Autoantibodies to cytokines - friends or foes?

Immunology Today, VoL 1L No. 5 1990

Au|oantibodies to cylokinesfriends or foes? Cytokines form a network of communication signals bet, veen cells of the imm~lne system, and between the immune system and other organs. They interact with structurally complex and often dynamically expressed target cell receptors. The recent demonstration of autoantibodies to cytokines, even in sera of normal individuals, suggests further complexities in the way that nature regulates cytokine functions. Based mainly on evidence obtained by investigating autoantibodies to interleukin 1~ (IL-I~), Klaus Bendtzen and colleagues discuss the possibility that naturally occurring antibodies may function as specific physiological carriers and regulators of cytokines. Cytokines, such as interferons (IFN), tumour necrosis factors (Tr,IF),interleukins (IL), and various growth factors, act via membrane or cytoplasmic receptors which may be upand down-regulated depending upon the cell cycle. Under normal conditions there are usually low concentrations of cytokines in the blood but under pathological conditions, and during cytokine therapy, significant blood levels may be reached. However, the cytokines are usually eliminated, or rendered inactive, very rapidly after entering the circulation 1,2 Naturally occurring or therapeutically induced antibodies to cytokines are generally thought to inhibit cytokine functions, and the appearance of such antibodies should therefore result in various degrees of 'cytokine deficiency '3. Indeed, it is a common concept that the development of antibodies against any autoantigen or drug is always undesirable. Such antibodies are often thought to be crucial for the pathology of autoimmune diseases and to inhibit the pharmacological effects of drugs including exogenously administered cytokines. We now propose that the presence of autoantibodies to certain natural peptides may be a common phenomenon, even in healthy individuals, and that these autoantibodies may serve beneficial functions not only as inhibitors, but also as specific carriers of these peptides in .he circulation.

Autoantibodies induced by treatment In 1968, it was reported that IgG antibodies may develop agair~st the cobalamin-transcobalamin complex in patients with pernicious anaemia undergo;ng tre.~tment with vitamin B~2 (Ref. 4). Rather than causing vitamin B~2 deficiency, these antibodies may act as beneficial carriers, because they retard the disappearance of the vitamin from the plasma s. Similar observations have occasionally been made in diabetic patients and even in individuals who have never received insulin therapy6. Rather than reducing the biological activity of insulin, these anti-insulin antibodies sometimes prolong the release of active insulin to the tissues, which results in

~Depts of Medicine ~A and Infectious DiseasesM, Rigshospitalet University Hospital, DK-2L00 CopenhagenN, Denmark. 2Dept of In temal Medicine and Haematology, Gentofte Hospital, Universi.~, of Copenhagen,DK-2900Hellerup, Denmark. ~) 1990, ElsevierScience Publishers Ltd. UK. 0167--49191901502 O0

Klaus Bendlzen, Morten Svmson1, Viggo Jensson2 and Erik Hip hypoglycaemia in non-diabetics and a marked reduction in the requirement for exogenous insulin in the diabetes patients. A large body of evidence shows that treatment with both natural and recombinant-derived IFN-o~ and IFN-13 may result in anti-IFN antibody formation 7 14. However, the appearance of such antibodies is not always associated with a decreased clinical response to therapy 14. More interesting perhaps is the indication from animal experiments that non-neutraliz;ng antibodies to human IFN-~, while failing to affect the in-vitro anti-viral and anti-proliferative properties of the cytokine, prevent normal clearance and degradation of free IFN-oL in the circulation~S. Based on these reports, we propose that the appearance of anti-cytokine antibodies may, at leas~in some cases, contribute to a positive therapeutic response, for example by retarding an otherwise rapid removal of cytokine from the circulation. This might favour a sustained supply of cytokine to effector cells and, because of the dynamic expression of cytokine receptors on these cells, increase the likelihood of mediator-receptor interactions.

Disease-associatedautoantibodi~s Antibodies to IFN-o~have been reported in patients with various autoimmune disorders (fcr example systemic lupus erythematosus~6), in human cord blood (reviewed in Ref. 17) and in the myeloma-prone Lou/c strain of rats ~8.It was recently shown that a significant percentage of individuals infected with hum_~nimmuqodeficiency vir~Js(HIV) possessed antibodies against IL-2, and these antibodies may have emerged because of homologous areas in the HIV envelope protein and in IL-2 (Ref. 19). IL-2 antibod;es have also been detected in lupus-prone mice2°.

Naturally occurringautoantibodies We have recently reported the presence of specific a~Jtoantibodies to IL-lo~ and TNF-~ in apparently normal adults 3,2~.22.The frequency of detectable autoantibodles to IL-lc~ and TNF-~ was 24% and 48%, respectively. While IgG and IgM classes were found against TNF-~, the antibodies against IL-I~ were almost exclusively of the IgG class and IgG4 was responsible for more than 40% of the binding capacity. IL-I~ binds avidly to the Fab fragments of these IgG molecules (K~ values < 5 x 10 -~ M), apparently with limited lattice formation (Ref. 23 and Svenson and Bendtzen, unpublished). Hence, precipitation of the antigen-antibody complexes is unlikely to occur to any significant degree in vivo. Furthermore, IgG4 antibodies fail to activate complement. The most important role of at least some of these naturally occurring autoantibodies, therefore, may be to transport cytokines

167

Immunology Today. Vol. 11, No. 5 1990

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than that between IL-lo= and other target cells, such as fibroblasts and enootheliai cells(~ 5 x 10-l° M) (Refs 24, 25). Thus, the presence of even a limited number of antibodies to IL-lot may prevent extensive absorption of the mediator to fibroblasts and endothelial cells (Fig. 1). On the other hand. the presence of high-affinity recep~ors for IL-le=on some lymphoid cell lines (Kd = 10-12-10-': -~) (Ref. 26) and on thyrocytes27suggests that the cytokine ma~,be released in an active form to specific targets containing high-affinity binding sites. The produGion of autoantibodies to TNF-~ and, possibly, IL-~ is augmented within a few days under acute pathological conditions, for example during Gramnegative bacterial infeGions;2. Moreover, the levels of anti-TNF-~ antibodies are significantly increased in patients suffering from chronic infections and various inflammatory disorders3.2L22. Since naturally occurring autoantibodies against IL-I~ interfere with its binding to the receptor23 and with the function of IL-lo~as a costimulator of T cells (Svenson and Bendtzen, unpublished), these antibodies may be crucial for neutralizing the adverse systemic effects of increased amounts of circulating cytokine during immunoinflammatory and infectious diseases3.22. Finally, since IL-lo=and TNF-o~are characteristically also expressed in the membrane of antigen-presenting macrophages, an immunoregulatory effect of these autoantibodies cannot be ruled out28.

Why are ¢ytokineautoantibodiesproduced7 It is widely accepted that the production of antibodies against autoantigens may result in disease29. Normal individuals possessB lymphocytes with receptors for autoantigens, and it is generally thought that these B cells produce autoantibodies if they are helped by T cells. The T-cell help is governed by genes in the major histocompatibility complex (MHC), and many autoimmune diseases are associated with specific genes of the MHC (ReL 30). However, in some cases of autoimmunity, there is no evidence for any genetically-linked susceptibility. it is not yet known whether the production of autoantibodies to cytokines is genetically linked or, indeed, whether such autoantibodies play a pathogenic role in any autoimn, une disease. The production of many, if not all, autoantibodies may be triggered by infectious agents, by certain adjuvants and drugs, and by the graft-versushost reaction29. interestingly, IL-loL and TNF-c~, the cytokines to which naturally occurring human autoantibodies have been most convincingly demonstrated, function as adjuvants in the stimulation of T and 3 lymphoq/tes 28. Also, the production of TNF-c~induced by Escherichia-coli-derived endetoxin is associated with specific alleles in the HLA-DR locus of the human MHC (Ref. 31). Are the cytokine autoantibodies cross-reactive and, if so, are they induced by a specific antigen or by polyclonal stimulation of the immune system? Antibodies against an HiV envelope peptide cross-react with an epitope on IL-2 (Ref. 19), which supports the suggestion that these antibodies may arise because of antigenic mimicry. In theory, this provides a mechanism by which HIV infection may trigger production of iL-2-binding antibodies. On the other hand, the exquisite specificity and avidity of binding of naturally occurring lgG autoantibodies to IL-I~ (Ref. 23) suggest that autoantibodies to at least some cytokines llldy i l U L U ~ Cl-O3",-r~dCLIV~. I FIIS, along Wll.l] l.lqe mgn incidence and early appearance of certain cytokine autoantibodies, even in healthy individuals 3,17,21-23, further indicates that some naturaily occurring cytokine autoantibodies are encnded in germ-line genes. If this is true, the postulated beneficial physiological role of autoantibodies to naturally occurring cytokines, even in healthy individuals, may explain why this apparent anomaly has been maintained during evolution. Hypothesis It is clear that the presence of low circulating cencentratlon: m s~edfl,_ rytokine autoantibodies is more common than was previously appreciated. These antibodies may not always impair the biological functions of the cytokines. On the contrary, such antibodies may act as beneficial and specific carriers of cytokines in the circulation (Fig. 1). This carrier fun~ion may retard the elimination of cytokines from the circulation, for instance by preventing urinary excretion and absorption to vessel walls and, possibly, by protecting the mediator against proteolytic degradation. Anti-cytokine antibodies may help to control potentially dangerous stimulation of circulating leucocytes, and antibody-bound cytokines may form a reservoir which enables a sustained release of active mediator molecules to targe', cells in the blood, lymphoid tissues and bone marrow, even in situations where delivery of the cjtokines to the circulation is intermittent.

Immunology Today, VoL 11, No. 5 1990

The above considerations do not exclude that some anti-cytokine antibodies may function as inhibitc~rs, especially if induced to high levels and accompanied by a switch in imrnunoglobulin isotype. The induction of neutralizing, cytotoxic or complement-fixing IgM and IgG anti-cytokine antibodies may also contribute to pathology in certain infectious and immunoinflammatory diseases. Consequently, we propose that a major role of naturally occurring autoantibodies to cytokines is to facilitate rather than neutralize functions of cytokines in the body. It is obviously important to test this hypothesis. One logical way would be to administer antibodies to cytokines in animal models of autoimmune and immunoinflammatopt disorders. However, this presupposes access to purified cytokine antibodies from the same animal species, preferably of different isotypes. Anotiler, more feasible, approach would be to monitor the kinetics of appearance and removal of cytokines, along with the clinical response, in patients treated with human antibody preparations vv,u, u~.~meu quantitias oi" cytokine antibodies. Also, measurements of serum levels of different classes of cytokine antibodies in the course of human immunoinflammatory diseases, and during therapeutic use of cytokines, would be helpful in evaluating the putative role of these antibodies. The studies reported herein were supported by the Danish Biotechnology Programme.

R~.ferences

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rostrum8 Trown, P.W., Dennin, R.A., Kramer, M.J. etal. (1983)Lancet i, 81-87 9 Billard, C., Sigaux, F., Castaigne, S. etal. (1986)Blood 67, 821-826 10 Steis, R.G., Smith, J.W., Urba, W.J. etal. (1988)NewEngl. J. Med. 318, 1409-1413 11 Moqensen, K.E., Daubas, P.H., Gresser, I., Sereni, D. and Varet, B. (1981) Lancet ii, 1227-1228 12 Spiegel, R.J.~Spicehandler, J.R., Jacobs, S.L. and Oden, E.M. (1986)Am. J. Mecl. Sci. 80, 223 13 Itri, L.M, Campion, M., Dennin, R.A etal. (1987) Cancer 59, 668-674 14 Vallbracht, A., Treuner, J., Fiehmig. B., Joester, K-E. and Niethammer, D. (1981) Nature 285,496-497 15 Rosenblum, M.G., Unger, B.W., Gutterman, J.U. et al. (1985) Cancer Res. 45, 2421-2424 16 Panem, S., Check, I.J., I-tenriksen, D. and Vtlcek, J. (1982) J. Immur, ol. 129, 1-3 17 Panem, S. (1984) Interferon 2, 175-183 18 Maeyer-Guignard, J. de, Cachard-Thomas, A. and Maeyer, E. de (1984)J. Immunol. 133, 775-778 19 Bost, K.L., Hahn, B.H., Saag, M.S. et al (1~)88) Immunology 65, 611-615 20 Ishizaka, S. and Tsujii, T. (1989) Cezl. lmmunol. 118, 100-107

21 Svenson, M, Poulsen, L.K., Fomsgaard, A. and Bendtzen, K. (1989) 5cand. J. Irnmunol. 29, 489-492 22 Fomsgaard, A., Svenson, M. and Bendtzen, K. (1989) Scand. J. Immuno!. 30, 2i9-223 23 Bendtzen, K., Svenson, M., Fomsgaard, A., Poulsen, L.K and Hansen, M.B. in Molecular and Cellular Biology of Cytokines II. (Pathophysiologic and Therapeutic Roles of Cytokines) (Powanda, M., Oppenheim, J.J., Kluger, M. and Dinarello, C.A., eds), Alan R. Liss (in press) 24 Dower, 5K., Kronheim, S.R., March, C.J. etal. (1985) J. Exp. Med. 1,52, 501-515 25 Thieme, T.R. and Wagner, C.R. (1989) Mol. Immunol. 26, 249-253 26 Lowentha t, J.W. and MacDonald, H.R. (1986)J. Exp. Med. 164, 1060-1074 27 Svenson, M., Kayser, L., The Thyroid Cell Group and Bendtzen, K. (1989)Scand. J. Imrnunol. 30, 631 28 Bendtzen, K. (1988) Irnmunol. Lett. 19, 183-192 29 Schwartz, R.S. (1977)J. Allergy Clin. Irnmunol. 60, 69-72 30 Svejgaard, A., Platz, P. and Ryder, L.P. (1984) Clin. Immunol. Allergol. 4, 567-580 31 Bendtzen, K., Morling, N., Fomsgaard, A. eta!. (1988) Scand. J. Immunol. 28, 599--606

The next issue of Immunology Today will include the following articles: Cytokines and switching: evolutionary divergence between mice and humans Robin Callard and Malcolm Turner Role of the CD28 receptor in 7-celI activation Carl June, Jeffrey Ledbetter and Craig Thcmpson Macrophages and the human immunodeficiency virus Monte Meltzer and colleagues Mechanisms of dendritic cell function Philip King and David Katz 169