, J,D,. Emkey. R.D. eta/. (1987) Arthn'bs Rheum. 30 (Suppl. 518) (Abstract) 7 Seitz, M,, Manz, G, and Franke, M. (1986)Z. Rheumatol. 45, 93-99 11Fierlbeck. G. and Rassner, G. (1986) Dtsch. Med. ~ r . 111, 1313-1316 9 Peska,S., Langer, J., Zoon, K.C. and Samuel, C.E. (1987) Annu. Rev./mmuno/. 56, 727-777 10 Bonnem, E.M. and Oldham, R.K. (1987) J. Biol. Response 6, 275-301 11 Rosenbach,T,O., Moshonov, S., Zor, U. and Yaron, M. (1984) Clin. Rheumato/. 3, 361-364 12 Rosenberg,Y J,, Steinberg, A.D. and Santoro, T.J. (1984)
Immunol. Today 5, 64-67 13 Dore-Duffy, P., Perry, W. and Kuo, H-H. (1983) Cell
Immunol. 79, 232-239 14 Rachmilewitz, D.. Karmeli, F. and Panet, A. (1985) J,/nterferon Res. 5, 629--635 1$ Bo~aschi,D, Censini, S., Bartalini. M. and Tagliabue, A. (1985)J. Immunol. 135, 502-505 tG Boraschi, D., Censini, S., Bartalini, M. eta/. (1987) J. Irnmunol. 138, 4341-4346 17 Browning, J and Ribolini, A. (1987)J. Immunol. 138, 2857-2863 111Ghiara, P., Bartalini, M., Tagliabue, A. and Boraschi, D. (1986) C//n. E~. Immunol. 66, 606-614 19 Heremans,J., Dijkmans, R., Sobis, H., Vandekerckhove, F. and Billiau,A. (1987)J. Immunol. 138, 4175-4179 20 Gowen, M.,Nedwin, G.E. and Mundy, G.R. (1986) J. Bone Mineral Res. 1,469-474 21 Hoffmann, O., Klaushofer, K., Gleispach, H. eta/. (1987) Biochem. Biophys. Re_s.Comm. 143, 38-43 22 Ignotz, R.A., Endo, T. and Massague, J. (1987) J. Biol. Chem. 262, 6443-6446 23 Centrella, M., McCarthy, T.I.. and Canalis, E. (1987) J. Biol. Chem. 262, 2869-2874 24 Freundlich, B., Bomalaski, J.S., Neilson, E.and Jimenez, S.A. (1986) Immunol. Today 7, 303-306 23 Goldring, M.B., Sandell, L.J., Stephanson, M. L. and Krane, S.M. (1986)J. Biol. Chem. 261,9049-9056
26 Granstein, R.D., Murphy, G.F., Margolis, R.J., Byrne, M.H. and Amento, E.P.(1987) J. C/in. Invest. 79, 1254-1258 27 Stolpen, A.H., Guinan, E.C., Fiers, W. and Pober, J.S. (1986) Am. J Pathol. 123, 16-24 Coffman, R.L. and Carty, J. (1986)J. Immunol. 136, 949-954 Mond, J.J., Carmen, J., Sarma, C., Ohara, J. and Finkelman, F.D. (1986) J. Immunol. 137, 3534-3537 Goodman, M. (1986)J. Immunol. 137, 3753-3757 31 Straite, N.G. and Panayi, G.S. (1984) lmmunol. Today5, 175-177 Lotz, M., Tsoukas, C.D., Curd, J.G., Carson, D.A. and Vaughan, J.H. (1987) J. Rheurnatol. 14, 42-45 33 Lotz, M., Tsoukas, C.D., Robinson, C.A. eta/. (1986) J. C/in. Invest. 78, 713-721 34 Malaise, M.G. and Franchimont, P. (1987) Arthritis Rheum. 30, 230--231 35 Brinkerhoff, C.E. and Guyre, P.M. (1985) J. Immunol. 134, 3142-3146 ]6 Hamilton, A.O., Jones, L., Morrison, L. and Whaley, K. (1987) Biochem. J, 242, 809--815 37 Fuse,A., Mahmud, I. and Kuwata, T. (1982) CancerRes. 42, 3209-3214 ]6 Peddinani, M.V., Savery, F. and Hang, L. (1986) C/in. Ther. 9, 39-42 Trinchieri, G. and Perussia,B. (1985)Immunol. Today6, 131-136 Pottathil, R., Chandrabose, K.A., Cuatrecasas, P. and Long, D.J. (1980) Proc. Natl Acad. Sci. USA 77, 5437-5440 41 Russell,S.W. and Pace,J.L. (1984)Mol. Immunol. 21, 249--254 42 Revel, M. and Chebath, J. (1986) Trends Biochem. Sci. 11, 166-170
43 Papiernik, M., Dombret, H., Stefanos, S. and Wietzerbin, J. (1986) Eur. J. Immunol. 16, 296-300 44 Piacibello, W., Rubin, B.Y. and Broxmeyer, H.E. (1986)Exp. Hematol. 14, 44-50 45 Duncan, M.R. and Berman, B. (1985)J. Exp. Med. 162, 516-527
genetic origin of autoantibodies Aut~'mmune disease appears to be a consequence of the generation of serf-reactive antibodies. The relationship between these autoantibodies and antibodies directed against exogenous antigens has fostered much recent work, especially on the murine models of systemic lupus erythematosus and rheumatoid arthritis, as Reinhard Kofler and his colleagues review here. While the complexities surrounding the origin of serf-specific antibodies are still to be completely unravelled, it appears that lupus autoantibody expression may not result from defects in !g germline genes nor in mechanisms generating antibody repertoires (variable region gene selection, rearrangement, somatic mutation) but follows the same general prindples governing responses to foreign ant~ens. A characteristic feature of the immune system is its ability to recognize, and interact with, essentially any antigen. However, this enormous recognition potential includes
374
1Depertmentof Immunology,ScrippsClinicand ResearchFoundation, la Jolla, CA 92037, USA; and 2Institutefor Generaland Experimental Pathology, Universityof Innsbruck,Austria,
R. KoA~1,2,F.J. DixonI and A.N. lheofilopoulos possible interactions with self components, some of which appear to be essential for the regulation of immune functions ~, whereas others can be pathogenic, particularly if expressed at high levels. Pathogenic expression of self reactivity may result from abnormalities in the generation of the 1"- and B-cell receptor :epertoire. Alternatively, such autoreactive receptors may represent normal components of the immune system that, under physiologic conditions, remain unstimulated or suppressed. Corresponding possibilities can be distinguished by defining the genetic origin of, and somatic mechanisms generating, the B- and T-cell receptors responsible for anti-self responses. Of particular importance to etiology and therapy is whether the autoimmune receptor germline gene repertoire is abnormal, whether anti-self receptors are encoded by unique gene segments, whether the anti-self response is genetically, structurally and/or idiotypically restricted, and to what extent somatic events contribute to the generation of self specificitieso (~ 1987,
Elsevier Publications.
Cambridge
0167-4919/871502.00
