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Natural aAb against IL-1 alpha (IL-1a) in humans were first found in 1988 by demonstration of direct binding of IgG from healthy individuals to radiolabeled human recombinant IL-1a and by IgG-mediated competitive interference with IL-1a binding to cellular IL-1 receptors (1). At the same time, IgG from patients with RA were found to interfere in vitro with the biological effect of IL-1a, and sera from these patients interfered with the effect of both IL-1a and IL-1 beta (2). Subsequently, sera of healthy individuals and of patients with various immunoinflammatory disorders as well as pharmaceutical preparations of human IgG were found to contain aAb that bind to IL-1a with high avidity (3-14).

Characterisation

The IL-1a aAb are dominated by the IgG isotype, mainly of the IgG4 class, and are the main binding molecules for IL-1a in the circulation (3, 8, 14). They bind with high avidities (Kd < 100 pM). Size exclusion chromatography of IgG or Fab fragments in complex with IL-1 alpha has shown a predominance of two binding sites on IL-1a (3, 14). However, IgG4 molecules, normally constituting only about 2% of total IgG in plasma, are functionally monovalent and complexes of this IgG class bind weakly to type 2 and type 3 Fc-receptors and do not activate complement (15-18). Accordingly, a reduced clearance of IL-1a in complex with human IL-1a aAb was seen in rats (8), and low amounts of IL-1a in complex with IgG have been reported in 25% of IL-1a aAb-positive individuals (13, 19). Thus, even though carrier functions cannot be excluded, the high binding avidity, comparable to the affinity of the IL-1 receptors, and the high stability of the complexes suggest that IL-1a aAb function as a specific IL-1a antagonist in vivo (6).

The IL-1a aAb detected in direct ligand binding radioimmunoassay neutralise receptor binding and the in vitro biological activity of natural IL-1a (4, 7, 10, 11, 14, 20). They also neutralise the activity of precursor and membrane-associated IL-1a (11). IL-1a aAb of low receptor blocking activity have been reported in some individuals, and the degree of inhibition afforded on the activity of IL-1a may depend upon the target cell (8, 11).

An IL-1a aAb has recently been cloned (21). This monoclonal aAb is an IgG4/kappa aAb reacting with IL-1a but not IL-1 beta, IL-1 receptor antagonist (IL-1ra) or several other cytokines. It binds with high affinity (Kd = 100 pM), and the presence of somatic mutations in the variable regions suggests an antigen-driven affinity maturation.

Since prolonged antigenic challenge results in predominance of IgG4 aAb (22), it is likely that some individuals may be efficiently primed to IL-1a early in life, and that the increased levels of IL-1a aAb with age is a consequence of persistent antigenic stimulation, perhaps by endogenous IL-1a.

Cited references:

1. Svenson M, Poulsen LK, Fomsgaard A, Bendtzen K. IgG autoantibodies against interleukin 1a in sera of normal individuals. Scand J Immunol 1989; 29:489-92.

2. Suzuki H, Akama T, Okane M, Kono I, Matsui Y, Yamane K, Kashiwagi H. Interleukin-1-inhibitory IgG in sera from some patients with rheumatoid arthritis. Arthritis Rheum 1989; 32:1528-38.

3. Svenson M, Hansen MB, Bendtzen K. Distribution and characterization of autoantibodies to interleukin 1a in normal human sera. Scand J Immunol 1990; 32:695-701.

4. Suzuki H, Kamimura J, Ayabe T, Kashiwagi H. Demonstration of neutralising autoantibodies against IL-1a in sera from patients with rheumatoid arthritis. J Immunol 1990; 145:2140-6.

5. Galley P, Mach J-P, Carrel S. Characterization and detection of naturally occurring antibodies against IL-1a and IL-1b in normal human plasma. Eur Cytokine Netw 1991; 2:329-38.

6. Hansen MB, Svenson M, Bendtzen K. Human anti-interleukin 1a antibodies. Immunol Lett 1991; 30:133-40.

7. Mae N, Liberato DJ, Chizzonite R, Satoh H. Identification of high-affinity anti-IL-1a autoantibodies in normal human serum as an interfering substance in a sensitive enzyme-linked immunosorbent assay for IL-1a. Lymphokine Cytokine Res 1991; 10:61-8.

8. Saurat J-H, Schifferli J, Steiger G, Dayer J-M, Didierjean L. Anti-interleukin-1a autoantibodies in humans: Characterization, isotype distribution, and receptor-binding inhibition--Higher frequency in Schnitzler's syndrome (urticaria and macroglobulinemia). J Allergy Clin Immunol 1991; 88:244-56.

9. Sunder-Plassmann G, Sedlacek PL, Sunder-Plassmann R, Derfler K, Swoboda K, Fabrizii V, Hirschl MM, Balcke P. Anti-interleukin-1a autoantibodies in hemodialysis patients. Kidney Int 1991; 40:787-91.

10. Suzuki H, Ayabe T, Kamimura J, Kashiwagi H. Anti-IL-1a autoantibodies in patients with rheumatic diseases and in healthy subjects. Clin Exp Immunol 1991; 85:407-12.

11. Svenson M, Hansen MB, Kayser L, Rasmussen ÅK, Reimert CM, Bendtzen K. Effects of human anti-IL-1a autoantibodies on receptor binding and biological activities of IL-1. Cytokine 1992; 4:125-33.

12. Svenson M, Hansen MB, Bendtzen K. Binding of cytokines to pharmaceutically prepared human immunoglobulin. J Clin Invest 1993; 92:2533-9.

13. Hansen MB, Svenson M, Abell K, Varming K, Nielsen HP, Bertelsen A, Bendtzen K. Sex- and age-dependency of IgG auto-antibodies against IL-1a in healthy humans. Eur J Clin Invest 1994; 24:212-8.

14. Satoh H, Chizzonite R, Ostrowski C, Ni-Wu G, Kim H, Fayer B, Mae N, Nadeau R, Liberato DJ. Characterization of anti-IL-1a autoantibodies in the sera from healthy humans. Immunopharmacol 1994; 27:107-18.

15. van der Zee JS, van Swieten P, Aalberse RC. Serologic aspects of IgG4 antibodies. II. IgG4 antibodies form small, nonprecipitating immune complexes due to functional monovalency. J Immunol 1986; 137:3566-71.

16. van der Zee JS, van Swieten P, Aalberse RC. Inhibition of complement activation by IgG4 antibodies. Clin Exp Immunol 1986; 64:415-22.

17. Parren PW, Warmerdam PA, Boeije LC, Arts J, Westerdaal NA, Vlug A, Capel PJ, Aarden LA, van de Winkel JG. On the interaction of IgG subclasses with the low affinity FcgRIIa (CD32) on human monocytes, neutrophils, and platelets. Analysis of a functional polymorphism to human IgG2. J Clin Invest 1992; 90:1537-46.

18. Warmerdam PA, van den Herik-Oudijk IE, Parren PW, Westerdaal NA, van de Winkel JG, Capel PJ. Interaction of a human FcgRIIb1 (CD32) isoform with murine and human IgG subclasses. Int Immunol 1993; 5:239-47.

19. Dower SK, Sims JE, Cerretti DP, Bird TA. The interleukin-1 system: Receptors, ligands and signals. Chem Immunol 1992; 51:33-64.

20. Jouvenne P, Fossiez F, Garrone P, Djossou O, Banchereau J, Miossec P. Increased incidence of neutralising autoantibodies against interleukin-1a (IL-1a) in nondestructive chronic polyarthritis. J Clin Immunol 1996; 16:283-90.

21. Garrone P, Djossou O, Fossiez F, Reyes J, Ait-Yahia S, Maat C, Ho S, Hauser T, Dayer JM, Greffe J, Miossec P, Lebecque S, Rousset F, Banchereau J. Generation and characterization of a human monoclonal autoantibody that acts as a high affinity interleukin-1a specific inhibitor. Mol Immunol 1996; 33:649-58.

22. Ferrante A, Beard LJ, Feldman RG. IgG subclass distribution of antibodies to bacterial and viral antigens. Pediatr Infect Dis J 1990; 9:S16-24.