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Soluble immune complex disease associated with antigen heterogeneity an HLA related disorder
Medical
Hypotheses
5:
635-640,
1979
SOLUBLE IMMUNE COMPLEX DISEASE ASSOCIATED WITH ANTIGEN HETEROGENEITY AN HLA RELATED DISORDER C. E. Vickerman, M.D., Department of Dermatology, State University of New York at Buffalo, 50 High Street, Buffalo, New York 14203.
ABSTRACT It is suggested that soluble immune complex diseases arising after infections may result from the liberation of partially synthesized bacterial polypeptide or viral nucleic acid antigens. These disrupted antigens will have heterogeneous molecular weights due to antigenic material which is incomplete as a result of premature termination of synthesis. Antigens of this type have been shown to result in significant soluble complex formation in vitro when reacted with antisera from many individuals. Interestingly, this demonstrated using an antigen which has been instrumental in defining, in the mouse, immune response genes. These genes are known to be linked to genes which code for lymphocyte antigens. If particular immune response genes are linked to HLA types in humans, as is thought to be the case, there may be a large number of soluble immune complex diseases caused by infectious agents which may be HLA type associated. Key Words:
Histocompatibility Antigens; Immune Complex Disease; Antigenic Determinants; Genes, Immune Response; Antigens, Viral; Antigens, Bacterial; Lupus Erythematosus, Systemic.
635
INTRODUCTION It has become apparent that circulating soluble immune complexes (I.C.) play a role in the pathogenesis of more diseases than previously suspected. A circulating immune complex aetiology for diseases such as serum sickness and leukocytoclastic vasculitis is well established and the study of the I.C. in systemic lupus erythematosus has been in progress for some time. The role of infectious agents in leukocytoclastic vasculitis has been reviewed (1). I.C. have also been demonstrated in pityriasis lichenoides (21, erythema multiforma (3,4), and dermatitis herpetiformis (5,6). ANTIGEN STRUCTURE AND IMMUNE COMPLEXES Recently, it has been shown that polypeptide antigens with certain structures may predispose to soluble immune complex formation (7). The antigen molecules have a broad distribution of molecular weights, probably caused by early termination of polymerization of some antigens during their synthesis. The molecular structure of this type of immune complex forming antigen, synthesized from glutamic acid, alanine and tyrosine, (Glu60Ala30 TyrlO) n (GAT) is shown in Figure 1.
1 2 3 4 * * *
A-x A-B-x A-B-C-x A-B-C-D-x ’ l
l
n
A-B-C-D-E-F-G-H-...
* * *
’ ’ l
Figure 1 The antigenic determinant distribution and molecular weight distribution of an immune complex forming antigen. Each numbered line represents an antigen molecule. Letters represent different antigenic determinants and -x denotes premature termination of polymerization during antigen synthesis.
636
Twenty-six different antibody species, produced by one individual, to the determinants of the GAT antigen have been demonstrated (8). The antibodies have been shown to combine with different determinants distributed over the length of the GAT antigen. The immune response to an antigen of this type may vary from production of antibody directed against all determinants to production of antibody directed against a few or no determinants. In such a system the usual idea that only I.C. formed in antigen excess are pathogenic is not meaningful, since this is not the sole determinant of I.C. size in this complex system. Interestingly, this is just the type of antigen that would be expected to be presented to the immune system by disruption of a bacterial cell during the synthesis of a bacterial polypeptide on ribosomes. There would be a distribution of antigen molecular weights due to incomplete transcription of genetic material coding for a particular polypeptide by ribosomes. Substantial portions of the carboxy terminal region would be expected to be incomplete in this case. There would thus be a deficiency of some carboxy terminal antigenic determinants which are present on the complete peptide. Nucleic acid antigens of this type could result from disruption of cells during the synthesis of viral nucleic acid antigens. BACTERIAL AND VIRAL ANTIGENS IN COMPLEXES Thus far, bacterial and viral antigens have been demonstrated in immune complexes in several diseases. Streptococcal antigens have been reported in leukocytoclastic vasculitis (9). In other cases of vasculitis, Australia antigen has been demonstrated in I.C. (10). Systemic lupus erythematosus is another disease for which there is evidence of an immune complex pathogenesis. Evidence for I.C. in the serum (11) and in the glomeruli (12) of patients with S.L.E. has been presented. These studies have suggested that the antigens in the 1-C. are DNA. I.C. have also been found in the choroid plexus of patients with S.L.E. and are thought to be of significance in the production of central nervous system symptoms (13). Although there is not conclusive evidence that S.L.E. is induced by a virus, the possibility has been suggested (14), and in the NZB/W mouse model of S.L.E. there is a lupuslike renal disease in which viral antigens are found in glomeruli (15: and immune complexes are found in skin (16). Erythema multiforme may be caused by circulating immune complexes (3,4) and its association with bacterial and viral infections is well known clinically. Recently, I.C. have been demonstrated in sera and synovial fluid of patients with rheumatoid arthritis (RA). Some of these sera contained heterophile antigen and antibody (17,18). There is some support for an association of RA with HLA-D antigens (19) and the association of HLA type with ankylosing spondylitis, which has features in common with RA, is well known. Thus, there are a number of pathologic states, apparently produced by I.C., in which bacterial or viral antigens may play a role. The number of diseases in which I.C. are implicated is apparently increasing.
637
CONCLUSIONS It is proposed that infectious diseases may give rise to subsequent I.C. mediated disease through the production of bacterial and viral antigew which have a molecular weight distribution and a partial deficiency of some antigenic determinants. The antigen, GAT, in which this phenomnon has been observed, has been described elsewhere (20). Interestingly, the GAT antigen has been used to study immune response (Ir) genes in mice. These genes are part of the major histocompatibility complex and are linked to genes which code for lymphocyte antigens. In humans, Ir genes are thought to be linked to genes determining human lymphocyte antigens (HLA). Recent evidence has indicated that multiple Ir genes may be involved in determining the exact nature of the humoral immune response to a synthetic polypeptide antigen such as GAT (21). It has also been shown, for the antigen staphylococcal nuclease, that markedly different proportions of antibodies to different determinants may be produced under H-2 linked Ir gene& control (22). Control of the immune response in this manner, to such an antigen, could account for the propensity of so~lbe individuals to produce more soluble immune complexes after exposure to the antigen than other individuals. A fortuitous correspondence of a high humoral antibody response to those antigenic determinants in great excess and a minimal or lacking antibody response to those deficient determinants (such as H in Figure 1) would result in the formation of high molecular weight antigen-antibody complexes incapable of producing disease. Other immune responses to the determinants would produce low molecular weight immune complexes which could be pathogenic. The concept has already been advanced that diseases associated with a particular HLA type may result from the linkage of specific Ir genes to genes determining that HLA type. It is now proposed that cases of immune complex disease caused by a particular infectious agent may be related to HLA type because of the Ir gene programmed humoral immune response to heterogeneous bacterial and viral antigens. In order to test the later hypothesis, it will be necessary to determine the HLA types of individuals with immune complex diseases caused by specific aetiologic agents. The selection of these patients would be placed on firmer ground by the characterization and identification of the antigens present in their immune complexes.
638
REFERENCES 1.
Sams WM, Thome EG, Small P, et al: Arch Dermatol 112:219, 1977.
2.
Clayton R, Haffenden G, DuVivier A, et al: Pityriasis lichenoides an immune complex disease. Br J Dermatol 97:629, 1977.
3.
Kazmierowski JA, Wuepper KD: Erythema multiforme, immune COI&deX vasculitis of the superficial cutaneous microvasculature. Clin Res 25:282A, 1977.
4.
Safai B, Good RA, Day NK: Erythema multiforme: report of two cases and speculation on immune mechanisms involved in the pathogenesis. Clin Immunol Immunopathol 7:379, 1977.
5.
Mohammed I, Holborow EJ, Fry L, et al: Multiple immune complexes and hypocomplementaemia in dermatitis herpetiformis and coeliac disease. Lancet ii:487, 1976.
6.
Mowbray JF, Hoffbrand AV, Holborow EJ, et al: Circulating immune complexes in dermatitis herpetiformis. Lancet i:400, 1973.
7.
Liberti PA, Vickerman CE: Non-precipitating antibodies in a sheep antipolypeptide system: a novel antigenic phenomenon. Immunochemistry 14:543, 1977.
8.
Liberti PA: Incremental combining site filling of antipolypeptide antibodies. Immunochemistry 12:303, 1975.
9.
Parish WE, Rhodes EL: Bacterial antigens and aggregated gamma globulin in the lesions of nodular vasculitis. Br J Dermatol 79:122, 1967.
Leukocytoclastic vasculitis.
10.
Gocke DJ, Hsu K, Morgan C, et al: Vasculitis in association with Australia antigen. J Exp Med 134:33Os, 1971.
11.
Tan EM, Schur PH, Carr RI, et al: Deoxyribonucleic acid (DNA) and antibodies to DNA in the serum of patients with systemic lupus erythematosus. J Clin Invest 45:1732, 1966.
12.
Koffler D, Schur PH, Kunkel HG, et al: Immunologic studies concerning the nephritis of systemic lupus erythematosus. J Exp Med 126:607, 1967.
13. Atkins AJ, Konden JJ, Quismorio FP, et al: The choroid plexus in systemic lupus erythematosus. Ann Intern Med 76:65, 1972. 14.
Hclman HR: Systemic lupus erythematosus. p 1004 in Immunological Diseases. 2nd ed. (M. Sampter,ed.) Little, Brown and Company, Boston, 1971.
639
15.
Dixon FJ, Oldstone MBA, Tonietti G: Pathogenesis of immune complex glomerulonephritis of New Zealand mice. J Exp Med 134:65s, 1971.
16.
Sommer VM, Rudofski UH, Gabrielsen AE: Immune complexes in skin of NZB/NZW mice. Clin Exp Immunol 22:461, 1975.
17.
Nishimaki T, Kane K, Milgrom F: Studies on immune complexes in rheumatoid arthritis. Arthritis Rheum 21:640, 1978.
18.
Nishimaki T, Kano K, Milgrom F: Studies on heterophile antibodies in rheumatoid arthritis. Arthritis Rheum 21:634, 1978.
19.
Stastny P: Mixed lymphocyte cultures in rheumatoid arthritis. J Clin Invest 57:1148, 1976.
20.
Liberti PA, Vickerman CE: Molecular weight dispersion and variation in incremental composition of (Glu60Ala30TyrlO)n. Biopolymers 17:527, 1978.
21.
Bluestein HG, Green I, Maurer PH, et al: Specific immune response genes V. Influence of the GA and GT immune response of the guinea pig. genes on the specificity of cellular and humoral immune response to a terpolymer of L-glutamic acid, L-alanine and L-tyrosine. J Exp Med 135:98, 1972.
22.
Berzofski JA, Schecter AN, Shearer GM, et al: Genetic control of the IV. H-2 linked control immune response to staphylococcal nuclease. of the relative proportion to antibodies produced to different determinants of native nuclease. J Exp Med 145:123, 1977.
640
Hypotheses
5:
635-640,
1979
SOLUBLE IMMUNE COMPLEX DISEASE ASSOCIATED WITH ANTIGEN HETEROGENEITY AN HLA RELATED DISORDER C. E. Vickerman, M.D., Department of Dermatology, State University of New York at Buffalo, 50 High Street, Buffalo, New York 14203.
ABSTRACT It is suggested that soluble immune complex diseases arising after infections may result from the liberation of partially synthesized bacterial polypeptide or viral nucleic acid antigens. These disrupted antigens will have heterogeneous molecular weights due to antigenic material which is incomplete as a result of premature termination of synthesis. Antigens of this type have been shown to result in significant soluble complex formation in vitro when reacted with antisera from many individuals. Interestingly, this demonstrated using an antigen which has been instrumental in defining, in the mouse, immune response genes. These genes are known to be linked to genes which code for lymphocyte antigens. If particular immune response genes are linked to HLA types in humans, as is thought to be the case, there may be a large number of soluble immune complex diseases caused by infectious agents which may be HLA type associated. Key Words:
Histocompatibility Antigens; Immune Complex Disease; Antigenic Determinants; Genes, Immune Response; Antigens, Viral; Antigens, Bacterial; Lupus Erythematosus, Systemic.
635
INTRODUCTION It has become apparent that circulating soluble immune complexes (I.C.) play a role in the pathogenesis of more diseases than previously suspected. A circulating immune complex aetiology for diseases such as serum sickness and leukocytoclastic vasculitis is well established and the study of the I.C. in systemic lupus erythematosus has been in progress for some time. The role of infectious agents in leukocytoclastic vasculitis has been reviewed (1). I.C. have also been demonstrated in pityriasis lichenoides (21, erythema multiforma (3,4), and dermatitis herpetiformis (5,6). ANTIGEN STRUCTURE AND IMMUNE COMPLEXES Recently, it has been shown that polypeptide antigens with certain structures may predispose to soluble immune complex formation (7). The antigen molecules have a broad distribution of molecular weights, probably caused by early termination of polymerization of some antigens during their synthesis. The molecular structure of this type of immune complex forming antigen, synthesized from glutamic acid, alanine and tyrosine, (Glu60Ala30 TyrlO) n (GAT) is shown in Figure 1.
1 2 3 4 * * *
A-x A-B-x A-B-C-x A-B-C-D-x ’ l
l
n
A-B-C-D-E-F-G-H-...
* * *
’ ’ l
Figure 1 The antigenic determinant distribution and molecular weight distribution of an immune complex forming antigen. Each numbered line represents an antigen molecule. Letters represent different antigenic determinants and -x denotes premature termination of polymerization during antigen synthesis.
636
Twenty-six different antibody species, produced by one individual, to the determinants of the GAT antigen have been demonstrated (8). The antibodies have been shown to combine with different determinants distributed over the length of the GAT antigen. The immune response to an antigen of this type may vary from production of antibody directed against all determinants to production of antibody directed against a few or no determinants. In such a system the usual idea that only I.C. formed in antigen excess are pathogenic is not meaningful, since this is not the sole determinant of I.C. size in this complex system. Interestingly, this is just the type of antigen that would be expected to be presented to the immune system by disruption of a bacterial cell during the synthesis of a bacterial polypeptide on ribosomes. There would be a distribution of antigen molecular weights due to incomplete transcription of genetic material coding for a particular polypeptide by ribosomes. Substantial portions of the carboxy terminal region would be expected to be incomplete in this case. There would thus be a deficiency of some carboxy terminal antigenic determinants which are present on the complete peptide. Nucleic acid antigens of this type could result from disruption of cells during the synthesis of viral nucleic acid antigens. BACTERIAL AND VIRAL ANTIGENS IN COMPLEXES Thus far, bacterial and viral antigens have been demonstrated in immune complexes in several diseases. Streptococcal antigens have been reported in leukocytoclastic vasculitis (9). In other cases of vasculitis, Australia antigen has been demonstrated in I.C. (10). Systemic lupus erythematosus is another disease for which there is evidence of an immune complex pathogenesis. Evidence for I.C. in the serum (11) and in the glomeruli (12) of patients with S.L.E. has been presented. These studies have suggested that the antigens in the 1-C. are DNA. I.C. have also been found in the choroid plexus of patients with S.L.E. and are thought to be of significance in the production of central nervous system symptoms (13). Although there is not conclusive evidence that S.L.E. is induced by a virus, the possibility has been suggested (14), and in the NZB/W mouse model of S.L.E. there is a lupuslike renal disease in which viral antigens are found in glomeruli (15: and immune complexes are found in skin (16). Erythema multiforme may be caused by circulating immune complexes (3,4) and its association with bacterial and viral infections is well known clinically. Recently, I.C. have been demonstrated in sera and synovial fluid of patients with rheumatoid arthritis (RA). Some of these sera contained heterophile antigen and antibody (17,18). There is some support for an association of RA with HLA-D antigens (19) and the association of HLA type with ankylosing spondylitis, which has features in common with RA, is well known. Thus, there are a number of pathologic states, apparently produced by I.C., in which bacterial or viral antigens may play a role. The number of diseases in which I.C. are implicated is apparently increasing.
637
CONCLUSIONS It is proposed that infectious diseases may give rise to subsequent I.C. mediated disease through the production of bacterial and viral antigew which have a molecular weight distribution and a partial deficiency of some antigenic determinants. The antigen, GAT, in which this phenomnon has been observed, has been described elsewhere (20). Interestingly, the GAT antigen has been used to study immune response (Ir) genes in mice. These genes are part of the major histocompatibility complex and are linked to genes which code for lymphocyte antigens. In humans, Ir genes are thought to be linked to genes determining human lymphocyte antigens (HLA). Recent evidence has indicated that multiple Ir genes may be involved in determining the exact nature of the humoral immune response to a synthetic polypeptide antigen such as GAT (21). It has also been shown, for the antigen staphylococcal nuclease, that markedly different proportions of antibodies to different determinants may be produced under H-2 linked Ir gene& control (22). Control of the immune response in this manner, to such an antigen, could account for the propensity of so~lbe individuals to produce more soluble immune complexes after exposure to the antigen than other individuals. A fortuitous correspondence of a high humoral antibody response to those antigenic determinants in great excess and a minimal or lacking antibody response to those deficient determinants (such as H in Figure 1) would result in the formation of high molecular weight antigen-antibody complexes incapable of producing disease. Other immune responses to the determinants would produce low molecular weight immune complexes which could be pathogenic. The concept has already been advanced that diseases associated with a particular HLA type may result from the linkage of specific Ir genes to genes determining that HLA type. It is now proposed that cases of immune complex disease caused by a particular infectious agent may be related to HLA type because of the Ir gene programmed humoral immune response to heterogeneous bacterial and viral antigens. In order to test the later hypothesis, it will be necessary to determine the HLA types of individuals with immune complex diseases caused by specific aetiologic agents. The selection of these patients would be placed on firmer ground by the characterization and identification of the antigens present in their immune complexes.
638
REFERENCES 1.
Sams WM, Thome EG, Small P, et al: Arch Dermatol 112:219, 1977.
2.
Clayton R, Haffenden G, DuVivier A, et al: Pityriasis lichenoides an immune complex disease. Br J Dermatol 97:629, 1977.
3.
Kazmierowski JA, Wuepper KD: Erythema multiforme, immune COI&deX vasculitis of the superficial cutaneous microvasculature. Clin Res 25:282A, 1977.
4.
Safai B, Good RA, Day NK: Erythema multiforme: report of two cases and speculation on immune mechanisms involved in the pathogenesis. Clin Immunol Immunopathol 7:379, 1977.
5.
Mohammed I, Holborow EJ, Fry L, et al: Multiple immune complexes and hypocomplementaemia in dermatitis herpetiformis and coeliac disease. Lancet ii:487, 1976.
6.
Mowbray JF, Hoffbrand AV, Holborow EJ, et al: Circulating immune complexes in dermatitis herpetiformis. Lancet i:400, 1973.
7.
Liberti PA, Vickerman CE: Non-precipitating antibodies in a sheep antipolypeptide system: a novel antigenic phenomenon. Immunochemistry 14:543, 1977.
8.
Liberti PA: Incremental combining site filling of antipolypeptide antibodies. Immunochemistry 12:303, 1975.
9.
Parish WE, Rhodes EL: Bacterial antigens and aggregated gamma globulin in the lesions of nodular vasculitis. Br J Dermatol 79:122, 1967.
Leukocytoclastic vasculitis.
10.
Gocke DJ, Hsu K, Morgan C, et al: Vasculitis in association with Australia antigen. J Exp Med 134:33Os, 1971.
11.
Tan EM, Schur PH, Carr RI, et al: Deoxyribonucleic acid (DNA) and antibodies to DNA in the serum of patients with systemic lupus erythematosus. J Clin Invest 45:1732, 1966.
12.
Koffler D, Schur PH, Kunkel HG, et al: Immunologic studies concerning the nephritis of systemic lupus erythematosus. J Exp Med 126:607, 1967.
13. Atkins AJ, Konden JJ, Quismorio FP, et al: The choroid plexus in systemic lupus erythematosus. Ann Intern Med 76:65, 1972. 14.
Hclman HR: Systemic lupus erythematosus. p 1004 in Immunological Diseases. 2nd ed. (M. Sampter,ed.) Little, Brown and Company, Boston, 1971.
639
15.
Dixon FJ, Oldstone MBA, Tonietti G: Pathogenesis of immune complex glomerulonephritis of New Zealand mice. J Exp Med 134:65s, 1971.
16.
Sommer VM, Rudofski UH, Gabrielsen AE: Immune complexes in skin of NZB/NZW mice. Clin Exp Immunol 22:461, 1975.
17.
Nishimaki T, Kane K, Milgrom F: Studies on immune complexes in rheumatoid arthritis. Arthritis Rheum 21:640, 1978.
18.
Nishimaki T, Kano K, Milgrom F: Studies on heterophile antibodies in rheumatoid arthritis. Arthritis Rheum 21:634, 1978.
19.
Stastny P: Mixed lymphocyte cultures in rheumatoid arthritis. J Clin Invest 57:1148, 1976.
20.
Liberti PA, Vickerman CE: Molecular weight dispersion and variation in incremental composition of (Glu60Ala30TyrlO)n. Biopolymers 17:527, 1978.
21.
Bluestein HG, Green I, Maurer PH, et al: Specific immune response genes V. Influence of the GA and GT immune response of the guinea pig. genes on the specificity of cellular and humoral immune response to a terpolymer of L-glutamic acid, L-alanine and L-tyrosine. J Exp Med 135:98, 1972.
22.
Berzofski JA, Schecter AN, Shearer GM, et al: Genetic control of the IV. H-2 linked control immune response to staphylococcal nuclease. of the relative proportion to antibodies produced to different determinants of native nuclease. J Exp Med 145:123, 1977.
640