Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is considered to be the prototypic systemic autoimmune disease. In contrast to autoimmune diseases such as multiple sclerosis and type 1 diabetes mellitus, SLE has the potential to involve multiple organ systems directly, and its clinical manifestations are extremely diverse and variable (reviewed by14Kotzin, B.L., and O'Dell, J.R. (1995). Systemic lupus erythematosus. In Samter's Immunologic Diseases, Fifth Edition, M.M. Frank, K.F. Austen, H.N. Claman, and E.R. Unanue, eds. (Boston: Little, Brown & Co.), pp 667–697.Google Scholar). For example, some patients may demonstrate predominantly skin rash and joint pain, show spontaneous remissions, and require little medication. The other end of the spectrum includes patients who demonstrate severe and progressive kidney involvement (glomerulonephritis) that requires therapy with high doses of steroids and cytotoxic drugs such as cyclophosphamide. Criteria for the classification of SLE have been established to facilitate the uniform reporting of SLE cases in studies. However, a multitude of different phenotypes are encompassed within this classification, and it remains unclear whether SLE represents a single pathologic entity with variable expression or a group of related conditions. This heterogeneity has greatly confounded studies of genetic associations and pathogenic mechanisms. Although SLE can occur at nearly any age, women of childbearing age are primarily affected. The female to male ratio is greatest (>8:1) for patients presenting between ages 15 to 50 years, whereas the ratio is closer to 2:1 for disease that develops during childhood or after menopause. Incidence rates for patients and studies in certain animal models support a role for estrogens enhancing and androgens protecting against disease development. In the United States, the chance of a caucasian female developing SLE in her lifetime is approximately 1 in 700, and the incidence may be two to four times greater for blacks and hispanics. The overall prevalence of SLE (∼1 in 2000) is about the same as multiple sclerosis and about 5- to 10-fold less than type 1 diabetes mellitus and rheumatoid arthritis. The common denominator among SLE patients is immunoglobulin G (IgG) autoantibody production, and the hallmark of this disease is elevated serum levels of antibodies to nuclear constituents (i.e., anti-nuclear antibodies). In contrast to the other autoimmune diseases discussed in this review series, T cells do not appear to play a direct role in tissue damage in SLE, although, as discussed below, T cells are clearly involved in the development of autoantibody production. Figure 1 presents a conceptual framework for the pathogenesis of SLE, and the major events in this model provide the basis for the discussion below. Studies using several animal models have contributed greatly to the elucidation of SLE pathogenesis (reviewed by27Theofilopoulos A.N Dixon F.J Murine models of systemic lupus erythematosus.Adv. Immunol. 1985; 37: 269-390Crossref PubMed Scopus (1372) Google Scholar, 5Cohen P.L Eisenberg R.A Lpr and gldsingle gene models of systemic autoimmunity and lymphoproliferative disease.Annu. Rev. Immunol. 1991; 9: 243-269Crossref PubMed Scopus (1123) Google Scholar). Examples include the F1 hybrid of New Zealand black (NZB) and New Zealand white (NZW) mice, MRL mice homozygous for the lymphoproliferation (lpr) gene (MRL-lpr/lpr), and BXSB mice, which carry the disease-accelerating Yaa gene on the Y chromosome. These different strains are primarily models of lupus-like glomerulonephritis associated with the production of IgG antibodies to DNA. Among the myriad of autoantibodies produced in SLE, principal targets include certain protein–nucleic acid complexes, notably chromatin, the U1 and Sm small nuclear ribonucleoprotein (snRNP) particles, and the Ro/SSA and La/SSB RNP complexes (reviewed by26Tan E.M Antinuclear antibodies diagnostic markers for autoimmune diseases and probes for cell biology.Adv. Immunol. 1989; 44: 93-151Crossref PubMed Scopus (1346) Google Scholar, 14Kotzin, B.L., and O'Dell, J.R. (1995). Systemic lupus erythematosus. In Samter's Immunologic Diseases, Fifth Edition, M.M. Frank, K.F. Austen, H.N. Claman, and E.R. Unanue, eds. (Boston: Little, Brown & Co.), pp 667–697.Google Scholar). The multivalent nature of these complexes and their ability to cross-link B cell receptors as well as their concentration on apoptotic cells have been proposed as explanations for their preferential immunogenicity (3Casciola-Rosen L.A Anhalt G Rosen A Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes.J. Exp. Med. 1994; 179: 1317-1330Crossref PubMed Scopus (1500) Google Scholar). Autoantibodies to phospholipids (complexed to β2 glycoprotein 1) are also relatively frequent and associated with thrombotic complications, a major clinical problem in some patients. A separate group of autoantibodies in SLE are directed to cell surface molecules. These latter specificities are easiest to understand in terms of their immunopathology, causing problems such as hemolytic anemia and platelet destruction (thrombocytopenia). The mechanism by which most autoantibodies in lupus may cause disease remains unclear. There is little evidence that anti-nuclear antibodies can readily penetrate cellular membranes and cause disease by binding to their intracellular targets. However, these autoantibodies may form immune complexes as described below for lupus nephritis, and a similar mechanism may be responsible for other disease manifestations such as arthritis, serositis, and vasculitis. IgG autoantibodies to double-stranded DNA appear to play a prominent role in the immune complex glomerulonephritis of SLE (reviewed by14Kotzin, B.L., and O'Dell, J.R. (1995). Systemic lupus erythematosus. In Samter's Immunologic Diseases, Fifth Edition, M.M. Frank, K.F. Austen, H.N. Claman, and E.R. Unanue, eds. (Boston: Little, Brown & Co.), pp 667–697.Google Scholar). Interestingly, anti-DNA antibodies do not appear to mediate renal damage through the deposition of circulating immune complexes, and two alternative theories have been proposed to explain their pathogenic mechanism. In the first, DNA initially binds to the glomerulus and is then recognized by anti-DNA antibodies, leading to in situ complex formation (1Bernstein K.A Valerio R.D Lefkowith J.B Glomerular binding activity in MRL/lpr serum consists of antibodies that bind to a DNA/histone/type IV collagen complex.J. Immunol. 1995; 154: 2424-2433PubMed Google Scholar). In an alternative model, the subset of pathogenic anti-DNA antibodies is able to cross-react with glomerular structures that are not DNA in origin. Although most studies have focused only on anti-DNA antibodies in the cause of lupus nephritis, considerable evidence indicates that autoantibodies to non-DNA antigens are also important. For example, in the (NZB × NZW)F1 model, genetic studies have suggested a major pathogenic role for autoantibodies to the endogenous retroviral glycoprotein (gp70) and gp70–anti-gp70 immune complexes (11Izui S McConahey P.J Clark J.P Hang L.M Hara I Dixon F.J Retroviral gp70 immune complexes in NZB × NZW F2 mice with murine lupus nephritis.J. Exp. Med. 1981; 154: 517-528Crossref PubMed Scopus (73) Google Scholar). Evidence strongly supports the conclusions that pathogenic IgG autoantibody production in SLE is selective for only certain self-antigens and that autoreactive B cells are driven by self-antigens. In SLE and lupus mice, studies have repeatedly shown that a subset of anti-DNA antibody–producing B cells are clonally expanded and that their immunoglobulin genes are modified by somatic mutation (reviewed by18Radic M.Z Mackle J Erickson J Mol C Anderson W.F Weigert M Residues that mediate DNA binding of autoimmune antibodies.J. Immunol. 1993; 150: 4966-4977PubMed Google Scholar). This process mimics a normal T cell–dependent response to foreign antigen, involving common mechanisms of somatic mutation, affinity maturation, and IgM to IgG class switching. Studies have shown that anti-DNA antibodies in lupus preferentially utilize certain VH and VL genes. Analysis of their complementarity-determining regions (CDRs), especially CDR3, have shown an increased number of arginine residues that enhance the binding of antibody to DNA and suggest selection by DNA itself (18Radic M.Z Mackle J Erickson J Mol C Anderson W.F Weigert M Residues that mediate DNA binding of autoimmune antibodies.J. Immunol. 1993; 150: 4966-4977PubMed Google Scholar). That self-antigen is involved in anti-nuclear antibody production in lupus is further supported by studies showing that multiple epitopes on the same autoantigen particle (e.g., chromatin or Sm/U1RNP) have been targeted by the autoantibody response. Experiments with mice expressing transgenes encoding self-reactive antibodies have demonstrated that B cell development involves a process of tolerance that deletes or functionally inactivates autoreactive cells, including some specificities characteristic of SLE (reviewed by9Goodnow C.C Cyster J.G Hartley S.B Bell S.E Cooke M.P Healey J.I Akkaraju S Rathmell J.C Pogue S.L Shokat K.P Self-tolerance checkpoints in B lymphocyte development.Adv. Immunol. 1995; 59: 279-378Crossref PubMed Scopus (252) Google Scholar, 4Chen C Nagy Z Radic M.Z Hardy R.R Huszar D Camper S.A Weigert M The site and stage of anti-DNA B-cell deletion.Nature. 1995; 373: 252-255Crossref PubMed Scopus (259) Google Scholar). However, it is important to note that provision of a powerful CD4 T cell driving force is sufficient for lupus-like IgG autoantibody production and disease to develop in normal animals. This is observed, for example, in models of chronic graft-versus-host disease in which the transferred T cells are alloreactive, and these studies indicate that potentially pathologic B cells are part of the peripheral repertoire or rapidly develop during this T cell–driven process. Thus, defects in central B cell tolerance do not appear to be necessary to allow for lupus-like autoantibody production. Furthermore, the ability of normal animals to generate autoantibody responses that spread to multiple determinants on a particular nuclear complex after immunization with one peptide or component of this complex also supports this conclusion (2Bockenstedt L.K Gee R.J Mamula M.J Self peptides in the initiation of lupus autoimmunity.J. Immunol. 1995; 154: 3516-3524PubMed Google Scholar, 28Topfer F Gordon T McCluskey J Intra- and intermolecular spreading of autoimmunity involving the nuclear self-antigens La (SS-B) and Ro (SS-A).Proc. Natl. Acad. Sci. USA. 1995; 92: 875-879Crossref PubMed Scopus (182) Google Scholar, 12James J.A Gross T Scofield R.H Harley J.B Immunoglobulin epitope spreading and autoimmune disease after peptide immunization Sm B/B′-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity.J. Exp. Med. 1995; 181: 453-461Crossref PubMed Scopus (313) Google Scholar). The association of SLE with particular class II major histocompatibility complex (MHC) alleles and the affinity maturation of IgG autoantibody production in this disease strongly suggest that CD4 T cells are important in the pathogenesis of disease. Furthermore, in all of the major murine models, treatment with anti-CD4 antibodies can ameliorate IgG autoantibody production and disease. Additional studies indicate that blocking T cell activation or T cell–B cell interactions will also prevent autoantibody production and disease (8Finck B.K Linsley P.S Wofsy D Treatment of murine lupus with CTLA4 Ig.Science. 1994; 265: 1225-1227Crossref PubMed Scopus (686) Google Scholar, 16Mohan C Shi Y Laman J.D Datta S.K Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis.J. Immunol. 1995; 154: 1470-1480PubMed Google Scholar). The specificities of the autoreactive T cells, however, have not been well characterized, and the nature of T cell help in SLE may indeed differ from conventional responses. In the anti-DNA response, it seems unlikely that T cells directed to DNA determinants are operative. Studies in murine lupus have shown that a non-DNA nucleosomal antigen stimulates some autoreactive T cells that drive anti-DNA antibody–producing B cells (15Mohan C Adams S Stanik V Datta S.K Nucleosome a major immunogen for pathogenic autoantibody-inducing T cells of lupus.J. Exp. Med. 1993; 177: 1367-1381Crossref PubMed Scopus (620) Google Scholar). Thus, a DNA-specific B cell could bind and internalize nucleosomes, with subsequent class II MHC presentation of histone or other chromosomal peptides to T cells. In other studies, immunoglobulin peptides derived from an IgG anti-DNA autoantibody were shown to stimulate T cells from (NZB × NZW)F1 mice and enhance IgG anti-DNA antibody production (25Singh R.R Kumar V Ebling F.M Southwood S Sette A Sercarz E.E Hahn B.H T cell determinants from autoantibodies to DNA can upregulate autoimmunity in murine systemic lupus erythematosus.J. Exp. Med. 1995; 181: 2017-2027Crossref PubMed Scopus (133) Google Scholar). In studies relevant to organ-specific autoimmune diseases such as multiple sclerosis and type 1 diabetes mellitus, the evidence indicates that autoimmune and potentially disease-causing T cells are present in the normal peripheral T cell repertoire. Thus, these T cells were not deleted during normal development in the thymus, and their inactivity appears to be maintained by protective mechanisms of peripheral tolerance—functional inactivation, immunoregulation, and immunological ignorance. The same scenario may exist for lupus-relevant T cells despite the ubiquitous nature of the target autoantigens. Studies in lupus mice, for example, have suggested that high affinity responses to self-antigens are tolerized normally in the thymus (10Herron L.R Eisenberg R.A Roper E Kakkanaiah V.N Cohen P.L Kotzin B.L Selection of the T cell receptor repertoire in lpr mice.J. Immunol. 1993; 151: 3450-3459PubMed Google Scholar). Other work has indicated that dominant determinants of a self-antigen that are processed and presented efficiently in the thymus will be effective tolerogens, but T cells directed to cryptic self-determinants may escape tolerance induction and be part of the normal peripheral T cell repertoire (reviewed by23Sercarz E.E Lehmann P.V Ametani A Benichou G Miller A Moudgill K Dominance and crypticity of T cell antigenic determinants.Annu. Rev. Immunol. 1993; 11: 729-766Crossref PubMed Scopus (792) Google Scholar). Therefore, abnormal presentation of such cryptic determinants in the periphery or a defect in peripheral T cell tolerance in SLE could allow activation of autoimmune T cells. Immunization of normal mice with cryptic peptides of a self-nuclear antigen has been shown to result in lupus-like autoantibody production (2Bockenstedt L.K Gee R.J Mamula M.J Self peptides in the initiation of lupus autoimmunity.J. Immunol. 1995; 154: 3516-3524PubMed Google Scholar). Patterns of cytokine production by T cells appear to be critically important in diseases such as multiple sclerosis and type 1 diabetes. These diseases appear to be dependent on Th1-type responses, and deviation from this pattern may lead to protection from disease expression. In SLE, Th2-type responses may be important in disease development, as demonstrated in the chronic graft-versus-host model of disease. However, in spontaneous murine models, the IgG isotypes most important for pathogenicity (IgG2a, IgG2b, and IgG3) suggest the additional influence of Th1-type cytokines and the importance of interferon-γ. Although there is a wealth of data regarding defects in cytokine production and immunoregulatory T cells in SLE, it is not clear at this time whether any are primary to the pathologic process. Environmental influences on the expression of disease manifestations are clearly seen in SLE. These include the exacerbation of skin rash (or even systemic symptoms) after sun exposure, exacerbations of disease after viral or bacterial infections, and changes in disease activity after administration of exogenous hormones. It is also clear that chronic treatment of patients with certain drugs (such as procainamide or hydralazine) can induce the production of anti-nuclear antibodies and a lupus-like disease (reviewed by14Kotzin, B.L., and O'Dell, J.R. (1995). Systemic lupus erythematosus. In Samter's Immunologic Diseases, Fifth Edition, M.M. Frank, K.F. Austen, H.N. Claman, and E.R. Unanue, eds. (Boston: Little, Brown & Co.), pp 667–697.Google Scholar) and that intraperitoneal injection with pristane (2,6,10,14-tetramethylpentadecane) can induce a lupus-like disease in normal mice (22Satoh M Kumar A Kanwar Y.S Reeves W.H Anti-nuclear antibody production and immune-complex glomerulonephritis in BALB/c mice treated with pristane.Proc. Natl. Acad. Sci. USA. 1995; 92: 10934-10938Crossref PubMed Scopus (154) Google Scholar). Despite this information, there is no clear evidence that an environmental trigger is involved in the initiation of human SLE. The fact that approximately 75% of monozygotic twins are discordant for disease expression has also been used as evidence to support the existence of an environmental stimulus. However, mouse strains can also be created such that 25% reproducibly develop disease or produce particular autoantibodies, and careful examination of positive mice has excluded environmental effects as the major factor in variable expression (7Eisenberg R.A Craven S.Y Warren R.W Cohen P.L Stochastic control of anti-Sm autoantibodies in MRL/MP-lpr/lpr mice.J. Clin. Invest. 1987; 80: 691-697Crossref PubMed Scopus (84) Google Scholar, 6Drake C.G Rozzo S.J Vyse T.J Palmer E Kotzin B.L Genetic contributions to lupus-like disease in (NZB×NZW)F1 mice.Immunol. Rev. 1995; 144: 51-74Crossref PubMed Scopus (61) Google Scholar). In these mice, the probability of disease appears to be totally genetically determined, and unknown stochastic (random) events determine which will develop disease. Overall, the importance of environmental triggers in human SLE remains unclear. Many aspects of the genetic basis of lupus are reviewed in a separate paper in this series. Even when one animal model and one phenotype is being considered, the genetic basis of lupus-like disease is remarkably complex, involving contributions from multiple genes in addition to class II MHC (6Drake C.G Rozzo S.J Vyse T.J Palmer E Kotzin B.L Genetic contributions to lupus-like disease in (NZB×NZW)F1 mice.Immunol. Rev. 1995; 144: 51-74Crossref PubMed Scopus (61) Google Scholar, 17Morel L Rudofsky U.H Longmate J.A Schiffenbauer J Wakeland E.K Polygenic control of susceptibility to murine systemic lupus erythematosus.Immunity. 1994; 1: 219-229Abstract Full Text PDF PubMed Scopus (432) Google Scholar, 13Kono D.H Burlingame R.W Owens D.G Kuramochi A Balderas R.S Balomenos D Theofilopoulos A.N Lupus susceptibility loci in New Zealand mice.Proc. Natl. Acad. Sci. USA. 1994; 91: 10168-10172Crossref PubMed Scopus (311) Google Scholar). Furthermore, it seems likely that different genetic contributions are operative in different animal models (and therefore in different patients), even when the same phenotype is being followed. Some traits appear to be determined in a threshold manner (17Morel L Rudofsky U.H Longmate J.A Schiffenbauer J Wakeland E.K Polygenic control of susceptibility to murine systemic lupus erythematosus.Immunity. 1994; 1: 219-229Abstract Full Text PDF PubMed Scopus (432) Google Scholar, 6Drake C.G Rozzo S.J Vyse T.J Palmer E Kotzin B.L Genetic contributions to lupus-like disease in (NZB×NZW)F1 mice.Immunol. Rev. 1995; 144: 51-74Crossref PubMed Scopus (61) Google Scholar). Thus, the particular combination of genes may be less important than just the accumulation of an adequate number of predisposing genes. An additional complexity relates to the fact that contributions are unlikely to represent genetic mutations rather than polymorphic alleles with subtle functional differences. Related to this issue, in some analyses of genes from lupus-prone strains, genes from the normal strain can be shown to have enhancing effects on disease expression (6Drake C.G Rozzo S.J Vyse T.J Palmer E Kotzin B.L Genetic contributions to lupus-like disease in (NZB×NZW)F1 mice.Immunol. Rev. 1995; 144: 51-74Crossref PubMed Scopus (61) Google Scholar). In addition to class II MHC genes, there is evidence that genetically determined complement deficiencies also contribute to disease susceptibility in a subset of SLE patients. The mechanism for this influence is unknown. Some investigators have postulated defects in the clearance of infectious particles or immune complexes, leading to enhanced autoantibody production. Alternatively, complement gene defects may exemplify genetic influences that operate distal to autoantibody production, and similar genetic contributions appear to be present in murine lupus nephritis. For example, these genetic contributions may allow enhanced deposition or formation of immune complexes in the kidney or possibly affect the inflammatory response or end-organ response to complexes. A possible step forward in understanding genetic contributions in lupus relates to the identification of lpr and gld as mutations in Fas and Fas ligands, respectively, which are involved in programmed cell death (apoptosis) (reviewed by5Cohen P.L Eisenberg R.A Lpr and gldsingle gene models of systemic autoimmunity and lymphoproliferative disease.Annu. Rev. Immunol. 1991; 9: 243-269Crossref PubMed Scopus (1123) Google Scholar, 29van Houten, N., and Budd, R.C., eds. (1994). Lessons from the lpr mouse. Semin. Immunol. 6, 1–69.Google Scholar). Homozygosity for these mutations results in the acceleration of lupus-like autoimmunity as well as a massive accumulation of CD4− CD8− (double negative) T cells. Full expression of lupus-like disease in MRL-lpr/lpr mice is dependent on contributions from other non-MHC genes. Although the mechanism by which mutations in Fas lead to accelerated autoimmunity is unknown, the strongest hypothesis is that self-reactive T and B cells arise when they fail to undergo apoptosis normally. Studies have shown that both T cells and B cells must carry the lpr mutation for maximal autoantibody production to occur. Fas may not be important in intrathymic tolerance during T cell development, and studies support the contention that peripheral T cell tolerance mechanisms are primarily affected by the lpr mutation (10Herron L.R Eisenberg R.A Roper E Kakkanaiah V.N Cohen P.L Kotzin B.L Selection of the T cell receptor repertoire in lpr mice.J. Immunol. 1993; 151: 3450-3459PubMed Google Scholar, 24Singer G.G Abbas A.K The Fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice.Immunity. 1994; 1: 365-371Abstract Full Text PDF PubMed Scopus (701) Google Scholar). Studies suggest that central B cell tolerance also may be relatively independent of Fas, and surface expression of Fas on B cells may be most important in preventing inappropriate CD4 T cell–dependent expansion of autoreactive B cells in the periphery (9Goodnow C.C Cyster J.G Hartley S.B Bell S.E Cooke M.P Healey J.I Akkaraju S Rathmell J.C Pogue S.L Shokat K.P Self-tolerance checkpoints in B lymphocyte development.Adv. Immunol. 1995; 59: 279-378Crossref PubMed Scopus (252) Google Scholar, 19Rathmell J.C Goodnow C.C Effects of the lpr mutation on elimination and inactivation of self-reactive B cells.J. Immunol. 1994; 153: 2831-2842PubMed Google Scholar, 20Rathmell J.C Cooke M.P Ho W.Y Grein J Townsend S.E Davis M.M Goodnow C.C CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4+ T cells.Nature. 1995; 376: 181-184Crossref PubMed Scopus (410) Google Scholar, 21Rothstein T.L Wang J.K.M Panka D.J Foote L.C Wang Z Stanger B Cui H Ju S.-T Marshak-Rothstein A Protection against Fas-dependent Th1-mediated apoptosis by antigen receptor engagement in B cells.Nature. 1995; 374: 163-165Crossref PubMed Scopus (413) Google Scholar). Fas mutations have been identified in a few children with lymphoproliferative syndromes and evidence of autoimmunity. However, it is important to emphasize that there is really no counterpart to the lpr or gld phenotype in human SLE, and recent studies have not found defects of these genes in SLE patients. Still, there is a belief that other genes involved in apoptosis or related cell signaling pathways may be involved in the emergence of autoreactive lymphocytes and genetic susceptibility in the human disease.